Dimethyl sulfite a potential agent for methylation

Article abstract of DOI:10.1016/j.tet.2015.09.075

The synthesis of methylated ether compounds is an important challenge. A pathway for the synthesis of methyl ethers was investigated using dimethyl sulfite (DMSi). Methylation of 1-octanol was carried out in liquid phase upon different heterogeneous organic and inorganic catalysts at 130°C. Aluminium oxide gave the best result with high conversion and moderate selectivity for methyl 1-octyl ether. Reactions in gas phase at higher temperatures (200°C) were also performed. Methyl 1-octyl ether was obtained in a very high level of selectivity up to 98%. Primary and secondary ethers from unsymmetrical alkyl methyl sulfite were also performed by SO₂ extrusion.

Full text of DOI:10.1016/j.tet.2015.09.075

Accepted Manuscript
Dimethyl Sulfite a potential agent for methylation
Rim Mouselmani, Eric Da Silva, Marc Lemaire
PII:
S0040-4020(15)30096-X
10.1016/j.tet.2015.09.075
TET 27172
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 19 June 2015
Revised Date: 28 September 2015
Accepted Date: 29 September 2015
Please cite this article as: Mouselmani R, Da Silva E, Lemaire M, Dimethyl Sulfite a potential agent for
methylation, Tetrahedron (2015), doi: 10.1016/j.tet.2015.09.075.
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ACCEPTED MANUSCRIPT
Dimethyl Sulfite a potential agent for methylation
R. Mouselmani, E. Da Silva and M. Lemaire*
Laboratoire Catalyse, Synthèse et Environnement, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), CNRS,
UMR 5246, Université Claude Bernard Lyon 1, Bât. CPE, 43 Boulevard du 11 novembre 1918, 69622, Villeurbanne, France. Corresponding
author: (Tel) +33 (0) 4 72 43 14 07; (Fax) +33 (0) 4 72 43 14 08; (Email) marc.lemaire.chimie@univ-lyon1.fr
1

ACCEPTED MANUSCRIPT
Dimethyl Sulfite a potential safer methylating agent agent for methylation
Rim Mouselmani, Eric Da Silva and Marc Lemaire*
Laboratoire Catalyse, Synthèse et Environnement, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), CNRS, UMR 5246,
Université Claude Bernard Lyon 1, Bât. CPE, 43 Boulevard du 11 novembre 1918, 69622, Villeurbanne, France. Corresponding author: (Tel) +33 (0) 4 72 43
14 07; (Fax) +33 (0) 4 72 43 14 08; (Email) marc.lemaire.chimie@univ-lyon1.fr
ABSTRACT
The synthesis of methylated ether compounds is a important challenge. A pathway for the synthesis of methyl ethers was investigated
using dimethyl sulfite (DMSi). Methylation of 1-octanol was carried out in liquid phase upon different heterogeneous organic and
inorganic catalysts at 130 °C. Aluminium oxide gave the best result with high conversion and moderate selectivity for methyl 1-
octylether. Reactions in gas phase at higher temperatures (200 °C) were also performed. Methyl 1-octyl ether was obtained in a very
high level of selectivity up to 98%. Primary and secondary ethers from unsymmetrical alkyl methyl sulfite was also performed by
SO2 extrusion.
synthesis of methyl ethers from aliphatic alcohols in good yields at
200 °C with a 1:15 weight ratio of alcohol/dimethyl carbonate in
the presence of basic alumina or hydrotalcite KW 2000 as
catalyst.12 It was found that the conversion was complete for the 1-
octanol giving 100% selectivity for the corresponding ether, while
secondary alcohols were methylated with lower selectivity reaching
87%. These catalysts also performed in gas phase using 1:3 weight
ratio of 1-pentanol/dimethyl carbonate at 180 °C in the presence of
basic alumina, giving 90% selectivity of methylpentyl ether.
Poliakoff et al. have showed that methyloctylether can be
Introduction
Several methods were developed to form methylethers of aliphatic
alcohols and research has focused on economical and
environmentally friendly reagents that operate with less toxic by
1
products. Methylethers are considered as good oxygenated
molecules due to their capacity to reduce CO emission, and to
enhance gasoline combustion increasing octane numbers. They also
exhibit excellent properties as solvents for extractions, and are used
in several applications such as coatings, inks, paints, cleaning
agents and pharmaceuticals.2 The well known Williamson ether
synthesis for linear alcohols employs toxic reagents such as alkyl
halides, and during the reaction inorganic salt byproducts are
formed.3 Diazomethane is widely used for the formation of methyl
ether in mild and neutral reaction conditions but its toxicity and
explosive nature limit its broad application.4 Dimethyl sulfate is
also used as a methylating agent. Ogawa et al. performed the
methylation of alcohols using alumina and excess of dimethyl
sulfate with cyclohexane as a solvent.5 For example, 1-heptanol
was successfully methylated in 99% yield. However in the case of
secondary alcohols, diols, and phenols, a decrease in yields was
observed. Concerning polyols, Chang et al. used a mixture of
dimethyl sulfate / glycerol (3:2 molar ratio), in the presence of
sodium hydroxide to methylate glycerol at 70°C. Di- and
trimethoxyglycerol ethers were obtained in 71% combined yield.6
Lemaire group has conducted the formation of ethers from glycerol
by phase transfer catalysis, so that 1,2,3-trimethoxypropane was
obtained in 95% yield and 96% selectivity in one step with
dimethyl sulfate as the methylating agent, potassium hydroxide as
the base, in the presence of tetrabutyl ammonium hydrogen sulfate
at room temperature.7 Despite that dimethyl sulfate is available in
industry, it is mutagenic showing very high toxicity.8 The use of
methanol provides safer catalytic reactions, but these reactions
require a large excess of MeOH as well as high temperatures which
ensure the degradation of alcohol leading to the formation of alkene
synthesized in 86% yield using
a 1:2 molar ratio of 1-
octanol/dimethyl carbonate in the presence of acidic alumina and
supercritical carbon dioxide under 100 bars at 262 °C.13 The group
has also reported the methylation of compounds containing
multiple hydroxyl groups such as 1,3-propanediol with yield
reaching 68%. Moreover, the etherification of glycerol formal or
solketal was done by Selva,14 at T ≥ 200 °C both were efficiently
alkylated affording the corresponding methyl ethers with selectivity
up to 99% and excellent yields (86-99%). The O-methylation of
phenols with dimethyl carbonate was also reported in the literature
using different catalysts, such as potassium carbonate at 160 °C,15
ionic liquids such as 1-n-butyl-3-methylimidazolium chloride at
120 °C,16 and 1,8-diazabicyclo[5.4.0]undec-7-ene at 220 °C.17 All
of these catalysts gave yield up to 90%. Therefore, the dimethyl
carbonate appears, for the moment, the best alternative in many
cases. Nevertheless, high temperature is required and alkylation of
primary alcohol remains by far the best results. This is mainly due
to the poor electrophilic properties of such reagent. Looking for
new methylating agent, we investigated alternatives to classical
alkylating agents with a lower toxicity, readily available and
cheaper like dimethyl sulfite (DMSi). Such reagent may be
expected more electrophilic than DMC (pKa of H2SO3 = 1.8 and
pKa of H2CO3 = 6.3). However, there is only two examples
showing the synthesis of methyl ethers using dimethyl sulfite. The
approach was done in 1984 by Nelson, 18 where he prepared
derivatives and dimethyl ether, finally giving moderate
alkylated
phenolic
ethers.
For
example
3,4,5-
9
selectivities.
More recently, the catalytic etherification of
trimethoxybenzaldehyde was obtained with 40% yield by the
reaction of syringaldehyde with potassium carbonate at 100 °C.
The second work showed the alkylation of enolate of
ethylacetonate by dimethyl sulfite in liquid SO2.19 In this article,
we described the O-methylation reaction of linear alcohols with
DMSi using various heterogeneous acid catalysts in both liquid and
isosorbide to methyl ethers has been reported in the presence of
1,2-dimethoxyethane as alkylating agent and tungstenic acid
catalyst.10 Dimethyl carbonate (DMC) has shown to be a great
interest as an alkylating agent due to its non-toxicity,
biodegradability, and its tunable reactivity: methoxy carbonylating
agent at 90 °C and methylating agent at higher reaction
temperatures. 11 For example, Tundo et al. have reported the
gas
phases.
1

ACCEPTED MANUSCRIPT
Table1. Comparison of the behavior of different inorganic and organic catalysts for the methylation of 1-octanol with dimethyl sulfite in liquid phase.[a]
Entry
Catalyst
Time [h]
Conv. [%][e]
Ratio [%][e]
unknown
2
13
62
9
3
-
4
5
-
6
-
1
2
-
4.5
24
7
4
87
37
78
37
-
-
-
Al2O3 acidic
Al2O3 acidic[b]
Al2O3 acidic[c]
Al2O3 acidic[d]
Al2O3 neutral
Al2O3 basic
Amberlyst 15
Amberlyst 35
Amberlyst 36
Amberlyst 36[c]
Amberlyst 36[d]
KSF
100
23
-
1
-
3
-
-
-
13
-
4
22
23
3.5
5.5
5
100
87
62
-
-
1
-
5
7
-
31
2
-
62
-
6
100
100
97
41
42
44
65
68
24
-
56
57
-
-
7
-
1
-
-
8
35
28
30
-
-
21
7
2
-
-
9
5
74
-
-
-
10
11
12
13
14
15
16
5
81
-
-
-
5
58
31
-
45
-
-
5
5
40
-
-
60
-
5.5
3
100
100
100
68
-
70
75
85
86
30
22
12
7
-
K10
3
-
-
-
ZMS-5
3
3
-
-
-
Al/Si(2H2O)
1.5
7
-
-
-
[a] Experimental conditions: 1 (1 equiv.), DMSi (5 equiv.), catalyst (2 g), T= 130 °C, argon flow (75 mL/min), stirring speed 700 rpm. [b] Without argon flow.
[c] Toluene (72 mmol, 1M). [d] N-Methyl-2-pyrrolidone (79 mmol, 1M). [e] Conversion and Ratio % were determined by GC.
This result could be explained by the inhibition of the catalyst by
SO2 gas, or by monomethyl sulfite species formed during the
reaction.22 Experiments were performed with different solvents in
the presence of acidic aluminium oxide. With a non-polar solvent
such as toluene (entry 4), we observed similar results than in the
absence of solvent (entry 2). When using a dipolar solvent such as
N-Methyl-2-Pyrrolidone (entry 5), 87% conversion of 1 was
observed after 23 hours, giving 7% of 3, 31% of 5, and 57% of
byproducts, where compounds 2 and 4 were not observed. The
possible combination of NMP and RSO3H species to make an ionic
2. Results and Discussion
2.1. Synthesis of methyl 1-octylether in liquid phase. Reactions
with 1-octanol (1, as model substrate) and DMSi were carried out
over several heterogeneous catalysts (Table 1). All experiments
were performed under argon at 130 °C in a batch system using 1:5
molar ratio of 1/DMSi, 2 g of catalyst. In the absence of catalyst
(entry 1), a low conversion of 1 was observed. Methyl 1-octylether
2 and methyl 1-octyl sulphite 4 were formed with a ratio of 13 and
87%, respectively.
-
liquid [H-NMP][RSO3 ] could avoid the etherification reaction.
Aluminium oxides. As described in the literature, methylation
reactions with dimethyl carbonate in the presence of aluminium
oxides showed moderate results towards the formation of the
methylether. With acidic aluminium oxide (entry 2), after 24 hours
the conversion of 1 was complete. Methyl 1-octylether was formed
in 62 %, 1-methyloctylsulfite in 37% and only 1% of the
dioctylsulfite 5. When following the reaction, it was noticed that
the amount of methyl 1-octylsulfite 4 decreased while the amount
of methyl 1-octylether increased (see supplementary materials,
SM3). Thus there is competition between two reactions: the direct
O-alkylation and the O-sulfoxymethylation. We suppose that
compound 4 could be an intermediate of the reaction by SO2
extrusion. The released sulfur dioxide has been highlighted using
Complete conversion of 1 was achieved with neutral and basic
aluminium oxides (entries 6 and 7) affording 2 in 41 and 42% of
yields, respectively. All aluminium oxides have the same specific
surface area (150 m2 g-1), but they possess different acidic
properties. Acidic aluminium oxide gave better selectivity for 2
than neutral and basic ones.
Resins. Polystyrene sulfonic acid resins such Amberlysts 15, 35
and 36 are well known catalysts for etherification reactions.23 The
high concentration of acidic sites make them really attractive as
catalysts. With Amberlyst 15 (entry 8), a conversion of 97% was
observed, giving 44% of 2, 35% of dioctyl ether 3 and 21% of
octene isomers 6. When using Amberlyst 35 (entry 9), conversion
of 1 was 74%. The composition of the reaction mixture was as
follows, 65% of 2, 28% of 3, and 7% of 6. With Amberlyst 36
(entry 10), 81% of 1 was converted to give 68% of 2, 30% of 3 and
only 2% of 6. Amberlysts 35 and 36 show a decrease in the
substrate conversion upon comparison with Amberlyst 15. Indeed,
the concentration of acidic sites is as follows, 4.7, 5.2 and 5.4
DABCO molecule as scavenger by forming bis(sulphur dioxide)-
20 21
1,4-diazabicyclo[2.2.2]-octane (DABSO as white solid).
-
Moreover, removing SO2 gas could improve the conversion and the
selectivity for the methyl 1-octylether. Indeed, the conversion of 1-
octanol was low in the absence of argon flow (entry 3). 9% of 2
and 78% of 4 were observed, with 13% of unknown byproduct.
2

ACCEPTED MANUSCRIPT
mmol g-1 for Amberlyst 15, 35 and 36 respectively.24 This strong
acidity could enhance the dehydration process of alcohols. With
Amberlyst 36 and in the presence of toluene (entry 11), the
conversion of 1 was 58%, and the composition of the reaction
mixture was as follows, 24% of 2, 31% of 4 and 45% of 5. By
using toluene, the amount of methyloctylether decreased but
neither dioctyl ether and octene were obtained. While with N-
Methyl-2-pyrrolidone (entry 12), the conversion reached only 5 %.
catalyst giving methyl octyl sulfite 4 in 38% isolated yield.
Compound 4 reacted in both liquid and gas phases, in the presence
of acidic aluminium oxide. Results are summarized in table 2. In
liquid phase (entry 1) at 130°C, 32% of 4 was converted giving
41% of 1, 25% of 2, 9 % of 3 and 25 % of 5. In gas phase with 5g
of acidic aluminium oxide (entry 2) at 200 °C, 4 was converted up
to 98%, giving 2 and 3 with a ratio of 97 and 3% respectively.
However, only 40% in weight of 2 was recovered at the end of the
reaction in gas phase. It is expected that the loss of weight is due to
a strong absorption of 2 onto the catalyst. Decreasing the catalyst
loading to 2 g (entry 3) dropped the conversion of 4 dropped to
90% giving 4% of 1, 78% of 2 and 18% of 3. A reaction was also
performed with 2-methyloctylsulfite in gas phase.
Inorganic catalysts.
A
reaction was conducted with
Montmorrilonite KSF (entry 13), where the conversion of 1 was
complete after 5.5 hours. 4 and 5 were observed with ratio of 70
and 30%, respectively. With Montmorillonite K10 (entry 14), 4
was obtained with 75% ratio, and 5 with 22%, the desired product 2
was observed with ratio of 3%. The formation of 2 is probably due
to the fact that K10 is a more acidic treated clay with a higher
surface area (250 m2 g-1) than KSF (10 m2g-1).25 With zeolite, type
ZMS-5 (entry 15), the conversion of 1 was complete giving 3%,
85% and 12% of 2, 4, and 5 respectively. Using alumina silicate
(entry 16), 68% of 1 was converted, giving 2 and 5 in 7% ratio each,
with 86% of 4. Due to the high conversion and good selectivity of
methyl 1-octyl ether, the acidic aluminium oxide was chosen as
catalyst for the further experiments.
Table 2. Performance of 4 with different reaction conditions.
Phase
T °C
Cat.
Conv.[%][d]
GC Ratio [%][d]
1
2
3
9
3
5
25
-
1[a] Liquid- batch
130
200
200
0.1
5
32
98
90
41 25
2[b]
Gas - flow
Gas - flow
-
97
3[c]
2
4
78 18
-
[a] 4 (500 mg, 2.4 mmol), acidic aluminium oxide as catalyst (g of catalyst /
500 mg of substrate), [b] 4 (500 mg, 2.4 mmol), syringe flow 1.02 mL/h, [c]
4 (1 g, 4.8 mmol), syringe flow 1.02mL/min, [d] Conversion and Ratio %
were determined by GC.
2.2. Synthesis of methyl 1-octylether in gas phase. In the
literature, etherification reactions worked better at high
temperatures in the presence of dimethyl carbonate, thus our work
was shifted towards the gas phase which operates at higher
temperatures. All gas phase reactions were carried out in a gas
phase reactor described in the experimental section. Composition
of the crude mixture was determined by gas chromatography and
by 1H NMR. Reaction with 1 and DMSi (1:5 molar ratio, flow rate
5.08 mL/h) was done at 200 °C, over 5 g of acidic aluminium oxide,
with an argon flow higher than 75 mL/min. After complete
injection of organic reactants, a conversion of 98% was observed
and 2 was obtained with an isolated yield of 43% after purification
by flash column chromatography. In comparison to Poliakoff et al.
work, the use of DMSi under acidic aluminium oxide gave similar
result than dimethyl carbonate for etherification reaction.26 The
reaction was done in the same gas phase column without washing
or removing the catalyst, the results showed 93% conversion of 1
with an isolated yield of 38% of 2.
2.3 Proposed mechanism
In the reaction of 1-octanol with DMSi in the presence in acidic
media, three pathways could be proposed leading to methyl 1-
octylether (Scheme 1). (i) The nucleophilic attack of octanol into
activated sulfonyl group of DMSi would lead to : (a) the formation
of methyl 1-octylsulfite removing methanol molecules; the
extrusion process would occur at high temperature giving the
methylated desired product (b) or SN2 reaction could also occur in
one-pot removing methanol and SO2 molecules (ii) The dioctyl
sulfite formed by the reaction of methyl 1-octylsulfite and octanol
could give the dioctyl ether while releasing methanol. (iii) Dioctyl
ether could also be the result of the interaction between two octanol
molecules in the presence of acid in liquid phase.
2.3 Synthesis of 2 from extrusion of methyl octyl sulfite. As
mentioned before for liquid phase reactions, methyl alkyl sulfite
could be intermediates to access methyl ethers. The synthesis of
methyl alkyl ethers from unsymmetrical methyl carbonates was
described in the literature. Methyl alkyl carbonates were obtained
in good yields from linear alcohols and dimethyl carbonate under
solvent free condition using triazabicyclodecene at 80 °C.27 Indeed,
the reaction of n-decylmethylcarbonate with 10% of magnesium-
aluminium oxide KW2000 at 252 °C, and in the presence of
solvent gave 80% of the corresponding n-decylmethylether.28 The
desulfoxylation of methyl alkyl sulfites was studied as described in
steps 1 and 2.
C8H7OH +CH3OSOOCH3 → C8H7OSOOCH3 (4) + CH3OH
C8H7OSOOCH3 (4) → C8H7OCH3 (2) + SO2
(1)
(2)
The O-sulfoxymethylation reaction was performed with 1:5 weight
ratio of 1/DMSi in the presence of 20 mol% copper (II) chloride as
Scheme 1. Postulated mechanisms for all reactions occurring with 1-octanol.
3

ACCEPTED MANUSCRIPT
2.4 Methylation of other substrates with dimethyl sulfite. In the
Extension of the scope under the optimal conditions in gas phase
was then undertaken. The synthesis of anisole from phenol in the
gas phase performed better than in liquid phase (6% of conversion).
The conversion was 88% with 100% selectivity towards the desired
ether. 1-Naphthol reacted with 36% conversion giving 87% of the
corresponding 1-methoxy-naphthalene. We found out that high
temperature is a crucial point for methylation process and
especially for phenol derivatives. Indeed, the general base-
literature the methylation of secondary alcohols is more difficult
than the methylation of primary ones. We have studied the O-
methylation of 2-octanol (7) in gas phase. Different parameters
were studied (temperature, amount of alumina catalyst, molar ratio
of DMSi). Results are shown in table 3. At 200 °C the conversion
of 7 reached 91%. The selectivity of 8 and 9 was 58 and 22%
respectively. It should be noted that 3% of 9 was already present in
the starting material. DMSi is a reducing agent, and usually ketones
are formed by the oxidation of alcohols in the presence of oxidants
such as TEMPO, molecular oxygen, etc... 29 Experiments are
underway to explain how such type of oxidation can occurr, and if
DMSi plays the role of oxidizing agent. Moreover, the high
percentage of 6 is due to the dehydration reaction occurring at high
temperature. By decreasing the temperature to 180 °C (entry 2), the
conversion of 7 dropped to 77%. A slight increase in the ratio of 8
and 9 was observed, reaching 61 and 29% respectively. The
amount of 6 decreased to 7%, and methyl 2-octylsulfite 11 was
observed in 3%.
catalysed methylation of phenol performed at 90 °C did not
30
proceed in liquid phase.
Octanoic acid reacts with 93%
conversion to form the corresponding ester in a very high
selectivity reaching 100% under our optimal conditions. Contrary
to a base-catalyzed methylation of carboxylic acids at 90 °C in
liquid phase31, octanoic acid can also play the role of acidic catalyst
Indeed, the reaction was performed in the absence of catalyst
showing 41% conversion after 22 hours giving the methyloctanoate
in 76%. With 1,2-octanediol a lot of products were obtained
including the mono and di-methyl ether and methyl sulfite at
different positions.
At 160 °C (entry 5), 58% conversion of 7 was observed, showing a
low activity for etherification reaction. The optimum temperature
giving an optimal balance between good conversion and few
byproducts was found to be at 180°C. The amount of catalyst was
increased to 10g in order to improve the conversion, and reactions
were done with different ratios of DMSi. With 5 equiv. of DMSi
(entry 3), the conversion reached 93%. Compound 8, 9 and 6 were
obtained with a ratio of 59, 32 and 9, respectively. Using 10 equiv.
of DMSi (entry 4), the conversion of 7 was complete. Compounds
8 and 6 were obtained in with a ratio of 61 and 12% respectively,
whereas the amount of 9 decreased to 24%.
Scheme 2. Formation of methyl ether molecules from corresponding
oxygen nucleophiles in gas phase.
Table 3. Synthesis of methyl 2-octyl ether 8 in gas phase.[a]
7
2-octanol ( )
3. Conclusion
OH
1:5 Molar ratio of 7/DMSi
5g Al2O3 acidic
Argon flow > 75mL/min
syringe flo 5.08mL/min
The selective O-methylation of aliphatic alcohols with dimethyl
sulfite was studied in the presence of acidic heterogeneous catalysts
in both liquid and gas phases. In liquid phase, Amberlyst 36 was
the best catalyst for the production of methyl alkylether but
suffered some limitations due to the presence of side reactions
collapsing the yield. The presence of argon flow plays a vital role
by facilitating the removal of SO2 gas and other species affecting
positively the selectivity towards methyl ethers. In gas phase, the
reaction maintained high selectivity without catalyst deactivation.
Moreover, we have proved that methyl alkyl sulfite could be an
intermediate for the corresponding methyl alkylether. Due to the
difficulty of this synthetic route and the need for enhancing new
methodologies, efforts on the synthesis of dimethyl sulfite from
direct sulfonation of monoalcohols by SO2 gas will be next
investigated within our group.
8
methyl 2-octylether ( )
O
9
2-octanone ( )
O
+ isomers
6
octene ( )
11
methtyl 2-octylsulfite (
)
O
O
S
O
T°C
7/DMSi
Conv. [%][b]
GC Ratio[%][b]
molar ratio
4. Experimental Section
8
9
6
11
General
1
2
3
4
5
200
180
180
180
160
1:5
1:5
1:5[c]
1:10[c]
1:5
91
77
93
98
58
58
61
59
61
49
22
29
32
24
27
20
7
-
3
All reagents, reactants, catalysts and solvents were purchased and
used without any further purification. Dimethyl sulfite, 2-octanol,
Toluene, N-Methyl-2-Pyrrolidone, Montmorillonite KSF and
Montmorillonite K10 were supplied by Sigma-Aldrich. Acidic and
neutral aluminiumoxides were purchased from STREM
CHEMICALS. Basic Aluminium oxide was purchased from
MERCK. 1-octanol and Zeolite type ZMS-5 were purchased from
9
-
12
8
-
16
[a] Experimental conditions: 7 (1 equiv.), DMSi (5 equiv.), acidic Al2O3 (5
g), argon flow (>75 mL/min), syringe flow (5.08 mL/h) [b] Conversion and
Ratio % were determined by GC and 1H NMR.[c] Catalyst (10 g).
4

ACCEPTED MANUSCRIPT
Acros Organics. Copper (II) chloride was purchased from
stopper is connected to a syringe connected to a flow meter, in
which the flow varies from one reaction to another, 5.08 mL/h is
the syringe flow for reactions with 1-octanol and 2-octanol, and
1.02 mL/h for the reactions with 1-methyloctylsulfite, after
complete injection, the system is kept under 200 °C for 2 hours.
Then it is cooled till room temperature. The crude reaction is
collected and analyzed by GC.
PROLABO. ROHM AND HAAS FRANCE S.A.S was the supplier
of Amberlysts 15, 35 and 36 resins. NMR spectra were recorded by
using a Bruker DRX 300 or Bruker ALS 300 (1H 300 MHz, 13C 75
MHz) in CDCl3 deuterated solvent. Chemical shifts are given in
ppm. Abbreviations are defined as follows: s=singlet, d=doublet,
t=triplet, q=quintet, m=multiplet. The ESI HRMS mass spectra
were recorded in positive-ion mode by using a hybrid quqdrupole
time-of-flight mass spectrometer (Micro-TQFQ-II, Bruker
Daltonics, Bremen) with an electrospray ionization (ESI) ion
source. The flow of spray gas was at 0.6 bar and the capillary
voltage was 4.5 kV. The solutions were infused at 180 µL h-1 in a
mixture of solvents (methanol/dichloromethane/water 45:40:15).
The mass range of the analysis was m/z 50-1000 and the calibration
was performed with sodium formate. GC-MS analyses were
performed by using a Focus GC (Thermo Electron Corporation,
Bremen, Germany) equipped with a DB-5 MS capillary column (30
m, 0.25 mm i.d., 0.25 µm film thickness) and a DSQ mass
spectrometer as a detector (Thermo Electron Corporation, Bremen,
Germany). The carrier gas was helium at a flow rate of 1 mL min-1
The column temperature was initially 70°C for 2 min, then
gradually increased to 310°C for 10 min. The injector temperature
was 200°C and the transfer-line temperature was 280°C. For GC-
MS detection, an electron ionization system was used with an
electron energy of 70 eV, and the mass analyzer was a simple
quadrupole. Flash column chromatography was performed with
silica gel Merck Si 60 (40-63µm). GC analyses were performed by
using a GC-2025 gas chromatograph (Shimadzu) equipped with a
ZB-5-MS column (30.0 m, 0.25 mm i.d., 025 µm film thickness).
The carrier gas was N2 at a flow rate of 1.27 mL min-1 . The column
was initially 40° C for 4 min, then gradually increased to 200°C at
15°C min-1, and finally kept at 200°C for 15 min. The injector
temperature was 250°C, and for detection a flame ionization
detector (FID) was used (280°C). Decane was used as internal
standard for all the experiments.
.
Procedure for the preparation of 1-methyloctylsulfite
25% mol of copper (II) chloride was introduced into a 50mL round
bottom flask, 1-octanol (10 g, 77mmol, 1 equiv.) and dimethyl
sulfite (42.3 g, 384.5 mmol, 5 equiv.) were then added. The
reaction mixture was stirred vigorously initially at 70 °C, then the
temperature was increased gradually to 90 °C. After 20 hours, 5%
mol of copper chloride was added again, the reaction was kept for
48 hours. The crude was washed with CH2Cl2 and filtrated, the
solvent was then evaporated under reduced pressure. Purification
by silica flash chromatography was done two times to isolate 1-
methyl octyl sulfite which is a very light yellow oil, first time with
air pressure (eluent: cyclohexane/ethetl acetate 9.8:0.2), second
time without air pressure (eluent: cyclohexane/ethyl acetate 9:1).
Procedure for the preparation of alkyl ethers in liquid phase
In a 25 mL two necked round bottom flask equipped with a cooling
condenser (ethylene glycol, 1°C) under argon flow (75mL/min), 2
g of catalyst, 1-octanol (1 g, 7.7 mmol, 1 equiv.) and dimethyl
sulfite (4.2 g, 38 mmol, 5 equiv.) were successively introduced then
was vigorously stirred at 130 °C. The crude was dissolved in
CH2Cl2, and the catalyst was removed by filtration after washing
several times with CH2Cl2. The solvent was then evaporated under
reduced pressure and directly analysed by gas chromatography.
Procedure for the preparation of 2-methyloctylsulfite
25% mol of copper (II) chloride was introduced into a 50 mL round
bottom flask, 2-octanol (5 g, 38 mmol, 1 equiv.) and dimethyl
sulfite (21 g, 190 mmol, 5 equiv.) were then added. The reaction
mixture was stirred vigorously at70 °C, then increased gradually to
90 °C for 45 hours. The crude was washed with CH2Cl2 and
filtrated more than one time due to the precipitation of copper, each
time the solvent was evaporated under reduced pressure.
Purification by silica flash column chromatography was done to
isolate 2-methyl octyl sulfite which is light yello oil without air
pressure (eluent: cyclohexane/ethyl acetate 9.8:0.2).
Procedure for the preparation of alkyl ethers in gas phase
The catalyst is put directly on the surface of the sintered column
with quartz beads above it, the column is then fixed in a heating
system. One opening of the two necked round bottom flask (RBF)
is connected to the end of the column and the other end is
connected to a gas washer (GW) which is equipped with an in and
out water flow in addition to an opening which allows the passage
of gases into an oil system then to the outside of the hood. A glass
stopper with two openings is placed at the top of the gas phase
column, one side connected to argon which passes to the system
with a controlled flow regulated by a flow meter (>75 mL/min).
The system is then heated to 200 °C during 2 hours, and it is kept
for two more hours to be stabilized. The other opening of the glass
Procedure for the formation of bis-(sulfur dioxide)-1,4-
diazabicyclo[2.2.2]-octane (DABSO) : 1,4-diazabicyclo[2.2.2]-
octane (DABCO, 870 mg, 1 eq./octanol) and 20 mL of toluene was
added to a flask and the system flushed with argon for 5 min at 0°C.
Sulfur dioxide generated during the experiment was introduced into
the system (argon flow: 75mL/min). Precipitation of DABSO is
observed shortly and the supernatant was removed when the
reaction was complete. The white solid (1.15 g, 62%) was washed
by triturating with toluene then and was dried under high vacuum.
5

ACCEPTED MANUSCRIPT
1
mp = 142°C, H NMR (300MHz, CD3OD) δ = 3.20 (s, 12H); 13C
9 C. Dong, Y. Geng, H. An, X. Zhao, Y. Wang, CIESC Journal,
2013, 64, 2086-2091. P. Licence, W. K. Gray, M. Sokolova, M.
Poliakoff, J. Am. Chem. Soc., 2005, 127, 293.
NMR (75 MHz) δ = 45.6 ppm
Methyl 1-octylether: Light yellow liquid; 1H NMR (300 MHz,
CDCl3): δ=0.87 (t, J = 6.9 Hz, 3H, CH3), 1.29 (m, 10H, CH2), 1.53-
1.58 (q, 2H, CH2), 3.32 (s, 3H, CH3), 3.33-3.37 ppm (t, J = 7.6 Hz,
2H, CH2); 13C NMR (75 MHz): δ=14.2 (CH3), 22.7 (CH2), 26.3
(CH2), 29.4 (CH2), 29.6 (CH2), 29.8 (CH2), 31.9 (CH2), 58.6 (CH3),
73.1 ppm (CH2); GC-MS: RT= 5.27 min; HRMS (ESI): m/z
[M+H]+ calcd for C9H20O: 145.1587; found: 145.1588.
Methyl 1-octylsulfite32 : Light yellow liquid; 1H NMR (300 MHz,
CDCl3): δ=0.87 (t, J = 6.8 Hz, 3H, CH3), 1.27 (m, 10 H, CH2),
1.64-1.69 (q, 2H, CH2), 3.62 (s, 3H, CH3), 3.94-3.98 ppm (qt, J1 =
10.1, J2 = 6.6 Hz, 2H, CH2); 13C NMR (75 MHz): δ= 14.1 (CH3),
22.6 (CH2), 25.7 (CH2), 26.9 (CH2), 29.2 ( CH2), 29.5 ( CH2), 31.8
( CH2), 47.9 (CH3), 62.8 ppm (CH2); GC-MS: RT= 9.3 min;
HRMS (ESI): m/z [M+Na]+ calcd for C9H20NaO3S: 231.1025;
found: 231.1021.
10 P. Che, F. Lu, X. Si, J. Xu, RSC Advances, 2015, 5, 24139-24143.
11 P. Tundo, M. Selva, Acc. Chem. Res, 2002, 35, 706.
12 P. Tundo, S. Memoli, D. Hérault, K. Hill, Green Chem., 2004, 6,
609.
13
M. Poliakoff, D.J. Irvine, P.N. Gooden, R.A. Bourne, A. J.
Parrott, H.S. Bevinakatti, Org. Process Res. Dev., 2010, 14, 411.
14 M. Selva, V. Benedet, M. Fabris, Green Chem., 2012, 14, 188.
15 S. Ouk, S. Thiébaud, E. Borredon, P. Le Gars, Green Chem.,
2002, 4, 431.
16
Z. L. Shen, X.Z. Jiang, W.M. Mo, B.X. Hu, N. Sun, Green
Chem., 2005, 7, 97.
17 U. Tilstam, Org. Process Res. Dev., 2012, 16, 1974.
18 R. Nelson, United States Patent, 1984, 4, 453.
19 Y. Hara, M. Matsuda, Bull. Chem. Soc. Jap., 1976, 4, 1126.
20 B. Nguyen, E. J. Emmett, M. C. Willis, J. Am. Chem. Soc. 2010,
132, 16372.
21 H. Woolven, C. Gonzalez-Rodriguez, I. Marco, A. L. thompson,
M. C. Willis Org. Lett. 2011, 13, 4876.
1
Methyl 2-octylether : Light yellow liquid; H NMR (300 MHz,
CDCl3): δ=0.81 (t, 3H, CH3), 1.03-1.05 (d, J = 5.3 Hz, 3H, CH3),
1.21 (m, 10H, CH2), 3.1 (m, 1H, CH), 3.24 ppm (s, 3H, CH3); 13C
NMR (75 MHz): δ=14.6 (CH3), 19.5 (CH3), 23.2 (CH2), 25.9 (CH2),
27.4 (CH2), 30.02 (CH2), 32.4 (CH2), 36.9 (CH3), 56.4 ppm (CH2);
GC-MS: RT= 4.7 min; HRMS (ESI): m/z [M+H]+ calcd for
C9H20O: 145.1587; found: 145.1582.
Methyl 2-octylsulfite32 : Light yellow liquid; 1H NMR (300 MHz,
CDCl3): δ=0.85 (t, J = 6.8 Hz, 3H, CH3), 1.25-1.31 (d, 8 H, CH2),
1.56 (d, 3H, CH3), 1.61 (m, 2H, CH2), 3.60 (s, 3H, CH3), 4.47 ppm
(m, 1H, CH); 13C NMR (75 MHz): δ=14.02 (CH3), 21.56 (CH3),
22.54 (CH2), 25.15 (CH2), 29.06 (CH2), 31.70 (CH2), 37.21 (CH2),
48.31 (CH3), 71.56 ppm (CH); GC-MS: RT= 8.76 min; HRMS
(ESI): m/z [M+Na]+ calcd for C9H20NaO3S: 231.1025; found:
231.1021.
22
J. B. De Coste, D.C. Doetschman, J.T. Schulte, Q. Meng,
Microporous Mesoporous Mater., 2011, 143, 141.
23 Y. C. Sharma, B. Singh, Biofuels, Bioprod. Bioref., 2011, 5, 69.
24 P. F. Siril, H.E. Cross, D.R. Brown, J. Mol. Cat. A Chem., 2008,
279, 63.
25 N. Kaur, D. Kishore, J. Chem. Pharm. Res., 2012, 4, 991.
26 M. Poliakoff, D.J. Irvine, A.J. Parrott, R.A. Bourne, P.N. Gooden,
H.S. Bevinakatti, Org. Process Res. Dev., 2010, 14, 1420.
27 M. A. R. Meier, H. Multu, J. Ruiz, S.C. Solleder, Green Chem.,
2012, 14, 1728.
28 P. Tundo, F. Arico, A.E. Rosamilia, S. Memoli, Green Chem.,
2008, 10, 1182.
29 R. B.-D. Daniel, P. Alsters, R. Neumann, J. Org. Chem., 2001,
66, 8650.
30 Y. Ji, J. Sweeney, J. Zoglio, D. J. Gorin, J. Org. Chem. 2013, 78,
11606.
31 W.-C. Shieh, S. Dell, O. Repič, J. Org. Chem. 2002, 67, 2188.
32
5. Acknowledgements: The authors thank Dr. F. Albrieux, C.
Duchamp and N. Henriques (Centre commun de spectrométrie de
Masse, ICBMS UMR-5246) for assistance and access to the Mass
Spectrometry facilities.
Additional data: the NMR spectra of unsymmetrical dialkyl
sulfite showed ABX3 patterns for the “diastereotopic” CH2 protons.
F. Kaplan, J. D. Roberts J. Am. Chem. Soc. 1961, 83, 4666.
6. Supporting information available: Expanded chromatograms
for gas and liquid experiments, additional NMR spectra of
characterized compounds.
7. Referees
1 G. Lamoureux, C. Agüero, ARKIVOC, 2009, 251.
2 L. Moity, M. Durant, A. Benazzouz, C. Pierlot, V. Molinier, J.-M.
Aubry, Green Chem. 2012, 14, 1132.
3 G. Crass, H. Kalinowski, D. Seebach, Angew. Chem., 1975, 87,
812-813. T. Ando, J. Yamawaki, T. Kawate, S. Sumi, T. Hanafusa,
Bull. Chem. Soc. Jpn., 1982, 55, 2504.
4 K. Ohno, H. Nishiyama, H. Nagase, Tetrahedron Lett. 1979, 20,
4405
5 H. Ogawa, Y. Ichimura, T. Chihara, S. Teratani, K. Taya, Bull.
Chem. Soc. Jpn., 1986, 59, 2481.
6 J.-S. Chang, Y.-D. Lee, L. C.-S. Chou, T.-R. Ling, T.-C. Chou,
Ind. Eng. Chem. Res. 2012, 51, 655.
7
M. Sutter, W. Dayoub, E. Métay, Y. Raoul, M. Lemaire,
ChemCatChem. 2013, 5, 1.
8 M. Selva, A. Perosa, Green Chem., 2008, 10, 457.
6

ACCEPTED MANUSCRIPT
Dimethyl Sulfite a potential agent for methylation
Rim Mouselmani, Eric Da Silva and Marc Lemaire*
Laboratoire Catalyse, Synthèse et Environnement, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), CNRS,
UMR 5246, Université Claude Bernard Lyon 1, Bât. CPE, 43 Boulevard du 11 novembre 1918, 69622, Villeurbanne, France. Corresponding
author: (Tel) +33 (0) 4 72 43 14 07; (Fax) +33 (0) 4 72 43 14 08; (Email) marc.lemaire.chimie@univ-lyon1.fr
SUPPORTING INFORMATION
SM1. Synthesis of methyl 1-octylether : GC chromatogram of crude reaction (Table 1, entry
2) after 4H30 of reaction time in liquid phase.
SM2. Synthesis of methyl 1-octylether : GC chromatogram of crude reaction (Table 1, entry
2) after 24H of reaction time in liquid phase.
SM3. Synthesis of methyl 1-octylether monitored by gas chromatography from 1-octanol and
dimethyl sulfite with 1 g of acidic aluminium oxide : (■) conversion of 1-octanol; (▲)
selectivity for methyl 1-octylsulfite and (♦) selectivity for methyl 1-octylether.
Sm4. Synthesis of methyl 1-octylether : GC chromatogram of crude reaction (Table 2, entry
2) in gas phase.
SM5. Synthesis of methyl 2-octylether : GC chromatogram of crude reaction (Table 3, entry
1) in gas phase.
Sm6. 1H NMR of methyl 1-octylether in CDCl3
SM7. 1H NMR of methyl 1-octyl sulfite in CDCl3
SM8. 1H NMR of methyl 2-octylether in CDCl3
SM9. 1H NMR of methyl 2-octyl sulfite in CDCl3
SM10. 1H / 13C NMR of DABSO in MeOD
1

ACCEPTED MANUSCRIPT
SM1. Synthesis of methyl 1-octylether : GC chromatogram of crude reaction (Table 1, entry
2) after 4H30 of reaction time in liquid phase.
SM2. Synthesis of methyl 1-octylether : GC chromatogram of crude reaction (Table 1, entry
2) after 24H of reaction time in liquid phase.
2

ACCEPTED MANUSCRIPT
SM3. Synthesis of methyl 1-octylether monitored by gas chromatography from 1-octanol and
dimethyl sulfite with 1 g of acidic aluminium oxide : (■) conversion of 1-octanol; (▲)
selectivity for methyl 1-octylsulfite and (♦) selectivity for methyl 1-octylether.
100
90
80
70
60
50
40
30
20
10
0
100
90
80
70
60
50
40
30
20
10
0
0
2
4
6
8
reaction time (hours)
3

ACCEPTED MANUSCRIPT
SM4. Synthesis of methyl 1-octylether : GC chromatogram of crude reaction (Table 2, entry
2) in gas phase.
SM5. Synthesis of methyl 2-octylether : GC chromatogram of crude reaction (Table 3, entry
1) in gas phase.
4

ACCEPTED MANUSCRIPT
SM6. 1H NMR of methyl 1-octylether in CDCl3 (300 MHz)
SM7. 1H NMR of methyl 1-octyl sulfite in CDCl3 (300 MHz)
RM5-F2
Proton
4E+08
4E+08
3E+08
3E+08
3E+08
3E+08
3E+08
2E+08
2E+08
2E+08
2E+08
2E+08
1E+08
1E+08
1E+08
8E+07
6E+07
4E+07
2E+07
0
-2E+07
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
f1 (ppm)
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
5

ACCEPTED MANUSCRIPT
SM8. 1H NMR of methyl 2-octylether in CDCl3 (300 MHz)
2MOE
Proton
1E+08
1E+08
1E+08
1E+08
9E+07
8E+07
7E+07
6E+07
5E+07
4E+07
3E+07
2E+07
1E+07
0
2MOE
Proton
2E+07
1E+07
5E+06
0
3.40
3.35
3.30
3.25
3.20
3.15
f1 (ppm)
2MOE
Proton
1E+08
5E+07
0
1.15
1.10
f1 (ppm)
1.05
1.00
-1E+07
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
f1 (ppm)
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
SM9. 1H NMR of methyl 2-octyl sulfite in CDCl3 (300 MHz)
6

ACCEPTED MANUSCRIPT
SM10. 1H / 13C NMR of DABSO in MeOD
7E+08
6E+08
6E+08
6E+08
5E+08
4E+08
4E+08
4E+08
3E+08
2E+08
2E+08
2E+08
1E+08
5E+07
0
-5E+07
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
f1 (ppm)
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
1E+09
1E+09
9E+08
8E+08
7E+08
6E+08
5E+08
4E+08
3E+08
2E+08
1E+08
0
-1E+08
220
210
200
190
180
170
160
150
140
130
120
110
100
f1 (ppm)
90
80
70
60
50
40
30
20
10
0
-10
7