Continuous-Flow Reductive Alkylation: Synthesis of Bio-based Symmetrical and Disymmetrical Ethers

Article abstract of DOI:10.1055/s-0036-1591861

For the first time, a reductive alkylation process in continuous flow has been elaborated for the conversion of bio-based alcohols and aldehydes into symmetrical and dissymmetrical high-value-added ethers for industrial companies. The developed method is an etherification associating liquid, solid and gas phases under green conditions (continuous flow, catalysis, bio-based starting materials).

Full text of DOI:10.1055/s-0036-1591861

SYNTHESIS
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©
Georg Thieme Verlag Stuttgart · New York
2018, 50, A–H
paper
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Synthesis
S. Bruniaux et al.
Paper
Continuous-Flow Reductive Alkylation: Synthesis of Bio-based
Symmetrical and Disymmetrical Ethers
Sophie Bruniauxa
Denis Luartb
Christophe Len*a,c
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a
Sorbonne Universités, Université de Technologie de Com-
piègne, Centre de Recherche Royallieu, CS 60 319, 60203
Compiègne cedex, France
christophe.len@utc.fr
Ecole Supérieure de Chimie Organique et Minérale, EA 4297
TIMR, Compiègne, France
PSL Research University, Chimie ParisTech, CNRS, Institut de
Recherche de Chimie Paris, 11 rue Pierre et Marie Curie, 75231
Paris Cedex 05, France
b
c
Received: 03.10.2017
Accepted after revision: 10.11.2017
Published online: 24.01.2018
than nine carbon atoms are used as additives to commercial
gasoil for upgrading the quality of the diesel blend. To
14
DOI: 10.1055/s-0036-1591861; Art ID: ss-2017-z0636-op
produce these linear symmetrical and unsymmetrical
ethers, four main strategies were described: (i) Williamson
Abstract For the first time, a reductive alkylation process in continu-
ous flow has been elaborated for the conversion of bio-based alcohols
and aldehydes into symmetrical and dissymmetrical high-value-added
ethers for industrial companies. The developed method is an etherifica-
tion associating liquid, solid and gas phases under green conditions
9–16
derived reaction;
(ii) bimolecular dehydration of prima-
ry alcohol over acid catalysts;1
4,21–24
(iii) addition of alcohol
2
1,39,40
to alkene in acidic conditions
and (iv) reductive
alkylation.7
,8,41
Unfortunately, most of the processes for the
(continuous flow, catalysis, bio-based starting materials).
industrial production of ethers generate large amounts of
waste, solid salts and require the handling of toxic reagents.
In regard to the development of green chemistry, academic
research has permitted the establishment of a new method
Key words reductive alkylation, ether, continuous flow, green chem-
istry, catalysis
8
for ether synthesis using the reductive alkylation. This pro-
Ethers are an important industrial class of organic com-
tocol is based on heterogeneous catalysis, atom economy,
less hazardous chemical syntheses, and safer solvents and
auxiliaries. Moreover, the starting materials can either be
bio-based carboxylic acid, aldehyde or alcohol. Due to our
interest in the topic of green chemistry and alternative
pounds having an oxygen atom bonded to two carbon
atoms. Depending the two groups connected to the oxygen
atom, different classes of ethers exist such as alkyl ethers
dimethyl ether, diethyl ether or tert-dibutyl ether), aryl
ethers (anisole, phenetole or vanilline) and cyclic ethers
tetrahydrofuran or 1,4-dioxane). Ethers can be used in a
(
technologies,
a continuous-flow system for reductive
(
alkylation was envisaged to develop an intensified process.
Recently, the use of homogeneous and heterogeneous flow
systems in organic chemistry has been widely studied be-
cause of their highly efficient heat transfer compared with
wide range of applications such as solvents, additives for
lubricants, paints, adhesives, diesel, pesticides, precursors
for polymers and fragrances or extraction of natural prod-
1–6
ucts. General methods for the synthesis of symmetrical
and unsymmetrical ethers have been reported and their ap-
plications are dependent of the nature of the target itself.
batch methodologies, good monitoring of temperature, and
enhanced mass transfer.4
2–47
This innovative approach also
permits the time required to progress from research to pilot
scale and production to be reduced.
Among the different processes, Williamson and modified
Williamson reactions,9–16 Mitsunobu reactions,
17–20
acid-
In the present work, a commercial continuous-flow sys-
tem (ThalesNano H-cube®) was used. Aldehyde was dis-
solved in pure alcohol and injected into the system with an
14,21–24
catalyzed condensation of alcohols,
alkoxymercura-
22
23–25
tion–demercuration, ring opening of epoxides,
reduc-
26–31
–1
tive condensation of ketones and esters,
hydroalkonyla-
and oxidative C–H alkoxylation of
HPLC pump (0.3–1.2 mL min ) at room temperature. The
32–35
tion of alkynes,
solution was then flowed into a cartridge (internal diameter
0.4 mm, length 70 mm, internal volume 0.88 mL) filled with
Pd(0) powder (340 mg Pd/C, 5% Escat 1431) placed into a
heating block (60–140 °C) (Scheme 1). This continuous-
36–38
arenes
can be cited.
Linear ethers with a low molecular weight such as di-
methyl or diethyl ether are mainly used as solvents in in-
dustry. The corresponding linear ethers containing more
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

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Synthesis
S. Bruniaux et al.
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Scheme 1 Continuous 1-butoxyoctane (3a) synthesis using reductive alkylation conditions
Table 1 Effect of the Concentration of Aldehyde 2aa
flow device permitted variation of the nature of the re-
agents and their concentrations, the residence time or con-
tact time and the temperature.
Entry
Octanal (2a) (mol L–1
)
Conv. (%)
Yield (%)b
TOF (min–1
)
Based on the optimized conditions developed by
Lemaire for the reductive alkylation in batch reactor, initial
1
2
3
4
5
6
7
8
9
0.05
0.1
0.2
0.33
1
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
31
48
51
51
48
49
49
42
35
21
0.3
0.9
8
studies were performed for butan-1-ol (1a) used as reagent
1.9
–1
and solvent and octanal (2a, 0.2 mol L ) as a model reac-
4.9
tion at 100 °C using 1 mol% of commercial Pd/C (5%) under a
–1
9.3
low pressure of H gas (1 bar) at a flow rate of 0.6 mL min ,
2
for a residence time of 1.5 minute. These parameters gave a
corresponding processing time of 34 minutes. The support-
ed catalytic system (Pd/C,5% Escat 1431) as 5% palladium on
activated wood carbon, reduced and dry, was constant
during all the study because it is the most frequently used
agent for industrial processes due to its low price, high cata-
lytic activity and easy removal after completion of the reac-
tion. After a single pass, more than 98% of the aldehyde 2a
was converted and 51% of the corresponding ether 3a was
obtained (Table 1, entry 3). Then, in order to maximize the
concentration of compound 2a, different quantities of oc-
1.2
1.3
1.5
2
11.2
12.3
12.4
13.1
10.9
10
2.7
aReaction conditions: octanal (2a) was diluted in butan-1-ol (1a) to a final
volume of 15 mL and flowed through a cartridge filled with 340 mg of Pd/C
5%, Escat 1431) at a flow rate of 0.6 mL min at 100 °C under H (1 bar)
2
for a residence time of 1.5 min.
GC yield.
–1
(
b
–1
tanal (2a) were compared (0.05–2.7 mol L ) (Table 1). In
our hands, the best conditions were defined with a concen-
tration of 1.3 M (entry 7) of aldehyde 2a in alcoholic solvent
Table 2 Influence of the Temperature Variationa
Yield (%)b
TOF (min–1
)
Entry
Temp (°C)
Conv. (%)
1
a. With a lower or a higher concentration, decreases to
1
2
3
4
5
60
80
>98
>98
>98
>98
>98
39
47
49
49
54
9.6
11.9
12.3
12.9
14.4
31% or 21%, respectively, were noted. The turnover frequen-
–1
cy (TOF) was almost 13 min for octanal (2a) at a concen-
–1
tration of 2.0 mol L . However byproducts such as dioctyl
ether or octanol also appeared under these conditions,
probably due to the high concentration of aldehyde 2a. By
using a batch reactor, Lemaire et al. produced 1-butoxy-
octane (3a) starting from a solution of aldehyde 2a (0.2 M)
diluted in alcohol 1a in the presence of Pd/C (10%) at 100 °C
100
120
140
aReaction conditions: octanal (2a, 1.3 M) was diluted in butan-1-ol (1a) to a
final volume of 15 mL and flowed through a cartridge filled with 340 mg of
–
1
Pd/C (5%, Escat 1431) at a flow rate of 0.6 mL min under H
residence time of 1.5 min.
2
(1 bar) for a
under H (40 bar) for 7 hours. Under these conditions, a
b
2
GC yield.
lower TOF was calculated (0.09 min– vs. 13 min ). This re-
sult was not surprising because the catalyst contact was
higher in the continuous-flow reactor than in the batch re-
actor.
1
–1
that an overpressure of 100 bar was observed when a tem-
perature of 60 °C was used. The commercial apparatus used
did not permit temperatures higher than 140 °C to be test-
ed under our conditions.
With the last optimized conditions (Table 2, entry 5) us-
ing octanal (2a) concentration of 1.3 M diluted in butan-1-
ol (1a) with a maximal volume of 15 mL and a temperature
Different temperatures from 60 to 140 °C were tested
with the optimized conditions described in Table 1 (entry
7). As shown in Table 2, the best yield and productivity
–1
were obtained at 140 °C with a flow rate of 0.6 mol L (en-
try 5). When the temperature was decreased to 60 °C, the
overpressure in the front of the cartridge increased. This
phenomenon was due to the viscosity of the media, which
is less significant at 140 °C. In our case, it was noticeable
–1
of 140 °C, variation of the flow rate from 0.3 mL min to 1.2
mL min–1 was conducted. With a flow rate of 0.9 mL min
–1
–1
and 1.2 mL min , an overpressure in the front of the
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

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Synthesis
S. Bruniaux et al.
Paper
cartridge was observed due to the high concentration of the
reaction media, the viscosity of the butan-1-ol (1a) and the
porosity of the Pd/C (Table 3, entries 3 and 4). The conse-
quence of this phenomenon was a decreasing yield of the
desired ether 3a. Thus, even if the best TOF was obtained
–1
with a flow rate of 1.2 mL min (Table 3, entry 4), the over-
pressure observed required the use of a lower flow rate (0.6
–1
mL min ) as a limiting step for our methodology.
Table 3 Effect of the Flow Variationa
Figure 1 Behavior of the catalyst Pd/C (5%, Escat 1431). a Reagents and
conditions: octanal (2a, 1.3 M) was diluted in butan-1-ol (1a) to a final
volume of 15 mL and flowed through a cartridge filled with 340 mg of
Entry
Flow
(
Residence
time (min)
Conv.
(%)
Yield
(%)
TOF
mL min–1
)
b
(min–1)
1
2
3
4
0.3
0.6
0.9
1.2
3
>98
>98
>98
>98
54
52
36
36
12.8
26.9
41.6
52.7
Pd/C (5%, Escat 1431) at a flow rate of 0.6 mL min at 140 °C under H2
–1
b
(
1 bar) for a residence time of 1.5 min. GC yield.
1.5
0.97
0.7
The scope of the continuous-flow reductive alkylation
aReaction conditions: octanal (2a, 1.3 M) was diluted in butan-1-ol (1a) to a
final volume of 15 mL and flowed through a cartridge filled with 340 mg of
was studied starting from (i) linear saturated alcohols 1 and
linear saturated aldehydes 2 and (ii) branched saturated
alcohol 4 and aldehydes 2 using the optimized conditions
Pd/C (5%, Escat 1431) at 140 °C under H
2
(1 bar).
b
GC yield.
(Table 5 and Table 6). Starting from butan-1-ol (1a), the cor-
responding butyloxybutane (3b), butyloxyhexane (3c), butyl-
oxyoctane (3a), and butyloxyundecane (3d) was obtained
in 79, 68, 52, and 43% yield, respectively. The use of hexan-
1-ol (1b) in the presence of the same aldehydes furnished
the target hexyloxybutane (3c), hexyloxyhexane (3e), hexyl-
oxyoctane (3f), and hexyloxyundecane (3g) in 67, 58, 50,
and 46% yield, respectively. Using our optimized process for
the reductive alkylation, the higher the viscosity, the lower
the yields. Irrespective of the alcohol (1a, 1b) and the alde-
hyde (2a–d) used, an overpressure was observed. However,
this overpressure was lower with butan-1-ol (1a) than with
hexan-1-ol (1b). It was notable that for the production of
butyloxyhexane (3c), the use of butan-1-ol (1a) or hexan-1-
ol (1b) led to similar yield (68% vs. 67%). In our hands, par-
tial reduction of aldehydes 2a–c was observed and caused
the formation of the corresponding alcohols but also the
formation of the corresponding symmetric ethers: dioctyl
ether, dihexyl ether and dibutyl ether. For the aldehyde 2d,
having a higher molecular weight, only reduction to the
corresponding alcohol was detected and no diundecyl ether
was observed.
Starting from aldehyde 2a concentration of 1.3 M, varia-
tion of the H pressure was realized with a flow rate of 0.6
2
–1
mL min at 140 °C (Table 4). Irrespective of the pressure
used, the yield of ether 3a was similar, showing that a H2
pressure of 1 bar was enough for the reductive alkylation
using our device.
a
Table 4 Effect of the H Pressure
2
Entry
Pressure
Conv.
(%)
Yield
(%)
TOF
b
(min–1)
(
bar)
1
2
3
4
1
5
>98
>98
>98
>98
52
54
53
54
25.6
26.9
26.4
27.7
10
20
aReaction conditions: octanal (2a, 1.3 M) was diluted in butan-1-ol (1a) to a
final volume of 15 mL and flowed through a cartridge filled with 340 mg of
Pd/C (5%, Escat 1431) at a flow rate of 0.6 mL min–1 at 140 °C for a resi-
dence time of 1.5 min.
b
GC yield.
Linear and branched saturated alcohols 4a–f and alde-
hydes 2a,b were then studied (Table 6). The viscosity of al-
cohols 4a–f increases with the number of carbon atoms
and, for the same molecular weight, the branched alcohols
are more viscous than those having linear structures. As ob-
served in the previous study (Table 5), for a same alcohol 4,
the aldehyde 2b always gave a better yield than that ob-
tained with aldehyde 2a. The regioisomers 4b and 4d, hav-
ing low molecular weight, have a similar reactivity (Table 6,
entries 1, 2, 7 and 8). It is notable that for an alcohol having
more than three carbon atoms, the secondary hydroxyl
group was less reactive than the primary one for the same
One advantage of a heterogeneous system is the poten-
tial for studying the reactivity of the catalysts. Therefore, by
using the optimized conditions (octanal (2a, 1.3 M) in
butan-1-ol (1a) with a maximal volume of 15 mL, Pd/C (5%,
Escat 1431; 1 mol%), 0.6 mL min , 140 °C), the recyclability
of the catalyst was tested to explore its limits. An increase
in the yield due to the start kinetic of the reaction was ob-
served until 50 minutes to yield ether 3a in 67%, the yield
then gradually decreased slowly for each sample (Figure 1).
Using the optimized process, ether 3a was obtained in 50%
yield after 8 hours of continuous flow.
–1
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

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S. Bruniaux et al.
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Table 5 Establishing the Scope of the Continuous-Flow Process in a Single Pass: Production of Ethers 3a–ga
Entry
1
Alcohol
Aldehyde
Product
Conv. (%) Yield (%)b
O
OH
OH
OH
OH
O
O
O
O
>98
>98
>98
>98
>98
>98
>98
>98
79
68
52
43
67
58
50
46
1a
1a
1a
1a
1b
1b
1b
1b
3b
2
2
2
2
2
2
2
2
b
c
O
2
3
4
5
6
7
3c
3a
3d
3c
3e
3f
O
a
d
b
c
O
O
OH
OH
OH
OH
O
O
O
O
O
O
a
O
8
3g
d
a
Reaction conditions: aldehyde 2 (1.3 M) was diluted in alcohol 1 to a final volume of 15 mL and flowed through a cartridge filled with 340 mg of Pd/C (5%, Escat
431) at a flow rate of 0.6 mL min– at 140 °C under H
1
1
2
(1 bar) for a residence time of 1.5 min.
b
GC yield.
isomer. Different ternary alcohols and benzylic alcohol
were tested in our process but no reductive alkylation was
observed.
talysis using an alcohol and an aldehyde without any leav-
ing group and addition of base or additive in continuous
flow are strong points of the process. The latter makes it
possible to have performances similar to those reported for
the production of ether, but from a green chemistry and
sustainable development point of view, this work is far su-
perior.
In conclusion, a novel, fast, efficient and more secure
catalytic method using continuous flow as alternative tech-
nology for the reductive alkylation has been realized. The
continuous-flow device was commercial (Thales Nano) and
the heterogeneous Pd/C catalyst was selected for reproduc-
ibility compared with homemade apparatus and the low
price and disposability, respectively. This new process gives
access to high-value-added bio-based symmetrical and
asymmetrical ethers with good yields and good conversions
All commercially available products and solvents were used without
further purification. The hydrogen was generated in situ in a H-Cube
ThalesNano system from water electrolysis and the flow solution
through a packed column containing different solid catalysts. Reac-
tions were monitored by TLC (Kieselgel 60F254 aluminum sheet) with
detection by UV light or potassium permanganate acidic solution.
Column chromatography was performed on silica gel 40−60 μm. Flash
(98–100%) in only 30 minutes for the processing time and
1.5 minute for the residence time. This optimized method
can be applied to primary and secondary bio-based alco-
hols with good results and selectivities. Heterogeneous ca-
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S. Bruniaux et al.
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Table 6 Establishing the Scope of the Continuous-Flow Process in a Single Pass: Production of Ethers 3h–sa
Entry
1
Alcohol
Aldehyde
Product
Conv. (%)
>98
Yield (%)b
88
O
OH
OH
O
O
4
4
b
b
3h
2
2
b
a
O
2
3
4
>98
>98
>98
59
71
57
3i
O
OH
OH
O
O
4
4
c
c
2b
2a
3j
O
3k
OH
OH
O
O
O
5
6
>98
>98
46
35
2
2
b
a
4
d
3l
O
4
4
4
4
4
4
4
d
e
e
f
3m
O
O
O
7
8
9
>98
>98
>98
>98
>98
>98
93
57
70
55
43
43
OH
OH
O
2b
2a
2b
2a
2b
2a
3n
O
O
O
O
3o
OH
OH
O
O
3p
3q
3r
1
0
1
2
f
1
OH
OH
O
O
g
g
1
3s
a
Reaction conditions: aldehyde 4 (1.3 M) were diluted in alcohol 1 to a final volume of 15 mL and flowed through a cartridge filled with 340 mg of Pd/C (5%, Escat
431) at a flow rate of 0.6 mL min– at 140 °C under H
1
1
2
(1 bar) for a residence time of 1.5 min.
b
GC yield.
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

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S. Bruniaux et al.
Paper
1
3
column chromatography was performed with an automatic appara-
C NMR (100 MHz, CDCl ): δ = 71.1, 32.0, 31.8, 2 × 29.9, 29.7,
3
1
13
tus, using silica gel cartridges. H and C NMR spectra were recorded
with a 400 MHz/54 mm ultralong hold. Chemical shifts (δ) are quoted
in parts per million (ppm) and are referenced to TMS as an internal
standard. Coupling constants (J) are quoted in hertz.
3 × 29.6, 29.5, 26.3, 26.0, 22.8, 22.7, 14.2, 14.1.
1
-Propoxybutane (3h)
Yield (GC): 88%.
1
H NMR (400 MHz, CDCl ): δ = 3.40 (t, J = 6.7 Hz, 2 H), 3.35 (t, J =
3
Ethers 3a–s; General Procedure
6
.8 Hz, 2 H), 1.64–1.49 (m, 4 H), 1.36 (m, 2 H), 0.97–0.86 (m, 6 H).
A solution containing 1.3 M of aldehyde in alcohol (15 mL) was
pumped in a prepacked catalyst cartridge (Pd/C 5%, Escat 1431, 70
13
C NMR (100 MHz, CDCl ): δ = 72.7, 70.7, 32.0, 23.1, 19.5, 14.1, 10.7.
3
–1
mm length, 0.87 mL internal volume) at a flow rate of 0.6 mL min at
40 °C under H (1 bar) for a residence time of 1.5 min. The reaction
1
-Propoxyoctane (3i)
1
2
mixture was subsequently injected into the GC after the addition of
an internal standard (octane, 0.1 M) to determinate the yield.
Yield (GC): 59%.
1
H NMR (400 MHz, CDCl ): δ = 3.42–3.31 (m, 4 H), 1.64–1.48 (m, 4 H),
3
1
13
.38–1.17 (m, 10 H), 0.95–0.80 (m, 6 H).
1
-Butoxyoctane (3a)
C NMR (100 MHz, CDCl ): δ = 72.6, 71.0, 31.9, 29.9, 29.6, 29.4, 26.3,
3
Yield (GC): 88%.
23.0, 22.8, 14.2, 10.7.
1
H NMR (400 MHz, CDCl ): δ = 3.40 (t, J = 6.7 Hz, 2 H), 3.35 (t, J =
3
6.8 Hz, 2 H), 1.64–1.49 (m, 4 H), 1.36 (m, 2 H), 0.97–0.86 (m, 6 H).
1-Butoxy-3-methylbutane (3j)
13
C NMR (100 MHz, CDCl ): δ = 72.7, 70.7, 32.0, 23.1, 19.5, 14.1, 10.7.
Yield (GC): 71%.
3
1
H NMR (400 MHz, CDCl ): δ = 3.42–3.31 (m, 4 H), 1.58–1.27 (m, 7 H),
3
1-Butoxybutane (3b)
0.94–0.82 (m, 9 H).
Yield (GC): 79%.
13
C NMR (100 MHz, CDCl ): δ = 70.8, 69.3, 38.7, 31.9, 25.2, 22.7, 19.4,
3
Molecule 3b is a commercial compound and was characterized by
14.0.
comparing the corresponding spectroscopic data.
1-(3-Methylbutoxy)octane (3k)
1
-Butoxyhexane (3c)
Yield (GC): 57%.
Yield (GC): 68%.
1
H NMR (400 MHz, CDCl ): δ = 3.46–3.31 (m, 4 H), 1.68 (m, 1 H), 1.59–
3
1
H NMR (400 MHz, CDCl ): δ = 3.41–3.34 (m, 4 H), 1.60–1.47 (m, 4 H),
1.50 (m, 2 H), 1.45 (m, 2 H), 1.39–1.17 (m, 10 H), 0.96–0.79 (m, 9 H).
3
1
.41–1.19 (m, 8 H), 0.94–0.82 (m, 6 H).
13
C NMR (100 MHz, CDCl ): δ = 71.1, 69.3, 38.7, 31.9, 29.9, 29.6, 29.4,
3
13
C NMR (100 MHz, CDCl ): δ = 71.1, 70.7, 31.9, 31.8, 29.8, 26.0, 22.7,
26.3, 25.2, 22.8, 22.7, 14.2.
3
19.5, 14.1, 14.0.
1
-Butoxy-(2-ethylhexane) (3l)
1-Butoxyundecane (3d)
Yield (GC): 46%.
Yield (GC): 43%.
1
H NMR (400 MHz, CDCl ): δ = 3.38 (t, J = 6.6 Hz, 2 H), 3.27 (d, J = 6.1,
3
1
H NMR (400 MHz, CDCl ): δ = 3.41–3.34 (m, 4 H), 1.59–1.48 (m, 4 H),
1.0 Hz, 2 H), 1.60–1.45 (m, 3 H), 1.42–1.17 (m, 10 H), 0.89 (m, 9 H).
3
1
.39–1.18 (m, 18 H), 0.94–0.82 (m, 6 H).
13
C NMR (100 MHz, CDCl ): δ = 73.9, 70.9, 39.7, 31.9, 30.7, 29.2, 24.0,
3
13
C NMR (100 MHz, CDCl ): δ = 71.1, 70.7, 2 × 32.0, 29.9, 29.7,
23.2, 19.5, 14.2, 14.1, 11.1.
3
3
× 29.6, 29.4, 26.3, 22.8, 19.5, 14.2, 14.0.
1-(2-Ethylhexyloxy)octane (3m)
1
-(Hexyloxy)hexane (3e)
Yield (GC): 35%.
Yield (GC): 58%.
1
H NMR (400 MHz, CDCl ): δ = 3.37 (t, J = 6.4 Hz, 2 H), 3.26 (d, J =
3
Molecule 3e is a commercial compound and was characterized by
comparing the corresponding spectroscopic data.
6.0 Hz, 2 H), 1.61–1.44 (m, 3 H), 1.43–1.17 (m, 18 H), 0.95–0.79 (m,
9 H).
13
C NMR (100 MHz, CDCl ): δ = 73.9, 71.2, 39.7, 32.0, 30.7, 29.8, 29.6,
3
1-(Hexyloxy)octane (3f)
29.4, 29.2, 26.3, 24.0, 23.2, 22.8, 2 × 14.2, 11.1.
Yield (GC): 50%.
1
1-Isopropoxybutane (3n)
H NMR (400 MHz, CDCl ): δ = 3.38 (m, 4 H), 1.62–1.50 (m, 4 H), 1.38–
3
1.18 (m, 16 H).
Yield (GC): 93%.
1
3
1H NMR (400 MHz, CDCl
2 H), 1.56–1.46 (m, 2 H), 1.41–1.29 (m, 2 H), 1.15–1.07 (m, 3 H), 0.89
C NMR (100 MHz, CDCl ): δ = 77.1, 71.1, 31.9, 31.8, 29.9, 29.9, 29.6,
3
): δ = 3.57–3.46 (m, CH), 3.38 (t, J = 6.7 Hz,
3
2
9.4, 26.3, 26.0, 22.8, 22.7, 14.2, 14.1.
(t, J = 7.4 Hz, 3 H).
13
1-(Hexyloxy)undecane (3g)
C NMR (100 MHz, CDCl ): δ = 71.3, 68.0, 32.3, 22.2, 19.5, 14.0.
3
Yield (GC): 46%.
1
1-Isopropoxyoctane (3o)
H NMR (400 MHz, CDCl ): δ = 3.42–3.35 (m, 4 H), 1.60–1.50 (m, 4 H),
3
1.38–1.17 (m, 22 H), 0.93–0.82 (m, 6 H).
Yield (GC): 57%.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

G
Synthesis
S. Bruniaux et al.
Paper
1
H NMR (400 MHz, CDCl ): δ = 3.52 (hept, J = 6.1 Hz, 4 H), 3.37 (t, J =
(7) Bethmont, V.; Fache, F.; Lemaire, M. Tetrahedron Lett. 1995, 36,
3
6.8 Hz, 2 H), 1.57–1.48 (m, 2 H), 1.35–1.18 (m, 10 H), 1.16–1.08 (m,
4235.
6
H), 0.86 (t, J = 8.1 Hz, 3 H).
(8) Bethmont, V.; Montassier, C.; Marecot, P. J. Mol. Catal. A: Chem.
2000, 152, 133.
13
C NMR (100 MHz, CDCl ): δ = 71.3, 68.3, 31.9, 30.3, 29.6, 29.4, 26.3,
3
(9) Williamson, A. W. J. Chem. Soc. 1852, 229.
22.7, 22.2, 14.1.
(
(
(
10) Cox, H. L.; Greer, P. S. US2050600 A, 11. August, 1936.
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sis 1983, 53.
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15) Gentzen, M.; Habicht, W.; Doronkin, D. E.; Grunwaldt, J.-D.;
Sauer, J.; Behrens, S. Catal. Sci. Technol. 2016, 6, 1054.
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Org. Chem. 2014, 50, 790.
17) Rano, T. A.; Chapman, K. T. Tetrahedron Lett. 1995, 36, 3789.
(18) Krchňák, V.; Flegelová, Z.; Weichsel, A. S.; Lebl, M. Tetrahedron
Lett. 1995, 36, 6193.
(19) But, T. Y. S.; Toy, P. H. Chem. Asian J. 2007, 2, 1340.
(20) Hughes, D. L. Org. Prep. Proced. Int. 1996, 28, 127.
21) Ruppert, A. M.; Parvulescu, A. N.; Arias, M.; Hausoul, P. J. C.;
Bruijnincx, P. C. A.; Gebbink, R. J. M. K.; Weckhuysen, B. M.
J. Catal. 2009, 268, 251.
22) Brown, H. C.; Kurek, J. T.; Rei, M.-H.; Thompson, K. L. J. Org.
Chem. 1984, 49, 2551.
(23) Ready, J. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 2687.
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(25) Rodriguez, C. G.; Ferrier, R. C. Jr.; Helenic, A.; Lynd, N. A. Macro-
molecules 2017, 50, 3121.
26) Shintou, T.; Mukaiyama, T. J. Am. Chem. Soc. 2004, 126, 7359.
27) Sassaman, M. B.; Prakash, G. K. S.; Olah, G. A.; Donald, P.; Loker,
K. B. Tetrahedron 1988, 44, 3771.
2
-Butoxybutane (3p)
Yield (GC): 70%.
1
H NMR (400 MHz, CDCl ): δ = 3.48–3.21 (m, 3 H), 1.58–1.45 (m, 2 H),
3
1.45–1.28 (m, 4 H), 1.09 (d, J = 6.2 Hz, 3 H), 0.93–0.82 (m, 6 H).
13
C NMR (100 MHz, CDCl ): δ = 76.7, 68.2, 32.4, 29.3, 19.5, 19.3, 14.0,
3
(
(
(
9.9.
1
-(1-Methylpropoxy)octane (3q)
Yield (GC): 55%.
1
H NMR (400 MHz, CDCl ): δ = 3.48–3.39 (m, 1 H), 3.37–3.21 (m, 2 H),
3
1
0
.61–1.45 (m, 2 H), 1.44–1.18 (m, 12 H), 1.14–1.01 (m, 3 H), 0.95–
.77 (m, 6 H).
13
C NMR (100 MHz, CDCl ): δ = 76.7, 68.6, 31.9, 30.3, 29.6, 29.4, 29.3,
3
(
26.4, 26.3, 26.2, 22.7, 19.4, 14.2, 9.9.
2
-Butoxyhexane (3r)
(
Yield (GC): 43%.
1
H NMR (400 MHz, CDCl ): δ = 3.47 (m, 1 H), 3.32 (m, 2 H), 1.58–1.44
3
(m, 2 H), 1.43–1.19 (m, 8 H), 1.11 (d, J = 6.1 Hz, 3 H), 0.94–0.85 (m,
6
H).
13
C NMR (100 MHz, CDCl ): δ = 75.4, 68.3, 36.6, 32.4, 27.9, 22.9, 19.8,
3
(
(
19.5, 14.2, 14.0.
1
-(1-Methylpentyloxy)octane (3s)
(
28) Carreño, M. C.; Des Mazery, R.; Urbano, A.; Colobert, F.; Solladié,
Yield (GC): 43%.
G. J. Org. Chem. 2003, 68, 7779.
1
H NMR (400 MHz, CDCl ): δ = 3.51–3.24 (m, 3 H), 1.59–1.44 (m, 2 H),
(29) Kopecky, D. J.; Rychnovsky, S. D. J. Org. Chem. 2000, 65, 191.
(30) Sakai, N.; Moriya, T.; Konakahara, T. J. Org. Chem. 2007, 72,
5920.
31) Sheldon, R. A. S.; Downing, R. Appl. Catal., A 1999, 189, 163.
32) Liu, Z.; Breit, B. Angew. Chem. Int. Ed. 2016, 55, 8440.
3
1
.42–1.20 (m, 16 H), 1.10 (d, J = 6.1 Hz), 0.96–0.77 (m, 6 H).
13
C NMR (100 MHz, CDCl ): δ = 75.4, 68.6, 36.6, 31.9, 30.3, 29.6, 29.4,
3
(
(
(
28.0, 26.4, 22.9, 22.8, 19.8, 14.2.
33) Dang, Y.; Qu, S.; Wang, Z.-X.; Wang, X. Organometallics 2013, 32,
2804.
Funding Information
(
34) Zhang, Z.; Widenhoefer, R. A. Org. Lett. 2008, 10, 2079.
35) Corma, A.; Ruiz, V. R.; Leyva-Pérez, A.; Sabater, M. J. Adv. Synth.
Catal. 2010, 352, 1701.
(
This work was performed in partnership with the SAS PIVERT within
the frame of the French Institute for the Energy Transition (Institut
pour la Transition Energetique (ITE)) P.I.V.E.R.T. (www.institut-
pivert.com) selected as an Investment for the Future (Inves- tisse-
ments d’Avenir). This work was supported, as part of the Investments
for the Future, by the French Government under reference ANR-001-
(
(
36) Zhang, C.; Sun, P. J. Org. Chem. 2014, 79, 8457.
37) Zhang, S.-Y.; He, G.; Zhao, Y.; Wright, K.; Nack, W. A.; Chen, G.
J. Am. Chem. Soc. 2012, 134, 7313.
(
(
(
38) Zhang, L.-B.; Hao, X.-Q.; Zhang, S.-K.; Liu, K.; Ren, B.; Gong, J.-F.;
Niu, J.-L.; Song, M.-P. J. Org. Chem. 2014, 79, 10399.
39) Hensen, K.; Mahaim, C.; Hölderich, W. F. Appl. Catal., A 1997,
0
1.Fre
n
ch
G
o
v
ern
m
e
nt
n
I
v
estm
e
nst
o
f
r
hte
F
u
uter
A(
N
R-0
0
1-01)
149, 311.
40) Radhakrishnan, S.; Thoelen, G.; Franken, J.; Degrève, J.;
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

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©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H