Heterogeneous palladium-catalyzed synthesis of aromatic ethers by solvent-free dehydrogenative aromatization: Mechanism, scope, and limitations under aerobic and non-aerobic conditions

Article abstract of DOI:10.1002/ejoc.201300485

Starting from cyclohexanone derivatives and alcohols, both non-aromatic precursors, aryl ethers could be synthesized in good yields and with good selectivities in the presence of a catalytic amount of Pd/C, in one step, without added solvent, in a reaction vessel open to air. For less reactive substrates, the addition of 1-octene in a closed system under non-aerobic conditions improved the conversion. In addition, the catalyst could be recycled several times with no decrease in the yield of the aryl ether. The process was also used with tetralone derivatives and polyols. Several reactions were performed to propose a mechanism for this transformation. The formation of an enol ether followed by a dehydrogenation reaction seem to be the key steps of this reaction. Aryl ethers were prepared in good yields and with good selectivities in a solvent-free and heterogeneous catalytic dehydrogenative alkylation of cyclohexanones with various alcohols. Three different complementary routes were used, and for the first time, non-aerobic, safe conditions could be used. Moreover, the catalyst could be recycled several times with no decrease in the yield of the aryl ether. Copyright

Full text of DOI:10.1002/ejoc.201300485

FULL PAPER
DOI: 10.1002/ejoc.201300485
Heterogeneous Palladium-Catalyzed Synthesis of Aromatic Ethers by Solvent-
Free Dehydrogenative Aromatization: Mechanism, Scope, and Limitations
Under Aerobic and Non-Aerobic Conditions
Marc Sutter,[a] Romain Lafon,[a] Yann Raoul,[b] Estelle Métay,[a] and Marc Lemaire*[a]
Keywords: Synthetic methods / Heterogeneous catalysis / Palladium / Dehydrogenation / Arylation / Etherification
Starting from cyclohexanone derivatives and alcohols, both
non-aromatic precursors, aryl ethers could be synthesized in
good yields and with good selectivities in the presence of a
catalytic amount of Pd/C, in one step, without added solvent,
in a reaction vessel open to air. For less reactive substrates,
lyst could be recycled several times with no decrease in the
yield of the aryl ether. The process was also used with tet-
ralone derivatives and polyols. Several reactions were per-
formed to propose a mechanism for this transformation. The
formation of an enol ether followed by a dehydrogenation
the addition of 1-octene in a closed system under non-aero- reaction seem to be the key steps of this reaction.
bic conditions improved the conversion. In addition, the cata-
of phenols and alcohols[10] or alkenes.[11] Examples of te-
lomerization processes with butadiene derivatives have also
Introduction
been reported.[12] Nevertheless, all these synthetic methods
require solvents, toxic substrates, and often a stoichiometric
amount of organic or organometallic reagents, and in many
cases they generate a large amount of waste and unwanted
by-products.
Aryl ethers are molecules with varied biological and
physical properties.[1] They have many applications ranging
from solvents, pharmaceuticals, cosmetics, paints, and var-
nishes to materials. Several of them are produced on an
industrial scale. For example, phenoxypropanol is mainly
used as a solvent, and its world output is estimated to be
tens of thousands of tons each year.[2] However, access to
these compounds is often difficult, and so many methods
for their synthesis have been developed over the last cen-
tury. The great majority of these methods involve aromatic
substrates, an example being the Williamson etherification
between alkyl halides and phenols under basic conditions.[3]
Transition-metal-catalyzed C–O cross-coupling reactions
between aryl halides and alcohols are also highly efficient,
examples being the copper-catalyzed Ullmann synthesis[4]
or the palladium-catalyzed Buchwald–Hartwig reaction.[5,6]
Other methods using arylboronic acid derivatives as sub-
strates (Chan–Lam etherification)[7] or bismuth coupling
reagents[8] have also been described. Aryl ethers can also be
obtained from epoxides[9] or by the catalytic etherification
Alternative routes starting from non-aromatic substrates
could be very attractive to give access to a variety of aryl
ethers with better atom economy. Thus, pioneering work on
the preparation of phenol[13] and aniline[14] derivatives by
dehydrogenation attracted our attention. Until now, only a
few very recent examples of the dehydrogenative arylation
of non-aromatic substrates with alcohols[15,16] or other nu-
cleophiles[17,18] have been reported. The use of molecular
oxygen as oxidant in most of these studies implied a flamm-
ability risk, and the need for solvents, additives, and homo-
geneous catalysts are drawbacks from both environmental
and economic points of view. As part of an ongoing study
into the preparation of glycerol ethers by alternative and
environmentally friendly routes,[19] our group developed a
solvent-free dehydrogenative arylation of readily available
cyclohexanone with alcohols and glycerol in air under
[a] Laboratoire de Catalyse, Synthèse et Environnement, Institut heterogeneous Pd/C catalysis.[20] This preliminary study
de Chimie et Biochimie Moléculaires et Supramoléculaires
gave straightforward and safe access to aryl ethers, but
(ICBMS), CNRS, UMR5246, Université Lyon 1,
some limitations for low boiling point alcohols were no-
ticed. Also, the reaction was less effective with secondary
alcohols and with polyols. This method gave encouraging
results under non-aerobic conditions.
The aim of this work was to extend this method by evalu-
ating other metal sources and also by exploring its scope.
To overcome the observed limitations, we went on to inves-
43 Boulevard du 11 Novembre 1918, Bat CPE,
69622 Villeurbanne, France
E-mail: marc.lemaire.chimie@univ-lyon1.fr
Homepage: http://www.icbms.fr/casyen/lemaire
[b] Sofiprotéol,
11, rue de Monceau, CS 60003, 75378 Paris Cedex 08, France
Homepage: http://www.sofiproteol.com/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300485
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Synthesis of Aromatic Ethers
Scheme 1. Strategies developed in this work for the preparation of 1-O-aryl ethers.
tigate alternative and safe non-aerobic conditions. Comple- ether 3aa were obtained with Ru/Al2O3 and Ru/C, respec-
mentary experiments were also performed to investigate the
reaction mechanism.
tively (Table 1, entries 3 and 4). Around 5 and 6% of hex-
anal (14a) were also otained as a by-product with these ru-
thenium catalysts, formed by dehydrogenation of the start-
ing alcohol, but no phenol was detected. Platinum and irid-
ium catalysts have also been described in the literature[21a,23]
as good catalysts for dehydrogenation, but neither was ef-
ficient for the synthesis of compound 3aa (Table 1, en-
tries 5–7). Finally, supported palladium catalysts were teste-
d.[13i,21b,24] With Pd/SiO2, the conversion of the starting cy-
clohexanone slightly increased, but the reaction also gave
ketal 13aa (Table 1, entry 8). With Pd/Al2O3, only traces of
the desired product were detected (Table 1, entry 9). Palla-
dium on charcoal was also tested at 110 °C, and after 15 h,
the aryl ether was formed in 16% yield (Table 1, entry 10).
At this temperature, enol ether 7aa was observed in 31%
yield. The best result was obtained with 1 mol-% of Pd/C
at 130 °C: the conversion was complete after 24 h, and aryl
ether 3aa was formed in 99% yield (Table 1, entry 11). Un-
der these conditions, no by-products (phenol or ketal) were
formed. The palladium played a key role in this transforma-
tion, both in the formation of enol ether 7aa and in the
dehydrogenation reaction to product 3aa, because a very
low conversion was observed when the reaction was per-
formed with 20 wt.-% of activated charcoal (Table 1, en-
try 12). In this experiment, only 7% of enol ether 7aa was
observed. Without any catalyst, no reaction was seen
(Table 1, entry 13). Thus, palladium on charcoal was used
when optimizing the other reaction parameters.
Thus, in this paper we report three different pathways for
the preparation of aryl ethers (Scheme 1). On the one hand,
we have explored the scope of the dehydrogenative arylation
in an open reaction vessel (A), and on the other hand, we
have developed non-aerobic conditions with cyclohexanone
derivatives (B) and tetralone derivatives (C).
Results and Discussion
Optimization of the Experimental Parameters
Based on preliminary results for the preparation of aryl
ethers,[20] the reaction between cyclohexanone derivatives
and alcohols was optimized by evaluating the influence of
the different experimental parameters. To define the best
conditions, supported metal catalysts (Table 1) known for
their efficiency in hydrogen-transfer reactions, were consid-
ered first. The dehydrogenative arylation of cyclohexanone
(2a) with hexanol (1a) in a 1:5 molar ratio at 130 °C was
investigated as a model reaction. The reaction was achieved
with 1 mol-% of metal catalyst in an open reaction vessel.
The nature of the catalyst’s solid support and of the metal
were both considered. When the reaction was performed
with rhodium catalysts (Rh/Al2O3 and Rh/C), conversions
were low, and only traces of the desired aryl ether (i.e., 3aa;
Table 1, entries 1 and 2) were detected, despite the reported
effectiveness of these catalysts in dehydrogenation reac-
The best conversions and selectivities were obtained
tions.[21] Ruthenium catalysts are also employed in such when reactions were performed with hexanol (1a) and cy-
transformations.[21a,22] However, only 4 and 7% yields of clohexanone (2a) in an open reaction vessel at 130 °C with
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M. Sutter, R. Lafon, Y. Raoul, E. Métay, M. Lemaire
Table 1. Catalyst screening for the dehydrogenative alkylation of cyclohexanone (2a) with hexanol (1a).[a]
FULL PAPER
Entry
Catalyst
Temp. [°C]
Conv. of 2a [%][b]
Yield [%][b]
7aa
3aa
13aa
14a
1
2
3
4
5
6
7
8
Rh/Al2O3 (5%)
Rh/C (5%)
Ru/Al2O3 (5%)
Ru/C (5%)
Pt/C (10%)
Pt/Al2O3 (5%)
Ir/C (1%)
Pd/SiO2 (5%)
Pd/Al2O3 (5%)
Pd/C (5%)
Pd/C (5%)
carbon[c]
130
130
130
130
130
130
130
130
130
110
130
130
130
4
9
8
10
5
4
Ͻ1
20
3
47
Ͼ99
9
3
3
4
7
4
4
0
11
2
16
99
0
0
Ͻ 1
0
2
Ͻ 1
0
0
2
0
31
0
0
Ͻ 1
0
0
0
0
0
6
0
0
0
Ͻ 2
0
3
1
5
6
0
0
0
Ͻ 1
Ͻ 1
Ͻ 1
Ͻ 1
0
9
10
11
12
13
7
Ͻ 2
–
Ͻ2
0
0
[a] Conditions: molar ratio cyclohexanone (2a)/hexanol (1a) = 1:5, catalyst (1 mol-%), 130 °C, 24 h, open reaction vessel. [b] Conversions
1
and yields were determined by H NMR spectroscopy. [c] 20 wt.-%.
1 mol-% of Pd/C (Table 1, entry 11). Lower reaction tem- and ether 3aa was formed in quantitative yield (Table 2, en-
peratures or lower catalyst loadings resulted in lower con- try 2). With a molar ratio of 1:10, the conversion dropped
versions. When 0.5 mol-% of Pd/C was used, a 60% conver- again to 67% (Table 2, entry 3).
sion was obtained after 24 h. The reaction conditions with
1 mol-% of Pd/C at 130 °C were used for further optimiza- vessels under the optimized conditions in order to under-
tion studies. stand the role of oxygen from air. As shown in Table 3 and
Finally, experiments were performed in different reaction
The arylation of cyclohexanone (2a) with hexanol (1a) Figure 1, when the reaction was performed in a sealed tube
was performed in the absence of solvent. The effect of under argon, the conversion was complete after 24 h, but a
changing the molar ratio between the two reactants was 50:50 mixture of aryl ether 3aa and cyclohexyl ether 4aa
studied (Table 2). To minimize the environmental impact of was formed (Table 3, entry 1). This result can be explained
the process, the ratio should be kept as high as possible. At by the release of H2 in the dehydrogenation of the interme-
a high concentration of cyclohexanone (2a) in hexanol (1a), diates formed during the reaction. To test this hypothesis,
the conversion was close to 70% after 24 h, and ether 3aa reactions were performed in non-aerobic conditions in se-
was obtained in 59% yield (Table 2, entry 1). The formation aled tubes with an alkene additive as a hydrogen scavenger.
of phenol was observed in this case. When the reactants With 1 equiv. of the additive, the selectivity for ether 3aa
were used in a ratio of 1:5, the conversion was complete, increased to 70% (Table 3, entry 2), and with 1.3 equiv. the
Table 2. Effect of the molar ratio of cyclohexanone (2a) to hexanol (1a) on the dehydrogenative alkylation reaction.[a]
Entry
Ratio 2a/1a
Conv. of 2a [%][b]
Yield of 3aa [%][b]
1
2
3
1:2
1:5
1:10
70
Ͼ 99
67
59
99
65
1
[a] Conditions: Pd/C (5%; 1 mol-%), 130 °C, 24 h, open reaction vessel. [b] Conversions and yields were determined by H NMR spec-
troscopy.
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Synthesis of Aromatic Ethers
Table 3. Effect of the type of reaction vessel, the atmosphere, and an additive (1-octene) on the arylation reaction of hexanol (1a) with
cyclohexanone (2a).[a]
Entry
Reaction vessel
Additive
Conversion of 2a [%][b]
Ratio [%][b]
3aa
4aa
1
2
3
4
5
6
7
sealed tube (Ar)
sealed tube (Ar)
sealed tube (Ar)
sealed tube (Ar)
sealed tube (Ar)
open reaction vessel (air)
sealed tube (O2)
–
Ͼ 99 (24 h)
Ͼ 99 (36 h)
Ͼ 99 (36 h)
Ͼ 99 (36 h)
50
70
89
99
99
99
15
50
30
11
Ͻ 1
Ͻ 1
0
1-octene (1 equiv.)
1-octene (1.3 equiv.)
1-octene (2 equiv.)
methyl oleate (2 equiv.) Ͼ 99 (48 h)
–
–
Ͼ 99 (24 h)
38 (24 h)
23
1
[a] Conditions: Pd/C (5%; 1 mol-%), 130 °C, 24 h. [b] Conversions and yields were determined by H NMR spectroscopy.
Figure 1. 1H NMR spectra of the crude product mixture from the dehydrogenative arylation of cyclohexanone (2a) with hexanol (1a)
after complete conversion in a sealed tube (a) without any additive (Table 3, entry 1), (b) with 1 equiv. of 1-octene (Table 3, entry 2),
(c) with 1.3 equiv. of 1-octene (Table 3, entry 3), (d) with 2 equiv. of 1-octene (Table 3, entry 4), and (e) in an open reaction vessel without
any additive (Table 3, entry 5).
product was formed in 89% yield (Table 3, entry 3). When under an oxygen atmosphere (Table 3, entry 7), which
2 equiv. of 1-octene was used, the yield of aryl ether 3aa was means that a different mechanism is probably operating. In
quantitative (Table 3, entry 4). When the biosourced methyl a sealed tube with an alkene, longer reaction times were
oleate (2 equiv.) was used as the hydrogen acceptor, the needed for complete conversion. This decrease in the reac-
same result were observed, but a longer reaction time was tion rate can be explained as being due to the lower concen-
needed to reach complete conversion (Table 3, entry 5). Oct- tration of both substrates in the reaction medium. When the
ane or methyl stearate was observed as the product of re- temperature was increased to 150 °C, the conversion was
duction, which confirmed that H2 had been released in mo- complete after 16 h with 1-octene. As can be seen from the
lecular form or adsorbed on the surface of the catalyst. A 1H NMR spectra of the crude product mixture after com-
similar result was observed without any additive under aer- plete conversion of the starting cyclohexanone (2a) (Fig-
obic conditions in a reaction vessel open to air (Table 3, ure 1), the selectivity for the formation of the aromatic
entry 6). In this case, the O2 from air consumed the hydro- product (i.e., 3aa) is linked to the quantity of alkene added
gen, and water was formed as sole by-product of the reac- to the reaction mixture.
tion. Surprisingly, and contrary to literature reports with
Consequently, two optimal sets of conditions for the
homogeneous catalysts,[16,18] the reaction was not efficient preparation of aromatic ethers starting from non-aromatic
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Scheme 2. Optimized conditions for the preparation of 1-O-aryl ethers: (A) under air in an open reaction vessel and (B) under argon in
a sealed tube, with 1-octene as additive.
precursors were considered (Scheme 2). First, hexanol (1a; nation. Very recently, he also demonstrated that reactive
5 equiv.) was heated with cyclohexanone (2a; 1 equiv.) at soluble Pd nanoparticles are formed during the reaction.[13]
130 °C with Pd/C (5%; 1 mol-%) in a reaction vessel open However, as we observed (Table 3, entry 7), our reaction
to air. In a second system, hexanol (1a) was mixed with was inefficient under O2 with heterogeneous Pd/C.[13j] With
cyclohexanone (2a) in a 5:1 molar ratio at 150 °C with Pd/ a copper complex, Li[16a] proposed that an enol ether as
C (5%; 1 mol-%) and 1-octene (2 equiv.) in a sealed tube formed with the elimination of water. In our study, several
under an argon atmosphere. As reported below, the two sys- observations prompted us to propose mechanisms for the
tems [under air without an additive (conditions A), and un- reactions under conditions A and B and also to explain the
der argon with 1-octene (conditions B)] were complemen- formation of saturated ether 4 (Scheme 3). First, in all three
tary for the preparation of various aryl ethers.
of the pathways, the palladium(0) on carbon activates the
carbonyl functionality, leading to the formation of hemi-
acetal 7, which is dehydrated to give enol ether 8. Indeed,
at low conversion, a mixture of compound 8 and the desired
Mechanism
Stahl[13f] proposed a mechanism for the formation of aryl ether (i.e., 3) was observed in the reaction mixture by
phenols from cylohexanone under an O2 atmosphere cata- GC–MS (see Supporting Information for details). The
lyzed by a homogeneous palladium(II) catalyst. A C–H ac- mechanism could be slightly different from that reported in
tivation α to the carbonyl by the metal is supposed to be the literature for a reaction under homogeneous condi-
the first step, and this is followed by a β-hydride elimi- tions.[13f,16a] Thus, we presume that the dehydrogenation
Scheme 3. Proposed mechanism for the dehydrogenative arylation of a cyclohexanone derivative 2 with an alcohol 1 (A) under aerobic
conditions and (B) in a closed system with an additive.
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Synthesis of Aromatic Ethers
proceeds on the palladium-supported carbon surface. In a mediate enol ether 8 is also dehydrogenated to the aromatic
reaction vessel open to air, this intermediate is then dehy- product 3 with excellent selectivity, and at the same time,
drogenated twice to give aryl ether 3. Under these aerobic the 1-octene is completely hydrogenated to give octane.
conditions, the H2 adsorbed on the Pd/C catalyst surface is
quickly consumed by O2 from air, and water is formed as
the sole by-product of the reaction. When cyclohexanone
(2a) was subjected to the optimized reaction conditions
Reaction with Different Cyclohexanone Derivatives
without any alcohol, phenol (5a) was observed as major
The two optimal sets of reaction conditions [i.e., under
product, formed by dehydrogenation. This by-product was air without additive (conditions A) and under argon with
also observed when reactions were carried out with less re- 1-octene (conditions B)] were compared for the dehydro-
active alcohols as substrates. In a sealed tube without a hy- genative arylation of various alcohols with cyclohexanone
drogen acceptor, intermediate enol ether 8 is partially hy- (2a), as shown in Table 4. The first system efficiently gave
drogenated by the released H2 in the reaction mixture to aryl ethers 3aa, 3ba, and 3ca, derived from high boiling
give ether 4, as shown in Table 3, entry 1. Finally, in a point primary alcohols, in good isolated yields (Table 4, en-
closed system with the required 2 equiv. of 1-octene, inter- tries 1–3).[20] However, the process in an open reaction ves-
Table 4. Dehydrogenative arylation of cyclohexanone (2a) with primary alcohols, secondary alcohols, and polyols.
[a] Conditions: molar ratio cyclohexanone (2a)/alcohol 1 = 1:5, Pd/C (5%; 1 mol-%), 130 °C, open reaction vessel. [b] Conditions: molar
ratio cyclohexanone (2a)/alcohol 1 = 1:5, Pd/C (5%; 1 mol-%), 1-octene (2 equiv.), 150 °C, sealed tube (argon). [c] Conversions were
determined by 1H NMR spectroscopy, reaction times in parentheses. [d] Yields from 1H NMR spectroscopy in parentheses. [e] Conditions:
molar ratio cyclohexanone (2a)/glycerol (1i) = 1:20, Pd/C (5%; 2 mol-%), 130 °C, 60 h, open reaction vessel. [f] Ratio between 3ha and
1
3haЈ was determined by H NMR spectroscopy.
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M. Sutter, R. Lafon, Y. Raoul, E. Métay, M. Lemaire
FULL PAPER
sel involved a reaction temperature of 130 °C, which was selectivity for aryl glycerol ether 3ia, the molar ratio of cy-
not suitable for lower boiling point alcohols. Thus, with 2- clohexanone/glycerol and the amount of Pd/C catalyst were
methylpropan-1-ol (1d; b.p. = 108 °C), the conversion was reconsidered (Table 5, entries 1–8). At high molar ratios of
around 78%, and the corresponding aryl ether (i.e., 3da) 1:2 and 1:5, the conversion was complete after 72 h, but the
was isolated in a moderate 55% yield (Table 4, entry 4). Un- selectivity for the desired aryl ether (i.e., 3ia) was low, and
der conditions B in a closed system, this limitation was phenol was obtained as the major reaction product
overcome, the conversion was complete, and a good isolated (Table 5, entries 1 and 2). Product 3ia was obtained in 51%
yield of the desired ether (i.e., 3da) was obtained (Table 4, yield when a lower ratio of 1:10 was used (Table 5, entry 3).
entry 4). The aerobic dehydrogenative arylation with less re- When the catalyst loading was increased to 2 and 4 mol-%,
active secondary alcohols [2-hexanol (1e) and cyclohexanol the yield of the desired ether (i.e., 3ia) also increased to 59
(1f)] gave the aromatic products (i.e., 3ea and 3fa) in 34 and and 64% respectively (Table 5, entries 4 and 5). The best
32% isolated yields, respectively (Table 4, entries 5 and 6). results were obtained with a molar ratio of 1:20 and above,
These lower yields can be explained by the formation of and under these conditions, aryl ether 3ia was formed in
phenol as the sole by-product in 54 and 50% yields (from 77% yield (Table 5, entries 6–8). When the reaction time
NMR spectroscopy), and by the volatility of product 3fa.
was decreased to 60 h under these optimized conditions, the
It is interesting to note that the selectivity for aryl ethers results were unchanged (Table 5, entry 9). However, acetal
3ea and 3fa (from secondary alcohols) was improved under 6ia was obtained in a higher yield after 48 h (Table 5, en-
conditions B. Indeed, less than 10% of phenol was observed try 10) and it was detected in 36% yield after 24 h (Table 5,
in each example, but the reactions required longer times to entry 11). Under non-aerobic conditions without an addi-
reach complete conversion. The reaction with ethylene tive, only acetal 6ia was formed (Table 5, entry 12). Finally,
glycol (1g) under aerobic conditions gave the corresponding a reaction under conditions B with 1-octene as additive was
aromatic ether (i.e., 3ga) in 43% isolated yield (Table 4, en- tested, however, the reaction was very slow, and only 15%
try 7). With propylene glycol (1h), a mixture of regioisomers of compound 3ia was observed after a reaction time of 72 h.
3ha and 3haЈ was obtained in 40% isolated yield in a ratio These results led us to conclude that in the case of glycerol,
of 61:39 (Table 4, entry 8). In both cases, phenol was also a slightly different mechanism was operating, as outlined in
obtained as the only by-product in 42 and 41% yields, Scheme 4. We supposed that acetal 6ia was first formed in
respectively. Finally, when glycerol, a bio-sourced polyol, the reaction. Then, enol ether 7ia was generated by hydro-
was used, the experimental parameters had to be reconsid- gen transfer, and finally the equilibrium was shifted towards
ered. Under aerobic conditions, the desired aryl ether (i.e., the formation of the final aryl ether (i.e., 3ia) by aromatiza-
3ia) was isolated in 67% yield with excellent regioselectivity, tion under aerobic conditions.
since no 2-O-aryl ether was detected (Table 4, entry 9). The
To validate this hypothesis, the conversion was investi-
reaction was slow under conditions B, and it led to the cor- gated as a function of time. This showed that intermediate
responding product in only 15% yield after 72 h; acetal 6ia 6ia was formed very quickly, before being progressively con-
was obtained as the major product. Thus, to improve the verted into the desired phenoxy glycerol (i.e., 3ia; Figure 2).
Table 5. Optimization of the reaction parameters for the dehydrogenative arylation of cyclohexanone (2a) with glycerol (1i).[a]
Entry Reaction time
[h]
Pd/C
[mol-%]
Ratio
Conversion of
Yield [%][b]
Acetal 6ia [%]
cyclohexanone (2a)/glycerol (1i)
2a [%][b]
Phenol (5a) [%]
Aryl ether 3ia [%]
1
2
3
4
5
6
7
8
72
72
72
72
72
72
72
72
60
48
24
24
72
2
2
1
2
4
2
2
2
2
2
2
2
1
1:2
1:5
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
97
38
42
20
25
31
19
18
19
19
18
8
32
25
29
16
5
5
7
4
4
11
36
99
85
31
33
51
59
64
76
75
77
77
71
54
Ͻ1
15
1:10
1:10
1:10
1:20
1:30
1:40
1:20
1:20
1:20
1:20
1:5
9
10
11
12[c]
13[d]
Ͼ99
Ͼ99
Ͻ1
Ͻ1
[a] Reaction in an open reaction vessel (air). [b] Conversions and yields were determined by 1H NMR spectroscopy. [c] Reaction in a
sealed tube (argon) without additive. [d] Reaction under conditions B, with 1-octene (2 equiv.) as additive.
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Synthesis of Aromatic Ethers
Scheme 4. Proposed mechanism for the dehydrogenative arylation of cyclohexanone (2a) with glycerol (1i) under aerobic conditions A.
Figure 2. Left: Reaction of cyclohexanone (2a) with glycerol (1i) under the optimized conditions (Table 5, entry 9). Right: GC–MS chro-
matogram of the crude product mixture obtained from the dehydrogenative arylation of cyclohexanone (2a) with glycerol (1i) after 48 h
(the excess glycerol was removed by extraction).
A GC–MS chromatogram of the crude product mixture af-
ter a 48 h reaction time showed that phenol was the only tionalized aryl ethers from cyclohexanone derivatives was
by-product formed in this reaction. evaluated under both conditions A and B (Table 6). The
To study the scope of this method, the synthesis of func-
The synthesis of a diphenyl ether was also studied, start- reaction of hexanol (1a) with 2-cyclohexenone (2b) under
ing from cyclohexanone and phenol (Scheme 5). Under aer- aerobic conditions gave aryl ether 3aa in 59% isolated yield,
obic conditions, less than 10% of diphenyl ether 5a2a was but phenol was formed as a by-product in the reaction. Un-
detected after 48 h, but rather phenol (5a) was obtained as der conditions B, the selectivity for the desired aryl ether
major product. Performing the reaction under conditions B (i.e., 3aa) was slightly improved, and it was formed in 63%
did not improve the yield.
isolated yield (Table 6, entry 1). From cyclohexanone deriv-
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atives such as 4-methylcyclohexanone (2c), 2-methylcyclo-
hexanone (2d), and 3-methylcyclohexanone (2e), the results
were surprisingly different for each substrate under aerobic
conditions. Product 3ac was isolated in 58% yield without
complete conversion of the starting material, whereas ethers
3ad and 3ae were isolated in 62 and 81% yields, respectively
(Table 6, entries 2–4). These differences could be due to a
difference in the conformations of the enol intermediates in
the three cases, with the methyl group in different positions.
Under non-aerobic conditions B, no difference between
these three substrates was observed, and complete conver-
sions and isolated yields of the aryl ethers of around 86%
Scheme 5. Dehydrogenative arylation of cyclohexanone (2a) with
phenol (5a). Conditions (A): molar ratio cyclohexanone (2a)/
phenol (5a) = 1:5, Pd/C (5%; 1 mol-%), 130 °C, 60 h, open reaction
vessel. Conditions (B): molar ratio cyclohexanone (2a)/phenol (5a)
= 1:5, Pd/C (5%; 1 mol-%), 1-octene (2 equiv.), 150 °C, 60 h, sealed
tube.
Table 6. Dehydrogenative alkylation of hexanol (1a) with various cyclohexanones 2 and non-aromatic substrates.
[a] Conditions: molar ratio substituted cyclohexanone 2/hexanol (1a) = 1:5, Pd/C (5%; 1 mol-%), 130 °C, open reaction vessel. [b] Condi-
tions: molar ratio substituted cyclohexanone 2/alcohol = 1:5, Pd/C (5%; 1 mol-%), 1-octene (2 equiv.), 150 °C, sealed tube (argon).
[c] Conversions were determined by 1H NMR spectroscopy, reaction times in parentheses. [d] Yields from 1H NMR spectroscopy in
parentheses. [e] See text and Scheme 6 for analysis of the by-products.
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Synthesis of Aromatic Ethers
Scheme 6. Proposed pathways for the formation of by-products 3aj1 and 3aj2 when starting from 2j (Table 6, entry 9).
were observed in all cases (Table 6, entries 2–4). The process anol can be exchanged under these conditions, as outlined
was also efficient with tetrahydrothiophen-3-one (2f), which in Scheme 6. A different result was also obtained for the
gave aryl ether 3af in 56% yield under aerobic conditions; dehydrogenative alkylation of 1,4-cyclohexanone (2l) with
the rate of the reaction was lower under argon (Table 6, hexanol (1a). Under conditions A, a mixture of monoether
entry 5). The reaction with 2-methyltetrahydrofuran-3-one 3al and diether 3alЈ was obtained in good overall yield,
(2g) was inefficient under conditions A. Under conditions whereas dialkylated compound 3alЈ was isolated as the
B, a complex mixture of by-products was formed, however, major product in 82% yield under non-aerobic conditions
33% of the desired product (i.e., 3ag) was detected (Table 6, (Table 6, entry 11).
entry 6). In the presence of more hindered or substituted
substrates such as 2,6-dimethylcyclohexanone (2h), 4-tert-
butylcyclohexanone (2i), 2-ethoxycyclohexanone (2j), and
l-menthone (2k), the reaction was ineffective under aerobic
Adaptation of the Method to Tetralone Derivatives
conditions (Table 6, entries 7–10). In contrast, aryl ethers
The transformation was also tested with tetralone deriva-
3ah, 3ai, and 3ak were isolated in 82, 95, and 96% yields tives. The dehydrogenative arylation of α-tetralone (2m)
under conditions B (Table 6, entries 7, 8, and 10). In the with hexanol (1a) under aerobic conditions A was not com-
case of 4-tert-butylcyclohexanone (2i), the ineffectiveness of plete after 24 h. But the conversion improved to 95% when
the reaction in an open reaction vessel could be explained the reaction was carried out in a sealed tube under non-
by a conformational blocking effect by the tert-butyl moi- aerobic conditions but without any alkene. In contrast to
ety. In a closed system, the higher reaction temperature, as the cyclohexanone derivatives, the selectivity for the desired
well as the presence of an alkene resulting in a rapid con- naphthyl ether (i.e., 3am) was excellent, and only traces of
sumption of hydrogen, may overcome this effect. The sole saturated ether 4am could be detected. The only by-prod-
limitation of the method that we found was with substrate ucts observed by GC–MS analysis were products of degra-
2j: only 48% conversion was observed after 120 h, and the dation of the starting material (Figure 3). When the reac-
desired ether (i.e., 3aj) was obtained in only 7% yield tion was performed at 150 °C, complete conversion was ob-
(Table 6, entry 9). This result was explained by the forma- served after 16 h, and when 1 equiv. of 1-octene was added
tion of 1,2-bis(hexyloxy)benzene 3aj1 as the major product to the mixture (i.e., conditions B), its total conversion into
in 24% yield after two consecutive additions of hexanol fol- octane was also observed, which confirms that 1 equiv. of
lowed by dehydrogenation of the ring. The reaction gave molecular hydrogen was released in the reaction. As shown
also 2-(hexyloxy)cyclohexanone 3aj2 in 16% yield. The for- in Scheme 7, we may conclude that the aromatization of
mation of these two by-products was certainly due to the the intermediate enol ether 14 was easier for the tetralone
low reaction rate, resulting from the low electrophilicity of derivatives as only one dehydrogenation step was needed.
the carbonyl functionality of substrate 2j. Indeed, the pres-
To test the versatility of this method, various alcohols
ence of an ethoxy group at position 2 certainly facilitates were tested in reactions with α-tetralone (2m) in a closed
the formation of the enol form and stabilizes it. Also, eth- reaction vessel without additive (Table 7). Experiments were
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Figure 3. GC–MS chromatogram of the reaction mixture in the dehydrogenative alkylation of α-tetralone (2m) with hexanol (1a) after a
reaction time of 16 h at 150 °C in a sealed tube under argon.
3cm were isolated in 67 and 75% yields, respectively. The
reaction was also efficient with low boiling point alcohols
such as ethanol (1j) and 2-methylpropanol (1d). The desired
products (i.e., 3jm and 3dm) were obtained in 53 and 71%
isolated yields, respectively. In the presence of fatty alcohols
like decanol (1k) and 2-nonylundecan-1-ol (1l), longer reac-
tion times were required, and the dehydrogenative arylation
finally gave products 3km and 3lm in 75 and 68% isolated
yields, respectively. Finally with bio-sourced tetrahydrofur-
furyl alcohol (1m), some complex by-products were ob-
served, but the desired naphthyl ether (i.e., 3mm) was iso-
lated in 43% yield. An experiment with a less reactive sec-
ondary alcohol 1f was also run, and the reaction gave the
product (i.e., 3fm) in 46% isolated yield. The reaction with
ethylene glycol (1g) was efficient, and the corresponding
aromatic ether (i.e., 3gm) was formed in 62% isolated yield.
With propylene glycol (1h), a mixture of regioisomers 3hm
and 3hmЈ was obtained in 49% overall yield, and a better
selectivity for the primary ether was observed (86:14). Fi-
nally, bio-sourced polyols glycerol (1i) and diglycerol (1n)
reacted with α-tetralone (2m) to give the corresponding
naphthyl ethers (i.e., 3im and 3nm) in 48 and 43% isolated
yields, respectively. Next, we explored the scope of the dehy-
Scheme 7. Proposed mechanism for the dehydrogenative alkylation
drogenative arylation of tetralone derivatives with hexanol
of a tetralone derivative with an alcohol.
(1a). The presence of a methoxy or two methyl groups on
the aromatic ring did not affect the efficiency of the reac-
tion, and products 3an and 3ao were isolated in 68 and 65%
yields, respectively. With 6-hydroxy-α-tetralone (2p), the
selectivity slightly decreased, and the desired naphthyl ether
carried out with linear or branched primary alcohols with
different alkyl chain lengths. For hexanol (1a) and 3-meth-
ylbutanol (1c), the corresponding naphthyl ethers 3am and
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Synthesis of Aromatic Ethers
Table 7. Dehydrogenative alkylation of α-tetralones with primary (i.e., 3ar) with a better selectivity. The sole by-product ob-
alcohols, secondary alcohols and polyols.[a]
served was the saturated ether (i.e., 4ar), which was formed
in a very small amount. This could be due to the more
electrophilic character of the carbonyl group of β-tetralone
(2r).
Thus, for hexanol (1a), dehydrogenative arylation with β-
tetralone (2r) gave product 3ar in 80% isolated yield
(Table 8). A similar result was observed with 3-methylprop-
anol (1c), and the naphthyl ether (i.e., 3cr) was isolated in
89% yield. With less reactive substrates like cyclohexanol
(1f) and ethylene glycol (1g), the desired ethers (i.e., 3fr and
3gr) were obtained in 63 and 66% isolated yields, respec-
tively. With propylene glycol (1h), a mixture of ethers 3hr
and 3hrЈ was obtained in 79% overall yield, but in this case,
the selectivity between the two regioisomers was around
76:24. Finally, the reactions with glycerol (1i) and diglycerol
(1n) as solvent and reagent gave the corresponding ethers
(i.e., 3ir and 3nr) in 69% and 52% yields, respectively.
Table 8. Dehydrogenative alkylation of β-tetralone (2r) with pri-
mary alcohols, secondary alcohols, and polyols.[a]
[a] Conditions: molar ratio α-tetralone 2m–2q/alcohol 1 = 1:5, Pd/
[a] Conditions: molar ratio β-tetralone (2r)/alcohol 1 = 1:5, Pd/C
(5%; 1 mol-%), 150 °C, sealed tube (argon). 1H NMR yields in pa-
rentheses. [b] Reaction time 16 h. [c] Reaction time 36 h. [d] Reac-
tion time 60 h. [e] Ratio between 3hr and 3hrЈ was determined by
1H NMR spectroscopy.
1
C (5%; 1 mol-%), 150 °C, sealed tube (argon). H NMR yields in
parentheses. [b] Reaction time: 16 h. [c] Reaction time: 36 h. [d] Re-
action time: 60 h. [e] Ratio between 3hm and 3hmЈ was determined
1
by H NMR spectroscopy.
(i.e., 3ap) was isolated in 47% yield. In the case of 4-methyl-
α-tetralone (2q), the reaction gave compound 3aq in 63%
yield.
Catalyst Recycling and Leaching Experiments
One of the main advantages of this process from both
To complete this study, the reaction between β-tetralone environmental and economic points of view is that the
(2r) and hexanol (1a) was also considered. Under the opti- heterogeneous Pd/C catalyst could potentially be recycled.
mized conditions developed for α-tetralone derivatives, the
Therefore, a series of reactions were carried out with α-
dehydrogenative alkylation gave the desired naphthyl ether tetralone (2m) and hexanol (1a) with the same recycled cat-
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M. Sutter, R. Lafon, Y. Raoul, E. Métay, M. Lemaire
FULL PAPER
alyst following a simple procedure. After each run, the reac- derivatives in one step, catalyzed by a heterogeneous and
tion mixture was diluted with a mixture of CH2Cl2 and recyclable Pd/C catalyst. Several experiments were per-
methanol and then filtered. The Pd/C catalyst was then formed to propose mechanisms for each of the procedures,
transferred into a sealed tube and left under an argon flow and the key intermediate in this transformation seems to be
for 2 h at room temperature in order to remove traces of an enol ether, which is dehydrogenated to give the aromatic
solvent. The two substrates, hexanol and α-tetralone, were product. In the specific case of glycerol, monitoring the re-
added to the catalyst to start a new reaction. The Pd/C was action demonstrated that an acetal was formed first before
recycled four times with no decrease in the yield of the de- being progressively converted into the desired aryl ether.
sired naphthyl ether (i.e., 3am), as shown in Figure 4. In-
Aerobic and non-aerobic conditions were complemen-
deed, after each run, the reaction led to product 3am with tary for the preparation of aryl ethers in good yields and
an unchanged yield of 80%. To check whether the palla- with good selectivities. The limitations observed under aer-
dium was leached into the reaction solvent at high tempera- obic conditions in our preliminary study[20] with low boiling
ture, resulting in homogeneous catalysis, the crude product points alcohol and less reactive substrates could be over-
mixture from the dehydrogenative alkylation of α-tetralone come in most cases when the reaction was performed in
(2m) with hexanol (1a) was filtered through a Millipore fil- non-aerobic conditions with an alkene as additive, but the
ter at 60–80 °C, following a slightly modified procedure (see reaction rate was often lower. Molecular oxygen was not
Supporting Information for details). Then, a new reaction necessary for these methods, and so flammability risks and
was carried out in another reaction vessel at 150 °C for 15 h the use of adapted reaction vessels could be avoided.
without catalyst but with additional β-tetralone (2r) to
The method was also applicable to the reactions of poly-
clearly distinguish product 3am (formed from 2m) from ols, such as glycerol or diglycerol, and of tetralone deriva-
1
product 3ar (which could be formed from 2r) by H NMR tives (without an additive), thus giving easy access to a wide
and GC–MS analysis. Even when 20 wt.-% of carbon was range of aryl and naphthyl ethers. Thus, this process is a
added as a support for the possible homogeneous palla- safe and straightforward alternative to existing methods for
dium leached into the solvent, no conversion into naphthyl C–O bond formation in organic synthesis. Further investi-
ether 3ar was observed. We may conclude that if palladium gations are in progress to extend this transformation to
is leached in the medium, only a very small amount is re- other nucleophiles.
leased. Moreover, an ICP (inductively coupled plasma) MS
analysis of the crude product mixture after removal of the
catalyst revealed no significant amount of palladium Experimental Section
(Ͻ10 ppm). In fact, as had previously been observed with
General Remarks: All reagents were used as received from commer-
cyclohexanone (Table 1, entries 12 and 13), only enol ether
cial suppliers. Alcohols, cyclohexanones, and tetralone derivatives
14ar was formed in these reactions by addition of the hexa-
were supplied by Acros, Sigma–Aldrich, Alfa Aesar, and TCI.
nol to the β-tetralone (2r) followed by dehydration at high
temperature. Product 14ar was formed in 8% yield in the
reaction without added carbon, and in 31% yield when 20
wt.-% of charcoal was added (See Supporting Information
for details).
Glycerol (99%, Reagentplus®) was purchased from Sigma–Ald-
rich, Diglycerol (80%) from TCI, and Pd/C (5% on activated car-
bon, reduced and dry; Escat 1431) from Strem Chemicals. GC–MS
analysis was performed on a Focus GC instrument equipped with
a DB-5MS capillary column (30 m, 0.25 mm, i.d. 0.25 μm) and
using a DSQ mass spectrometer as a detector. The carrier gas was
helium, and the flow rate was 1 mL/min. The column temperature
was initially 70 °C for 2 min, then this was gradually increased to
310 °C at 15 °C/min and finally kept at 310 °C for 10 min. The
injector temperature was 220 °C, and the transfer-line temperature
was 280 °C. For GC–MS detection, an electron ionization system
was used, and the mass analyzer was a simple quadrupole.
General Procedures
Procedure A: The alcohol (15 mmol) was put into a round-bot-
tomed flask equipped with a condenser fitted with a CaCl2 drying
tube, and the cyclohexanone derivative (3 mmol) was added. Next,
Pd/C (5%; 64 mg, 0.03 mmol, 1 mol-%) was added to the mixture.
The mixture was stirred at 130 °C at 800 rpm for 24–60 h, de-
pending on the substrate. Then CH2Cl2 was added, and the mixture
was filtered (Millipore Durapore filter 0.01 μm). The solvent was
evaporated from the filtrate under reduced pressure, and the crude
product was purified by silica column chromatography (cyclohex-
ane/ethyl acetate, 100:0–1:1) to give the desired aromatic ether.
Figure 4. Catalyst recycling experiments (Pd/C) for the dehydro-
genative arylation of α-tetralone (2m) and hexanol (1a). Condi-
tions: molar ratio α-tetralone (2m)/hexanol (1a) = 1:5, Pd/C (5%;
1 mol-%), 150 °C, 16 h, sealed tube (argon).
Procedure B: Procedure A was followed, but instead of a round-
bottomed flask, a sealed tube was used under an inert argon atmo-
sphere, and 1-octene (2 equiv.) was added. The mixture was stirred
Conclusions
In summary, three sets of reaction conditions have been
developed for the arylation of alcohols with cyclohexanone at 150 °C at 800 rpm for 16–96 h, depending on the substrate.
5914 Eur. J. Org. Chem. 2013, 5902–5916
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Synthesis of Aromatic Ethers
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Acknowledgments
The authors warmly thank Sofiprotéol for financial support and
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.
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Received: April 4, 2013
Published Online: July 30, 2013
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5902–5916