Catalytic aerobic synthesis of aromatic ethers from non-aromatic precursors

Article abstract of DOI:10.1002/anie.201200698

Only little waste: Aryl ether formation is accomplished by oxidative condensation of alcohols and 2-cyclohexenones. The reaction complements the existing methods used by synthetic chemists to obtain aryl ethers, and allows a straightforward access to a wide range of functionalized products. In addition, the catalytic reaction with O₂ as the oxidant generates water as the only by-product and provides a greener approach to aryl ethers. Copyright

Full text of DOI:10.1002/anie.201200698

Angewandte
Chemie
DOI: 10.1002/anie.201200698
Aryl Ether Formation
Catalytic Aerobic Synthesis of Aromatic Ethers from Non-Aromatic
Precursors**
Marc-Olivier Simon, Simon A. Girard, and Chao-Jun Li*
Aryl ethers are ubiquitous compounds and intermediates
widely used in the synthesis of dyes, cosmetics, materials,
fragrances, plant protection agents, stabilizers for plastics,
natural products, and pharmaceuticals.[1] Within these mole-
cules, the ether functionality confers particular properties to
the aromatic ring. The ability to synthesize aryl ethers with
a wide range of aliphatic and aromatic moieties represents
a challenge and has thus attracted constant interest through-
out the history of organic chemistry. Nevertheless, all existing
methods for the preparation of aromatic ethers are based on
the same reaction schemes, starting from aromatic precursors,
either with a pre-existing oxygen atom (phenols) or with
a pre-installed reactive functionality (Scheme 1, left). For
example, aryl alkyl ethers can be prepared by nucleophilic
ated in most of these syntheses, which goes against the trend
of developing more environmentally friendly processes.[11]
The development of new synthetic approaches toward
known molecules is highly desirable, as it goes hand in hand
with a re-evaluation of known procedures and generally
allows access to a wider variety of related structures. We
herein report a novel methodology for the synthesis of
aromatic ethers through oxidative condensation of alcohols
and 2-cyclohexenones (Scheme 1, right).
We reasoned that a straightforward and convenient
approach toward aryl ethers could involve the in situ gen-
eration of the aromatic moiety through condensation of an
alcohol and a 2-cyclohexenone, followed by an oxidative
aromatization (Scheme 1, right). This pathway is very attrac-
tive, as it formally consists of the elimination of water and two
hydrogen atoms from the starting materials. However, such
a reaction is very challenging, because it requires the right
catalyst that will efficiently mediate the formation of the
adduct and its selective oxidation in the presence of the
alcohol[12] and the 2-cyclohexenone,[13] both of which can
potentially be oxidized. A few examples of such a reactivity
have been reported earlier, but they suffer from the use of
several equivalents of relatively expensive metal oxidants and
the use of an alcohol as solvent.[14] It occurred to us that the
use of copper catalysts might address this issue, because of
their dual properties of Lewis acidity and oxidizing abil-
ity.[15–17]
To begin our study, we investigated the reaction of 3-
phenyl-1-propanol (1a) with 2-cyclohexenone (2a; Table 1).
We found that use of CuCl2 in toluene under an O2
atmosphere at 1008C led to aryl alkyl ether 3aa with a yield
of 96% (Table 1, entry 1). Interestingly, running the reaction
under O2 allowed the use of only one equivalent of the copper
source instead of the two equivalents theoretically required,
which was confirmed by the lower yield obtained under an
inert atmosphere (Table 1, entry 2). Other copper sources
were also screened (Table 1, entries 3–12). CuBr2 was less
effective with a yield of 44% (Table 1, entry 3), and copper(I)
halide complexes did not seem to catalyze the reaction
(entries 4–6). Copper(I) and copper(II) trifluoromethanesul-
fonate showed moderate activities and gave the ether in 24%
and 21%, respectively (Table 1, entries 7–8). Other precur-
sors, such as CuO, CuSO4, and Cu(CN)2, did not afford any
product (Table 1, entries 9–11). Finally, hydrated CuCl2
turned out to be as efficient as anhydrous CuCl2 and led to
3aa with a yield of 97% (Table 1, entry 12).
Scheme 1. General approaches for the preparation of aryl ethers
substitution reactions of either a phenol with an aliphatic
substrate (Williamson reaction),[2,3] or of an alcohol with an
aromatic precursor.[4] In the same manner, other approaches
have been developed more recently, such as transition-metal-
catalyzed allylic O alkylation reactions of phenols, electro-
philic addition reactions of phenols to alkenes,[5] coupling
reactions between alcohols and aryl halides through palla-
dium (Buchwald–Hartwig reaction)[6] or copper (Ullmann
ether synthesis)[7,8] catalysis, and copper-catalyzed coupling
reactions of alcohols with arylboron (Chan-Lam type cou-
pling)[9] or arylbismuth[10] compounds, but all these
approaches still require aromatic substrates. In addition,
stoichiometric amounts of unwanted by-products are gener-
[*] Dr. M.-O. Simon, S. A. Girard, Prof. Dr. C.-J. Li
Department of Chemistry and FQRNT Center for
Green Chemistry and Catalysis, McGill University
Montreal, QC, H3A 2K6 (Canada)
E-mail: cj.li@mcgill.ca
Homepage: http://cjli.mcgill.ca/cj page.htm
[**] We are grateful to the Canada Research Chair (Tier 1) foundation (to
C.-J.L.) and the NSERC for their support to our research. M.-O.S.
would also like to thank the FQRNT for a postdoctoral fellowship.
The optimized conditions were then applied to a wide
range of substrates (Scheme 2). Phenyl alkyl ethers were
obtained very efficiently from the reaction of 2-cyclohexe-
none and various primary and secondary alcohols.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201200698.
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In particular, several functional groups, such as methoxy
(3ba), nitro (3 fa), ester, and internal alkynes (3ha), were well
tolerated in this reaction. In addition, the reaction proceeded
readily in the presence of an iodo-substituted aromatic
derivative (3ea), which allows further functionalizations
through classical coupling reactions.[18] Natural functionalized
alcohols, such as b-citronellol (3ga), (À)-borneol (3ka), (À)-
menthol (3la), and cholesterol (3ma), were also successfully
converted into the corresponding phenyl ethers with good
yields. Interestingly, 5-hexyn-1-ol, which bears a terminal
alkyne functionality, can also be functionalized under these
conditions (3na). Protected serine could also be used in this
reaction, though it afforded the ether 3oa in a moderate yield.
1,6-Diphenoxyhexane 3pa was also prepared from 1,6-
hexanediol (1p) and afforded the diether as the sole product.
However, in the case of a secondary diol, such as trans-1,2-
cyclohexanediol (1q), a mixture of mono- and diether (3qa
and 3qa’, respectively) was obtained with a good overall yield.
The corresponding aryl ether was not observed when a tertiary
alcohol (likely because of a steric effect) or phenol was used
under the present conditions.
Table 1: Optimization of the copper catalyst for the oxidative conden-
sation of 1a with 2a.
Entry
[Cu]
Yield [%][a]
1
2
3
4
CuCl2
CuCl2
CuBr2
CuCl
96
38[b]
44
0
5
CuBr
9
6
CuI
0
7
8
9
Cu(OTf)2
[Cu(OTf)]2·toluene
CuO
21
24
0
We also studied various 2-cyclohexenone derivatives to
afford functionalized aryl ethers (Scheme 3). The reaction of
3-methyl-, 3,5-dimethyl-, 3-ethoxy-, and 3-bromo-substituted
10
11
12
CuSO4
Cu(CN)2
CuCl2·2H2O
0
0
97
[a] Yields were determined by 1H NMR spectroscopy using 1,3,5-
trimethoxybenzene as internal standard. [b] Reaction performed under
inert argon atmosphere at 1308C. OTf=trifluoromethanesulfonate.
Scheme 3. Copper-catalyzed reaction of substituted 2-cyclohexenones
and cyclohexane-1,3-dione (2g) with 3-phenyl-1-propanol (1a). Reac-
tion conditions: alcohol, 2a (2 equiv), CuCl2·2H2O (1 equiv), toluene,
O2, 1008C, 18 h. Yields of isolated products are given. [a] Reaction
conducted at 1308C.
2-cyclohexenone with 1a proceeded smoothly under the
optimized conditions, leading to the corresponding ethers in
30–47% yield (3ab–3ae). Interestingly, even (R)-carvone
could be used as a substrate, though at a higher temperature,
and afforded 3af with a low yield of 19%. Finally, we also
considered the reaction of 1a with 1,3-cyclohexanedione 2g
(Scheme 3, bottom) and obtained diether 3ag in 64% yield.
In our continued efforts to develop more sustainable
chemical reactions,[19] we next attempted to further improve
this reaction by reducing the amount of copper catalyst
required and using O2 as the sole terminal oxidant. Toward
this goal, we investigated the oxidative condensation of 3-
Scheme 2. Oxidative condensation of alcohols and diols with 2-cyclo-
hexenone. Reaction conditions: alcohol, 2a (2 equiv), CuCl2·2H2O
(1 equiv), toluene, O2, 1008C, 18 h. Yields of isolated products are
given. [a] Reaction conducted at 808C.
2
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Table 3: Scope of the copper-catalyzed oxidative condensation.
phenylpropan-1-ol (1a) with 2-cyclohexenone (2a) in the
presence of 10 mol% of copper complexes and 20 mol% of
N-hydroxyphthalimide (NHPI; Table 2). NHPI is a cheap and
nontoxic precursor of the phthalimido-N-oxyl (PINO) radi-
cal, which is the actual reactive species that can abstract
Entry
Product
Yield[a]
Entry
Product
Yield[a]
8[b]
9
3ha
3ia
3ja
3ka
3la
3ma
49
71
64
40
81
39
Table 2: Optimization of the reaction conditions for the oxidative
condensation of 1a with 2a using catalytic amounts of copper.
1
2
3
3aa
3ba
3ca
3da
3ea
3 fa
3ga
83
58
73
38
59
60
74
10[b]
11
12
13
4[b]
5[b]
6[b]
7
Entry
[Cu]
Additive (equiv)
Yield [%][a]
[a] Yields of isolated products. [b] Reaction conducted at 1208C for 24 h.
1
CuCl2
–
6
2
3
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
–
47
68
13
86
KI (1)
KI (1)
KI (1), water (1)
KI (1), water (1)
the sole product. The following mechanism can thus be
proposed (Scheme 4). The hemiacetal 4 may be formed
through electrophilic activation of the ketone by the copper
complex, and elimination of water could lead to the alkox-
ydiene 5 (or an isomer). The abstraction of a hydrogen atom
by the in situ formed N-oxyl radical would lead to 6, which
undergoes another abstraction of a hydrogen atom to afford
3aa.[20]
4[b]
5
6[c]
92 (83)[d]
[a] Yields were determined by 1H NMR spectroscopy using 1,3,5-
trimethoxybenzene as internal standard. [b] Reaction run without NHPI.
[c] Reaction run under 1 bar of O2. [d] Yield of isolated product.
hydrogen atoms from organic molecules.[20] However, under
these conditions, the use of CuCl2 only gave the expected
product in 6% yield (Table 2, entry 1). A screening of copper
sources showed that Cu(OTf)2 was the most active copper
complex and allowed the formation of 3aa in 47% yield
(Table 2, entry 2; for additional screening results, see the
Supporting Information, Table S1, entries 1–15). Subse-
quently, we studied the effect of various additives (Table S1,
entries 16–41), and the addition of potassium iodide stabilized
the catalytic species by preventing the formation of a dark
precipitate, thus significantly improving the reaction and
leading to 3aa in 68% yield (Table 2, entry 3). NHPI turned
out to be crucial, because only 13% of product was generated
in its absence (Table 2, entry 4). Addition of one equivalent of
water also proved to be beneficial, allowing the formation of
the product in 86% yield (Table 2, entry 5). Finally, conduct-
ing the reaction under 1 bar of O2 further increased the yield
to 92% (Table 2, entry 6), which is comparable to the result
obtained under the previous conditions (Scheme 2).
We next investigated the scope of the reaction under these
conditions (Table 3) and found that aryl ethers could be
isolated with similar yields as under the initial conditions. In
some cases, however, a higher temperature was found to be
helpful to achieve higher conversions (Table 3, entries 4–6, 8,
and 10), particularly in the case of benzylic alcohols.
To gain insights into this reaction, several control experi-
ments were carried out to elucidate the mechanism. When
cyclohexenone 2a was reacted under both optimized con-
ditions in [D8]toluene, no phenol was detected, whereas 3aa
was quantitatively formed in the presence of 1a. When
cyclohexanone was used, no reaction was observed. The use
of phenol instead of 2a under both reaction conditions did not
afford any product. However, when the commercially avail-
able 1-methoxy-1,3-cyclohexadiene was submitted to the
optimized conditions in [D8]toluene, anisole was formed as
Scheme 4. Proposed mechanism for the formation of aryl alkyl ether
3aa from 1a and 2a.
In summary, we have developed an original approach for
the synthesis of aryl ethers. The method advantageously
enriches and complements the existing toolbox used by
synthetic chemists, and allows a straightforward access to
a wide range of functionalized products. In addition, the
catalytic reaction with O2 as the terminal oxidant generates
water as the only by-product and provides a “greener”
approach to aryl ethers. Considering the wide utility of ethers,
these results will certainly pave the way for important
applications and developments in both the academic and
industrial fields through the shortening and simplification of
synthetic sequences.
Received: January 25, 2012
Revised: March 28, 2012
Published online: && &&, &&&&
Keywords: aromatization · aryl ether · copper · oxidation
.
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Angew. Chem. Int. Ed. 2012, 51, 1 – 5
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Chemie
Communications
Aryl Ether Formation
M.-O. Simon, S. A. Girard,
C.-J. Li*
&&&& — &&&&
Catalytic Aerobic Synthesis of Aromatic
Ethers from Non-Aromatic Precursors
Only little waste: Aryl ether formation is
accomplished by oxidative condensation
of alcohols and 2-cyclohexenones. The
reaction complements the existing
methods used by synthetic chemists to
obtain aryl ethers, and allows a straight-
forward access to a wide range of func-
tionalized products. In addition, the cat-
alytic reaction with O2 as the oxidant
generates water as the only by-product
and provides a “greener” approach to aryl
ethers.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!