Unexpected copper-catalyzed aerobic oxidative cleavage of C(sp 3)-C(sp3) bond of glycol ethers

Article abstract of DOI:10.1021/ol301220s

An unexpected Cu-catalyzed oxidative cleavage of the C(sp ³)-C(sp³) bond in glycol ethers by using air or molecular oxygen as the terminal stoichiometric oxidant is demonstrated. As a result, the corresponding α-acyloxy ethers and fo

Full text of DOI:10.1021/ol301220s

ORGANIC
LETTERS
2012
Vol. 14, No. 12
3218–3221
Unexpected Copper-Catalyzed Aerobic
Oxidative Cleavage of C(sp3)ꢀC(sp3)
Bond of Glycol Ethers
Zhong-Quan Liu,*,† Lixing Zhao,‡ Xiaojie Shang,† and Zili Cui†
State Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou Gansu 730000, P. R. China, and Gannan Normal University, Ganzhou,
Jiangxi 341000, P. R. China
liuzhq@lzu.edu.cn
Received May 13, 2012
ABSTRACT
An unexpected Cu-catalyzed oxidative cleavage of the C(sp3)ꢀC(sp3) bond in glycol ethers by using air or molecular oxygen as the terminal
stoichiometric oxidant is demonstrated. As a result, the corresponding R-acyloxy ethers and formates of 1,2-ethanediol are formed by direct
coupling of carboxylic acids and aldehydes with glycol ethers under the reaction conditions. This method represents the first example of
Cu-catalyzed aerobic cleavage of saturated CꢀC bond in ethers.
The transition-metal-catalyzed selective cleavage of
CꢀC bonds is of fundamental interest and plays a great
role in the chemical industry.1 In the past decades, a variety
of catalytic systems involving activation of CꢀC bonds
have been developed.2 However, there are only a few
examples of catalytic cleavage of inert CꢀC bonds by
using oxygen or air as the ultimate stoichiometric oxidant.3
To the best of our knowledge, no examples have been
described in the literature of catalytic aerobic cleavage of
the C(sp3)ꢀC(sp3) bonds of ethers.4 We report herein a
highly selective Cu-catalyzed aerobic cleavage of the
C(sp3)ꢀC(sp3) bond in glycol ether molecules. This system
would represent the first example of Cu-catalyzed aerobic
cleavage of the saturated CꢀC bond in ethers, which
could be applied to degrade plastics and polymers made
by glycol. Additionally, it could also provide an efficient
and convenient protocol to synthesize R-acyloxy ethers by
a coupling reaction of carboxylic acids and aldehydes with
glycol ethers under mild conditions.
R-Acyloxy ethers are widely appearing substructures
occurring in various pharmaceuticals such as Artemisinin,
Sanguiin H-5, Candesartan Cilexetil, Fosinopril Sodium,
etc. Generally, these compounds are synthesized via nu-
cleophilic substitution of R-halo ethers by acid,5 addition
of alkenyl ethers with acid,6 esterification of hemiacetals,
† Lanzhou University.
‡ Gannan Normal University.
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r
10.1021/ol301220s
Published on Web 06/05/2012
2012 American Chemical Society

or more complex routes.7 Very recently, Wan et al. re-
ported a Bu4NI-catalyzed method to form R-acyloxy
ethers by an oxidative coupling reaction of acid with ethers
using tert-butyl hydroperoxide (TBHP) as the terminal
oxidant.8 We report here a novel protocol to prepare
R-acyloxy ethers by an oxidative coupling reaction of ethers
with carboxylic acids and aldehydes catalyzed by Cu(I) with
O2 as an environmentally benign oxidant (Scheme 1).
(entry 8). Air can also act as an effective oxidant (entry 9).
Finally, the desired products could be nearly quantitatively
isolated by using O2 as the oxidant catalyzed by 1 mol % of
Cu2O and 1 mol % of K2CO3 (entries 10ꢀ16).
Various carboxylic acids involving aromatic and benzylic
carboxylic acids were very effective substrates in this system
(Figure 1). Aromatic carboxylic acids with either electron-
donating or -withdrawing groups gave good yields of the
products (3bꢀ3g). As a result, the electronic effect of the
substituents in aromatic carboxylic acids is not obvious.
The ortho-substituted benzoic acids were also effective
substrates (3h and 3i). The amide group was tolerated in
this reaction (3j), and the corresponding product 3j was
isolated as a white solid and its structure was confirmed by
X-ray diffraction analysis. Naphthoic acid gave a 75%
yield of the desired product (3k). It is noteworthy that
heterocyclic carboxylic acids such as indole, pyrole, benzo-
furan, etc. gave good yields of the products (3lꢀ3n).
Benzylic acids were also effective substrates (3o and 3p).
Scheme 1. Methods for Preparation of R-Acyloxy Ethers
Initially, we chose p-anisic acid and 1,4-dioxane as the
model substrates to optimize suitable conditions for this
reaction (Table 1). It was found that the catalyst, base, and
oxidant affect the reaction efficiency critically. The cata-
lysts were screened, and it was found that Cu2O was more
efficient than others (entries 1ꢀ4). The oxidant Ag2CO3
was better than other Ag(I) salts (entries 5 and 6). Surpris-
ingly, molecular oxygen can be used as a terminal oxidant
in this reaction (entry 7). The yields increased significantly
when the concentration of the reaction mixture decreased
Table 1. Modification of the Typical Reaction Conditionsa
catalyst
(mol %)
yield of yield of
entry
additive (equiv)
Ag2CO3 (2)
3a (%)b 3a0 (%)b
Figure 1. Reactions of various carboxylic acids with 1,4-diox-
ane. Reaction conditions: Carboxylic acid (1.0 mmol), Cu2O
(0.01 mmol), K2CO3 (0.01 mmol), 1,4-dioxane (20 mL), 1 atm
O2, 110 °C. Reaction times, indicated by TLC and isolated yields
are shown. For 3l, the same reaction conditions are used except
Ag2CO3 (0.01 mmol) was used instead of K2CO3 (0.01 mmol).
1
CuI (10)
35
16
55
21
20
40
48
78
55
70
76
80
68
29
0
31
19
40
14
18
12
35
21
43
28
23
19
16
13
0
2
CuBr2 (10) Ag2CO3 (2)
Cu2O (10) Ag2CO3 (2)
Fe2O3 (10) Ag2CO3 (2)
Cu2O (10) Ag2O (2)
Cu2O (10) Ag2SO4 (2)
3
4
5
6
7
Cu2O (5)
Cu2O (5)
Cu2O (5)
Ag2CO3 (0.1) þ 1 atm O2
A series of linear glycol ethers were found to react well
with carboxylic acids under the conditions. The methoxy-
methyl 4-methoxybenzoate 3q was isolated as the major
product in 70% yield by reaction of glycol dimethyl ether
with p-anisic acid (eq 1). Glycol diethyl ether gave the
corresponding product 3r in 43% yield (eq 2). Interest-
ingly, 2-methoxyethyl ether gave two products by cleavage
of different CꢀC bonds, a 50% yield of 3q and 35% yield
of 3q00, respectively (eq 3), which might potentially be
8c
9c
Ag2CO3 (0.1) þ 1 atm O2
Ag2CO3 (0.1) þ 1 atm Air
Ag2CO3 (0.05) þ 1 atm O2
10c Cu2O (5)
11c Cu2O (1) Ag2CO3 (0.01) þ 1 atm O2
12c Cu2O (1) K2CO3 (0.01) þ 1 atm O2
13c Cu2O (1)
14c Cu2O (1)
15c Cu2O (1)
KOH (0.01) þ 1 atm O2
NaOAc (0.01) þ 1 atm O2
1 atm O2
16c
ꢀ
K2CO3 (0.01) þ 1 atm O2
0
0
a Reaction conditions: p-anisic acid (1.0 mmol), 1,4-dioxane (3 mL)
as solvent, 110 °C, 5ꢀ22 h, unless otherwise noted. b Crude 1 H NMR
yields using 4-bromobenzaldehyde as an internal standard. c 1,4-Diox-
ane (20 mL).
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Org. Lett., Vol. 14, No. 12, 2012
3219

Figure 2. Reactions of various aldehydes with glycol ethers. Reaction conditions: Aldehyde (1.0 mmol), CuBr (0.01 mmol), K2CO3
(0.01 mmol), 1,4-dioxane (20 mL), 1 atm O2, 110 °C. Reaction times and isolated yields are shown. For 3q and 4kꢀm, glycol dimethyl
ether (15 mL) was used instead of 1,4-dioxane.
applied to the degradation of plastics and polymers made
by glycol.
to react smoothly with various aldehydes under the typical
reaction conditions (3q, 4kꢀ4n).
As demonstrated in the following equations, it is very
interesting that the copper-catalyzed aerobic CꢀC bond
cleavage of glycol ethers could also be successfully achieved
by coupling of some phenols with 1,4-dioxane under the
typical conditions (eqs 4 and 5). The product 4o was
isolated in almost quantitative yield by reaction of 4-hydro-
xybenzaldehyde with 1,4-dioxane (eq 4). The 3-methoxy-4-
hydroxybenzaldehyde (vanillin) gave a 60% yield of 4f and
a 32% yield of 4f (eq 5). Further studies on the coupling
reactions of phenols with glycol ethers are ongoing in this
laboratory. This protocol could be used as a novel strategy
for the protection of phenols in synthetic chemistry.
Under similar reaction conditions, a variety of aromatic
aldehydes and an aliphatic aldehyde were very effective
substrates in this system (Figure 2). Aromatic aldehydes
with either electron-donating or -withdrawing groups gave
good yields of the products (3aꢀ3g, 4a, and 4b). The
product 4c with retention of one aldehyde group was
isolated in 86% yield by reaction of 1,4-phthalaldehyde
with dioxane (4c). The ortho, meta, and polysubstituted
benzaldehydes were also effective substrates (4dꢀ4g). It is
noteworthy that heterocyclic aldehydes such as furfural
and 2-thienylaldehyde gave 85% and 82% yields of the
corresponding products, respectively (4h and 4i). Benzylic
aldehyde and the phenylpropyl aldehyde were also
effective substrates (3o and 4j). Other glycol ethers such
asglycoldimethyletherandglycoldiethyletherwerefound
Additionally, this Cu-catalyzed aerobic cleavage of the
CꢀC bond reaction could be scaled up. For example, a
mixture of p-anisic acid (10.102 g, 0.066 mol), Cu2O
3220
Org. Lett., Vol. 14, No. 12, 2012

12
reaction of radical 1 with O2 could generate peroxide
(0.019 g, 0.13 mmol), K2CO3 (0.046 g, 0.33 mmol), and
1,4-dioxane (100 mL) was heated under reflux at 110 °C.
Molecular oxygen or air was bubbled into the system for 70 h.
When the reaction was finished as indicated by TLC, the
solvent was evaporated under vacuum for reusing, and the
residue was purified by flash column chromatography
(petroleum ether/ethyl acetate) to afford the desired product
3a (8.1 g, 48%) and 3a (3.48 g, 22%). Moreover, the results
showed that the turnover number (TON) increases with
the increasing amount of the substrate (see Supporting
Information). It indicates that this process might be conve-
niently scaled up in industry.
radical 2 which would give product A, another peroxide
radical 3, and product B followed by a series of electron
transfer and Cu-promoted homolysis of activated CꢀH and
CꢀC bonds in glycol ethers. This process should be far
more complicated than the present primary mechanism
which would be the subject of our future investigations.
To gain mechanistic insight, a competing kinetic isotope
effect (KIE) experiment was carried out (eq 6). As a result, a
significant KIE was observed with the kH/kD = 8.0 (see
Supporting Information). It suggests that the CꢀH bond
cleavage should be the rate-determining step of this proce-
dure. Furthermore, 1,4-dioxane gave 1,4-dioxan-2-ol as a
major product along with the mono- and diformates of 1,2-
ethanediol as minor products without carboxylic acid in this
system, which is similar to the results given by Jewett and
Lawless9 that autoxidation of p-dioxane gave formate esters
of 1,2-ethanediol. The addition of (2,2,6,6-tetramethyl-
piperidin-1-yl)oxyl (TEMPO) does not trap any radical
intermediate but stops the reaction. No reactions occur
when 4-methylmorpholine replaces dioxane. These two
experiments indicate that the copper catalyst may be deac-
tivated by coordination with a N-atom, which was further
confirmed by addition of several nitrogen ligands such as
N,N-dimethylethylenediamine (DMEDA), N,N,N,N-tetra-
methylethylenediamine (TMEDA), and 1,10-phenanthro-
line giving the same results as above. The minor product
cannot give the open-chain product by further reaction with
dioxane under the typical conditions. With the experimental
data and literature precedent in hand, a plausible mecha-
nism for this catalytic aerobic cleavage of CꢀC bonds is
depicted in Scheme 2. This procedure is most likely a copper-
catalyzed autoxidation rather than the copper-O2 pathways
in some enzymes such as tyrosinase and catechol oxidase.10
Radical intermediate 1 would be formed by hydrogen
abstraction from dioxane with a copper(II) peroxide radical,
which could be generated by a combination of molecular
oxygen with copper(I),11 and the CꢀH bond cleavage
should be the rate-determining-step. Auto-oxidation via
Scheme 2. Possible Mechanism
In conclusion, this work demonstrates an unexpected Cu-
catalyzed oxidative cleavage of the C(sp3)ꢀC(sp3) bond of
glycol ether by using air or molecular oxygen as the terminal
stoichiometric oxidant. As a result, the corresponding
R-acyloxy ethers and formates of 1,2-ethanediol are formed
by direct coupling of carboxylic acids and aldehydes with glycol
ethers under the reaction conditions. This system would
represent the first example of Cu-catalyzed aerobic cleavage
of the saturated CꢀC bond in ethers, which could be
potentially applied to the degradation of plastics and poly-
mers made by glycol. Additionally, it could also provide an
efficient and convenient protocol for large-scale preparation
of various valuable pharmaceuticals containing an R-acyloxy
ether subunit by simply coupling carboxylic acids and alde-
hydes with glycol ethers under mild conditions. Moreover,
this process not only could be conveniently scaled up but also
is atom-efficient and environmentally benign. This novel
system may draw much attention from scientists focused on
oxidation chemistry and copper enzymes in biology. Further
studies of this system on the mechanism and expansion of the
substrate scope are underway in our laboratory.
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Acknowledgment. This project is supported by the Na-
tional Science Foundation of China (No. 21002045) and the
Fundamental Research Funds for the Central Universities
(lzujbky-2012-55). We also thank the State Key Laboratory
of Applied Organic Chemistry for financial support.
Supporting Information Available. Full experimental
details and characterization data for all products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(12) (a)Walling, C. InActive Oxygen in Chemistry; Foote, C. S., Valentine,
J. S., Greenberg, A., Liebman, J. F., Eds.; Blackie: 1995; pp 24ꢀ65. (b)
Chudasama, V.; Fitzmaurice, R. J.; Caddick, S. Nat. Chem. 2010, 2, 592.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 12, 2012
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