C(sp3)–H bond functionalization of non-cyclic ethers by decarboxylative oxidative coupling with α,β-unsaturated carboxylic acids

Article abstract of DOI:10.1007/s11426-017-9142-1

A copper-catalyzed decarboxylative oxidative coupling of α,β-unsaturated carboxylic acids with non-cyclic ethers is developed. This method provides a new approach for C(sp³)–H bond functionalization of non-cyclic ethers. Mechanism study shows the reaction involves a radical process.

Full text of DOI:10.1007/s11426-017-9142-1

SCIENCE CHINA
Chemistry
doi: 10.1007/s11426-017-9142-1
• ARTICLES •
C(sp3)–H bond functionalization of non-cyclic ethers by
decarboxylative oxidative coupling with α,β-unsaturated
carboxylic acids
Tong Zhang1,2, Xing-Wang Lan1,2, Yu-Qiang Zhou1,2, Nai-Xing Wang1,2*, Yue-Hua Wu1,2,
Yalan Xing3* & Jia-Long Wen4
1Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, China
2University of Chinese Academy of Sciences, Beijing 100049, China
3Department of Chemistry, William Paterson University of New Jersey, New Jersey 07470, United States
4Beijing Key Laboratory of Lignocellulosic Chemistry, Beijing Forestry University, Beijing 100083, China
Received August 1, 2017; accepted September 13, 2017; published online November 17, 2017
A copper-catalyzed decarboxylative oxidative coupling of α,β-unsaturated carboxylic acids with non-cyclic ethers is developed.
This method provides a new approach for C(sp3)–H bond functionalization of non-cyclic ethers. Mechanism study shows the
reaction involves a radical process.
C(sp3)–H bond functionalization, non-cyclic ethers, decarboxylative, oxidative coupling, α,β-unsaturated carboxylic acids
Citation:
Zhang T, Lan XW, Zhou YQ, Wang NX, Wu YH, Xing Y, Wen JL. C(sp3)–H bond functionalization of non-cyclic ethers by decarboxylative oxidative
coupling with α,β-unsaturated carboxylic acids. Sci China Chem, 2017, 60, 10.1007/s11426-017-9142-1
1 Introduction
transition metal catalysts and bases, carboxylic acid deriva-
tives can release CO2 and generate desired reactive interme-
diates in situ without producing large amounts of byprod-
ucts. Since then, lots of remarkable progress has been made
in this field including Pd-catalyzed decarboxylative aryla-
tion of aryl carboxylic acids and cinnamic acids with aryl
halids by Goossen et al. [6,7], Pd-catalyzed decarboxyla-
tive acylation of α-oxocarboxylic acids with 2-arylpyridine
by Ge et al. [8], Ru-catalyzed decarboxylative condensation
of α-oxocarboxylic acids with amine by Lei et al. [9], and
Cu-catalyzed decarboxylative coupling reaction of potassium
polyfluorobenzoates with aryl iodides and bromides by Liu et
al. [10]. In addition, oxidative coupling reactions catalyzed
by Cu, Fe and Ni salts have also been of interest [11–14].
Many reactions of functionalization of C–H bond adjacent
to a heteroatom have been explored [15–26]. In our previ-
ous work, Ni- and Mn-catalyzed decarboxylative coupling
of cinnamic acids with cyclic ethers, such as tetrahydrofu-
ran, tetrahydropyran and 1,4-dioxane, has been reported [15].
C(sp3)–H bond functionalization has always been a dynamic
topic of organic chemistry. As one of the powerful meth-
ods for C–H bond functionalization, decarboxylative cou-
pling has attracted much attention [1–3].
In recent decades, coupling reactions have gained consid-
erable progress [4]. Due to high yields and mild reaction
conditions, coupling reactions have been widely used in or-
ganic synthesis. However, conventional coupling reactions
normally use organometallic reagents and halides as coupling
components, which are expensive and toxic. In 2002, Myers
et al. [5] reported a Heck-type decarboxylative cross-cou-
pling reaction. Instead of aryl halides, this work used in-
expensive, stable, non-toxic and readily available carboxylic
acid derivatives as coupling components. In the presence of
*Corresponding authors (email: nxwang@mail.ipc.ac.cn; xingy@wpunj.edu)
© Science China Press and Springer-Verlag GmbH Germany 2017
chem.scichina.com link.springer.com

2
Zhang et al. Sci China Chem
In this study, we would like to describe a new copper-cat-
alyzed decarboxylative oxidative coupling of α,β-unsaturated
carboxylic acids with non-cyclic ethers (Scheme 1). This
method provides a new approach for C(sp3)–H bond function-
alization of non-cyclic ethers under mild conditions.
view of the coordination for copper salts, typical ligands,
1,10-phenanthroline and triphenylphosphine, were added
into the optimal condition as additives, but the yields were
not improved (entries 15 and 16). Notably, when reaction
was carried out at 60ꢀ°C, the yield was dramatically de-
creased (entry 17), indicating the temperature is crucial for
the transformation. But considering the nature of low boiling
point of diethyl ether, we finally chose 80ꢀ°C for the synthesis
of unsaturated oxygenous derivates. A controlled experi-
ment without any catalysts were carried on, but no desired
product was observed. We also tried some Cu(I)-catalysts
like CuI, and the reaction could proceed at room temperature.
However, esterification reaction happened instead of decar-
boxylative coupling reaction. No desired decarboxylative
product was observed.
2 Experimental
2.1 General considerations
All reagents were commercially available and used with-
out further purification. 1H and 13C NMR spectra (400 or
100ꢀMHz, respectively) were measured in CDCl3 with TMS
as internal standard at room temperature. High resolution
mass spectrometer (HRMS) were shown in Supporting
Information online.
2.2 General procedure
Taking the synthesis of (E)-1-(3-ethoxybut-1-enyl)-4-
methylbenzene (3a) as an example.
Copper powder
Scheme 1 Coupling of α,β-unsaturated carboxylic acids with non-cyclic
(0.03ꢀmmol), Na2CO3 (0.03ꢀmmol), tert-butyl hydroperoxide
(0.9ꢀmmol, 70% in water) was added successively into a
mixture of 4-methylcinnamic acid (0.3ꢀmmol) and ethyl ether
(3ꢀmL) at room temperature in sealed tube. The mixture
reacted at 80ꢀ°C for 17ꢀh. After the reaction was completed,
the resulting mixture was concentrated by a rotary evaporator
and then separated by column chromatography on silica gel
by using petroleum ether and ethyl acetate as eluent.
3a: Yellow oil. 1H NMR (400ꢀMHz, CDCl3) δ 7.27
(d, J=7.68ꢀHz, 2H), 7.11 (d, J=7.72ꢀHz, 2H), 6.47 (d,
J=15.92ꢀHz, 1H), 6.06 (dd, J1=15.90ꢀHz, J2=7.64ꢀHz, 1H),
4.01–3.95 (m, 1H), 3.60–3.52 (m, 1H), 3.43–3.36 (m,
1H), 2.32 (s, 3H), 1.32 (d, J=6.28ꢀHz, 3H), 1.20 (t,
J=6.80ꢀHz, 3H). 13C NMR (100ꢀMHz, CDCl3) δ 137.38,
134.01, 131.15, 130.73, 129.27, 126.37, 76.42, 63.54, 21.80,
21.18, 15.46. HRMS (EI-TOF): m/z calcd. for [C13H18O+H]+
190.1358; found 190.1356.
ethers.
Table 1 Reaction condition optimization a)
Entry
1
Catalyst
Mn(OAc)2
Ni(OAc)2
Co(OAc)2
Zn(OAc)2
MnCl2
Cu(OAc)2
Cu
Base
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
NaOAc
K2CO3
DBU
Oxidant
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
DTBP
K2S2O8
BPO
Yield (%) b)
21
23
19
<10
<10
47
64
42
58
51
53
0
2
3
4
5
6
7
8
Cu
9
Cu
10
11
12
13
14
Cu
Cu
DABCO
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
−
Cu
3 Results and discussion
Cu
0
We began our investigation using cinnamic acid 1a (1 equiv.,
0.3ꢀmmol) and diethyl ether 2a (1ꢀmL, both as reagent and
solvent) as model coupling partners, and the results were
shown in Table 1. After screening transition metal catalysts
(entries 1–7), a 64% yield of the desired product 3a was
achieved by using Cu powder in the presence of Na2CO3
and tert-butyl hydroperoxide (TBHP). The effect of different
bases in the coupling reaction was also tested. It was found
that Na2CO3 as a base gave the best results (entries 8–11).
When other oxidizing reagents such as di-tert-butyl peroxide
(DTBP), K2S2O8 and benzoyl peroxide (BPO) were used
instead of TBHP, the yields were lower (entries 12–14). In
Cu
47
37
49
22
55
0
c)
15
16ꢀd)
Cu
TBHP
TBHP
TBHP
TBHP
−
Cu
e)
17
Cu
18
19
20
Cu
Cu
Na2CO3
Na2CO3
Na2CO3
Na2CO3
−
TBHP
TBHP
TBHP
0
f)
21
22ꢀg)
Cu
23
0
Cu
a) Reaction condition: cinnamic acid (1 equiv., 0.3ꢀmmol), diethyl ether
as solvent, metal catalyst (0.1 equiv.), base (0.1 equiv.), TBHP (70% in
water, 3 equiv.) in sealed tube at 80ꢀ°C for 17ꢀh, unless otherwise noted;
b) isolated yields; c) 1,10-phenanthroline (0.2 equiv.); d) PPh3 (0.2 equiv.);
e) 60ꢀ°C; f) BHT (1 equiv.); g) TEMPO (1 equiv.).

Zhang et al. Sci China Chem
3
To confirm that the reaction involves a radical process, we
designed and performed some mechanistic studies. When
1 equiv. of radical inhibitor 2,2,6,6-tetramethyl-1-piperidiny-
loxyl (TEMPO) were added as additive, no product was ob-
tained.
Co(OAc)2 as the catalyst, but unfortunately, only poor yields
of the carbonyl products 4a–4d were given comparing with
the unsaturated compounds using Cu as catalyst.
Notably in 1H NMR spectra, we found an interesting phe-
nomenon. The signal of two protons in methylene at the β-po-
sition of chiral carbon atom was split into two peaks. Actu-
ally two protons in methylene adjacent to the chiral center
are magnetic nonequivalent and chemically nonequivalent,
no matter optical purity or racemation of these compounds.
Two protons in the same carbon atom have been affected by
asymmetric microenvironment of chiral center. Herein, pro-
tons in methylene are at the β-position of chiral center, an
oxygen atom is in the middle of chiral center and methylene,
but herein the two protons in methylene are still chemical shift
inequivalence, –CH2– group actually is –CHaHb– structure in
these products.
With the optimal conditions in hand, the substrate scope
of this coupling reaction was investigated by testing various
α, β-unsaturated carboxylic acids 1 and ethers 2 (Scheme 2).
Firstly, a series of cinnamic acids containing electron-with-
drawing and electron-donating substituents were explored to
react with diethyl ether in sealed tubes as shown in Scheme 2.
It was found that these reactions can take place smoothly
and the desired products were generated in moderate yields.
Notably, when (E)-3-(furan-2-yl)acrylic acid was used as a
substrate, a 53% yield of the desired product 3g was achieved.
We also tried cinnamic acid with strong electron-withdraw-
ing substituent like nitro, however, 3-(4-nitrophenyl)acrylic
acid did not work with this method. It was almost impossible
to obtain pure products since the yield was very low and
too many byproducts were generated. Subsequently, several
ethers were investigated as coupling partners with cinnamic
acid 1b. In addition, diethylsulfane and tetrahydrothiophene
were used instead of ethers, but only trace amount of desired
product 3j was generated. We also tried coupling reaction of
carboxylic acids 1 and some nitrogen aliphatic heterocyclic
compounds like 1-phenylpyrrolidine and 1-methylpyrro-
lidine, but no reaction was observed. In the process of
exploring conditions, we found an interesting result that
carbonyl compounds were generated when employing
On the base of our previous report [15,25,26], a possible
reaction mechanism of the Cu-catalyzed decarboxylative ox-
idative coupling is proposed in Scheme 3. TBHP produced
tert-butoxy radical and hydroxyl radical, which oxidized cop-
per powder to Cu(II) and generated ether radical. Cu(II) cata-
lyst reacted with cinnamic acid to produce a salt of Cu(II) car-
boxylate, and then ether radical and hydroxyl radical added to
salt of Cu(II) carboxylate. Then Cu(I) catalyst and CO2 elimi-
nated and desired product was generated, and Cu(I) would be
oxidized to Cu(II) by tert-butoxy radical and hydroxyl radi-
cal.
Scheme 2 Substrate scope for the reaction of α,β-unsaturated carboxylic
acids and ethers. Reaction condition: 1 (1 equiv., 0.2ꢀmmol), 2 (3ꢀmL) as sol-
vent, Cu (0.1 equiv.), Na2CO3 (0.1 equiv.), TBHP (70% in water, 3 equiv.) in
sealed tube at 80ꢀ°C for 17ꢀh, unless otherwise noted. a) 120ꢀ°C; b) Co(OAc)2
as catalyst.
Scheme 3 Proposed possible reaction mechanism.

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Zhang et al. Sci China Chem
The mechanism of Co-catalyzed process is different. Ether
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In summary, we have developed a copper-catalyzed decar-
boxylative oxidative coupling of α,β-unsaturated carboxylic
acids with non-cyclic ethers. This method provides a new
approach for C(sp3)–H bond functionalization of non-cyclic
ethers. Further study is ongoing in our group.
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