Copper-catalysed oxidative C-H/C-H coupling between olefins and simple ethers

Article abstract of DOI:10.1039/c4cc00867g

The first copper-catalysed oxidative alkenylation of simple ethers to construct allylic ethers was successfully achieved. Different substituted olefins and simple ethers could be cross-coupled well to generate the corresponding alkenylation products. Notably, open-chain ethers were also found to be efficient coupling partners in this reaction. This reaction is likely to proceed via a radical process. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc00867g

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Copper-catalysed oxidative C–H/C–H coupling
between olefins and simple ethers†
Dong Liu,‡a Chao Liu,‡a Heng Lia and Aiwen Lei*ab
Cite this: Chem. Commun., 2014,
50, 3623
Received 2nd February 2014,
Accepted 11th February 2014
DOI: 10.1039/c4cc00867g
www.rsc.org/chemcomm
The first copper-catalysed oxidative alkenylation of simple ethers
to construct allylic ethers was successfully achieved. Different
substituted olefins and simple ethers could be cross-coupled well
to generate the corresponding alkenylation products. Notably,
open-chain ethers were also found to be efficient coupling partners
in this reaction. This reaction is likely to proceed via a radical process.
Transition-metal catalysed C–H functionalization to construct
C–C bonds has attracted much attention owing to their remarkable
potential for atom-economy and environmental sustainability.
Simple ethers are important organic synthons and widely used
Scheme 1 Proposed mechanism of oxidative alkenylation of simple ethers.
solvents. Due to their inert properties, direct a-functionalization is a that oxidative alkenylation of simple ethers might proceed through
very challenging task. However, a-functionalized ether derivatives the following three steps (Scheme 1): (1) generation of a-carbon-
abundantly exist in numerous biologically active molecules and centered radical II from simple ethers.9 Usually, this step could be
natural products.1 Thus, direct functionalization of simple ethers is realized by hydrogen abstraction with the aid of transition metals
of great significance. Recently, different nucleophiles such as or peroxides; (2) addition of an a-carbon-centered radical to olefins
arenes or heteroarenes,2 aryl-metal reagents,3 alcohols (including to generate radical III.10 This step is one of the classic transforma-
phenols and thiophenols),4 carboxylic acids,5 alkanes6 and alkynes7 tions of radicals, which has been proved in many reports; (3) radical
have been employed to couple with simple ethers to provide higher oxidation of III to generate the corresponding alkenylation product
functionalized ether derivatives. While to the best of our knowl- IV.8f,11 This step generally requires oxidants or transition-metal
edge, no direct alkenylation of simple ethers utilizing olefins has salts with strong oxidizing capacity, thus challenges still remain.
been successfully achieved to date.
When the radical oxidation step is not fast enough, radical
In the past few decades, the direct alkenylation of the sp3 intermediate III will be probably reduced to generate alkylation
carbon with olefins has been considered to be challenging. Even products,10a,b,d,f or captured by an oxidant to generate alcohols
the alkenylation of Csp3–X (alkyl halides) was rare.8 The direct or ketones.10c,e Due to these aspects, direct oxidative alkenylation
Csp3–H alkenylation with olefins would be more appealing, as it of simple ethers with olefins has not been achieved to date.
represents an atom-economical and sustainable approach. For Herein, we communicated the first oxidative coupling between
simple ethers, an a-Csp3–H bond has a relatively weak bond simple ethers and olefins to construct allylic ethers.
dissociation energy (BDE), thus it is easy to generate a-carbon-
Allylic ethers are important chemical feedstocks which widely
centered radical under oxidative conditions.1c,9 Hence, we proposed exist in various bioactive molecules and functionalized materials.12
In addition, introducing allylic ether blocks for the synthesis of
a College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072,
P. R. China. E-mail: aiwenlei@whu.edu.cn; Fax: +86-27-68754067;
Tel: +86-27-68754672
different natural products and functional molecules has also gone
through a rapid development recently.13 In this report, we demon-
strated a convenient synthetic strategy for allylic ether derivatives by
direct oxidative coupling of olefins with simple ethers. From the
bond formation point of view, employing simple C–H compounds
to achieve Csp2–H & Csp3–H oxidative coupling for the synthesis of
allylic ethers would be a very fascinating approach.14
b National Research Center for Carbohydrate Synthesis, Jiangxi Normal University,
Nanchang 330022, Jiangxi, P. R. China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc00867g
‡ These authors contributed equally.
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A previous study by our group revealed that simple ethers such
as tetrahydrofurans could generate an a-carbon-centered radical in
the presence of peroxide.3d Based on this assumption, we tried the
oxidative coupling of 1,1-diphenylethene (1a) with tetrahydrofuran
(2a) by employing Ni(acac)2/PPh3 as catalysts, K3PO4 as the base,
di-tert butyl peroxide (DTBP) as the oxidant at 100 1C for 16 h.
Indeed, the desired alkenylation product was observed. However,
the reaction only afforded 3a in 16% yield with a poor conversion,
along with 10% yield of the alkylation by-product. Even so, this
promising result suggested that direct oxidative alkenylation of
simple ethers through a radical pathway is probable, which
inspired us to carry out further investigations.
By testing various reaction parameters with 1a and 2a as the
model substrates, we found that in the presence of catalytic
amounts of CuI and KI using DTBP as the oxidant at 120 1C for
24 h, the desired direct oxidative alkenylation product 3a could
be obtained in 92% GC yield, along with an isolated yield of 87%
(Table 1, entry 1). Other metal salts such as Cu(OAc)2, Ni(acac)2
or CoBr2 showed less reaction efficiency, generating 3a in lower
yields (Table 1, entries 2, 3 and 5). No reaction occurred when
utilizing FeCl3 as the catalyst (Table 1, entry 4). Further oxidant
screening revealed that DTBP is the best choice for this reaction.
TBHP, K2S2O8 and m-CPBA all showed no reaction efficiency
(Table 1, entries 6–8). KI is essential to the reaction efficiency.
Lower yield and lower selectivity were obtained in the absence of
KI (Table 1, entry 9). Other iodide additives such as nBu4NI could
also catalyse this reaction with good efficiency (Table 1, entry 11).
NaI is inferior to KI, affording the target product in 36% yield
(Table 1, entry 12), while I2 totally shut down this reaction
Scheme 2 Substrate scope for the copper-catalysed oxidative alkenylation of
tetrahydrofuran (2a) with different olefins. Reaction conditions: 1 (0.3 mmol), 2a
(2.0 mL), CuI (10 mol%), KI (20 mol%), DTBP (0.6 mmol), 120 1C, 24 h.
Under the above optimized reaction conditions, the oxidative
(Table 1, entry 10). High temperature such as 120 1C is required alkenylation of tetrahydrofuran with a series of aryl alkenes was tested
for the homolysis of DTBP, and when temperature decreased to and the results are listed in Scheme 2. As shown in Scheme 2, 1,1-
100 1C, only a trace amount of the desired product was observed diphenylethene derivatives with electron-rich or electron-poor substi-
(Table 1, entry 13).
tuents on the benzene ring reacted well to give the corresponding
alkenylation products in good to excellent yields (Scheme 2, 3b and
3c). Halogen substituents such as F, Cl and Br could be well tolerated
in this transformation to afford the target products in 80–83% yields,
respectively (Scheme 2, 3d, 3e and 3f), providing more chance
for further functionalization or modification of these molecules.
2,20-(Ethene-1,1-diyl)dinaphthalene could also react smoothly with
tetrahydrofuran to give a satisfactory yield of the alkenylation product
(Scheme 2, 3g). Moreover, 1-aryl-1-alkyl olefins, such as a-methyl
styrene, were also suitable substrates for this reaction, generating
the alkenylation product in moderate yield (Scheme 2, 3h). Because of
the two different elimination patterns, two isomers were obtained.
It is noteworthy that styrene derivatives such as 1-methoxy-4-vinyl-
benzene were also good coupling partners with tetrahydrofuran,
giving the corresponding product in moderate yield (Scheme 2, 3i).
Considering the great importance of direct functionalization
of different ethers, we further investigated the applicability of
various simple ether derivatives with 1,1-diarylethenes in this
transformation (Scheme 3). 1,4-Dioxane was first employed to
react with 1,1-diarylethenes under standard conditions. Delight-
Table 1 Condition optimization for copper-catalysed oxidative alkenylation
of THF (2a) with 1aa
Entry
[Cat.]
[O]
Additive
Yieldb (%)
1
2
3
4
CuI
DTBP
DTBP
DTBP
DTBP
DTBP
TBHP
K2S2O8
m-CPBA
DTBP
DTBP
DTBP
DTBP
DTBP
KI
KI
KI
KI
KI
KI
KI
KI
92 (87)
63
46
n.d.
62
5
n.d.
n.d.
60
n.d.
76
36
Trace
Cu(OAc)2
Ni(acac)2
FeCl3
CoBr2
CuI
5
6c
7
CuI
8
9
CuI
CuI
/
I2
10
11
12
13d
CuI
CuI
CuI
CuI
nBu4NI
NaI
KI
a
Reaction conditions: 1a (0.3 mmol), 2a (2 mL), [Cat.] (10 mol%), [O]
b
(0.6 mmol), additive (20 mol%), 120 1C, 24 h. Yield was determined by fully, good to excellent yields of the corresponding alkenylation
GC analysis, calibrated using biphenyl as the internal standard. Iso-
lated yield in parentheses. 70% in aqueous solution. 100 1C. DTBP =
di-tert-butyl peroxide. TBHP = tert-butyl hydroperoxide. m-CPBA = meta-
chloroperbenzoic acid.
products were obtained smoothly (Scheme 3, 3j and 3k). To our
pleasure, common simple ethers such as tetrahydropyrane and
1,3-dioxolane all reacted smoothly with 1,1-diphenylethene to
c
d
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Scheme 5 Regioselectivity of copper-catalysed oxidative alkenylation reaction.
Scheme 3 Substrate scope for the copper-catalysed oxidative alkenyla-
tion of 1,1-diphenylethene derivatives with different ethers. Reaction
conditions: 1 (0.3 mmol), 2 (2.0 mL), CuI (10 mol%), KI (20 mol%), DTBP
(0.6 mmol), 120 1C, 24 h.
generate the alkenylation products in 79% and 97% yields,
respectively (Scheme 3, 3l and 3m). Because of the two different
kinds of hydrogens in 1,3-dioxolane, two isomers were obtained
with a selectivity of 3 : 2. Notably, one of these two products,
2-(2,2-diphenylvinyl)-1,3-dioxolane could be hydrolyzed to
3,3-diphenylacrylaldehyde 3m0 in quantitative yield by diluted
hydrochloric acid at room temperature. In addition, benzo[d]-
[1,3]dioxole could be well tolerated in this reaction (Scheme 3, 3n).
Direct oxidative functionalization of open-chain ethers has
always been a very challenging task in the past few years.4g,6a,b,d
Notably, not only cyclic ethers were good substrates in this
reaction, but also open-chain ethers could be well transformed
into the corresponding alkenylation products in excellent yields
(Scheme 4). Different substituted a-alkenylated diethyl ethers
were generated in excellent yields by utilizing diethyl ether as
the reactant (Scheme 4, 3o, 3p and 3q).
Scheme 6 Radical-trapping experiment.
position of the methylene group rather than of the methyl group,
which probably accounts for the better stability of the secondary
carbon radical than of the primary carbon radical.
For direct functionalization reactions of simple ethers, radical
intermediates were generally involved. In order to clarify the possible
radical mechanism of this transformation, a radical-trapping
experiment was carried out utilizing a commonly used radical-
trapping reagent TEMPO (Scheme 6). The formation of the
desired product was totally suppressed, meanwhile, radical-
trapping product 3I was isolated in 53% yield based on TEMPO.
This result suggested that a radical process is most likely
involved in the C–H cleavage of simple ethers.
In summary, we have developed the first copper-catalysed
oxidative alkenylation of simple ethers. Different substituted olefins
and various simple ethers cross-coupled well, transforming into the
corresponding alkenylation products in good to excellent yields.
Notably, open-chain ethers could also be well alkenylated in this
novel process. Preliminary mechanistic studies suggested that this
reaction probably proceeds through a radical pathway. Further
studies on the reaction mechanism are currently underway and will
be reported in due course.
Lately, in order to obtain information on the regioselectivity
of this reaction, direct alkenylation of glycol dimethyl ether with
1,1-diphenylethene was investigated under the present reaction
conditions (Scheme 5). The result revealed that direct alkenylation
products at different positions 3r and 3r0 were obtained in a ratio of
1
10 : 1 detected by H NMR analysis (see the ESI† for details). It
indicated that direct alkenylation is more likely to occur at the C–H
This work was supported by the 973 Program (2012CB725302),
the National Natural Science Foundation of China (21390400,
21025206, 21272180 and 21302148), the Research Fund for the
Doctoral Program of Higher Education of China (20120141130002)
and the Program for Changjiang Scholars and Innovative Research
Team in University (IRT1030).
Notes and references
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Scheme 4 Substrate scope for the copper-catalysed oxidative alkenyla-
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tions: 1 (0.3 mmol), diethyl ether (2.0 mL), CuI (10 mol%), KI (20 mol%),
DTBP (0.6 mmol), 135 1C, 24 h.
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