Chloroacetate-promoted selective oxidation of heterobenzylic methylenes under copper catalysis

Article abstract of DOI:10.1002/anie.201409580

The efficient selective oxidation and functionalization of C-H bonds with molecular oxygen and a copper catalyst to prepare the corresponding ketones was achieved with ethyl chloroacetate as a promoter. In this transformation, various substituted N-heterocyclic compounds were well tolerated. Preliminary mechanistic investigations indicated that organic radical species were involved in the overall process. The N-heterocyclic compounds and ethyl chloroacetate work synergistically to activate C-H bonds in the methylene group, which results in the easy generation of free radical intermediates, thus leading to the corresponding ketones in good yields.

Full text of DOI:10.1002/anie.201409580

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Chemie
DOI: 10.1002/anie.201409580
Selective Oxidations
Chloroacetate-Promoted Selective Oxidation of Heterobenzylic
Methylenes under Copper Catalysis**
Jianming Liu, Xin Zhang, Hong Yi, Chao Liu, Ren Liu, Heng Zhang, Kelei Zhuo,* and
Aiwen Lei*
Abstract: The efficient selective oxidation and functionaliza-
oxygen as the oxidant is still regarded as one of the main
challenges for catalysis. Molecular oxygen is a convenient and
green oxidant for catalytic chemistry.[8–10] It is important to
À
tion of C H bonds with molecular oxygen and a copper
catalyst to prepare the corresponding ketones was achieved
with ethyl chloroacetate as a promoter. In this transformation,
various substituted N-heterocyclic compounds were well
tolerated. Preliminary mechanistic investigations indicated
that organic radical species were involved in the overall
process. The N-heterocyclic compounds and ethyl chloroace-
À
explore the direct oxidation of C H bonds with molecular
oxygen for the construction of carbonyl compounds in both
academic and industrial communities due to its economic and
environmentally benign features.[11–14] Recently, the groups of
Maes, Miura, and Chiba have reported successful base-metal-
catalyzed oxidations of aryl(di)azinylmethanes and indoles
with molecular oxygen.[15] In spite of the impressive progress
À
tate work synergistically to activate C H bonds in the
methylene group, which results in the easy generation of free
radical intermediates, thus leading to the corresponding
ketones in good yields.
À
made in this area, the oxidation of aliphatic C H bonds of N-
heterocyclic compounds with molecular oxygen to produce N-
heterocyclic ketones is an almost untouched area. Therefore,
further research in this area is still warranted.
À
T
he direct oxidation and functionalization of C H bonds
À
under mild conditions is one of the most powerful strategies
to construct complex carbonyl compounds.[1] N-heterocyclic
ketones represent an important structural motif frequently
found in natural products, pharmaceuticals, and agrochem-
icals.[2] Traditionally, N-heterocyclic ketones are prepared
with stoichiometric quantities of a hazardous oxidant.[3]
Meanwhile, this process often produces large amounts of
unwanted by-products. Besides, transition-metal-catalyzed
oxidations of heterobenzylic methylenes with peroxides
have also been developed as an efficient approach toward
the synthesis of N-heterocyclic ketones.[4,5] Considerable
À
The key issues of the oxidation of aliphatic C H bonds of
N-heterocyclic compounds that have to be overcome are two
significant limitations: a) the coordination between the N-
heterocyclic compound and the transition metal; b) the low
reactivity of the aliphatic methylene. To solve these problems,
we decided to introduce an activating group at the hetero-
atom to generate the salts of the N-heterocyclic compounds.
According to the hypothesis, we take advantage of the
interaction between activating group and N-heterocyclic
À
compound to generate the covalent C N bond. This process
would not only decrease the coordination between the
À
efforts have also been made in the oxidation of Csp3
H
substrate and the catalyst, but also activate the C H bond
À
bonds by utilizing catalytic systems without transition
in the methylene group. Then the aliphatic C H bond of the
metals.[6] More interestingly, recent advances in the selective
N-heterocyclic compound is oxidized with molecular oxygen
and the help of a copper catalyst to generate a radical
intermediate. Once the N-heterocyclic ketone is formed, the
activating group is reduced and removed from the N-
heterocyclic compound. Overall, the copper-catalyzed selec-
À
functionalization of C H bonds have been achieved with new
types of transition metal catalysis.[7] In particular, the direct
À
oxidation and functionalization of C H bonds with molecular
À
tive oxidation of aliphatic C H bond of N-heterocyclic
[*] Dr. J. Liu, H. Yi, Dr. C. Liu, Dr. H. Zhang, Prof. Dr. A. Lei
College of Chemistry and Molecular Sciences, Wuhan University
Wuhan, 430072 (P. R. China)
compounds promoted by ethyl chloroacetate under mild
conditions would be established (Scheme 1). It was important
to realize that ethyl chloroacetate is essential for the selective
E-mail: aiwenlei@whu.edu.cn
Homepage: http://aiwenlei.whu.edu.cn/Main_Website/
À
oxidation of the aliphatic C H bond of N-heterocyclic
compounds.
Dr. J. Liu, X. Zhang, R. Liu, Prof. Dr. K. Zhuo
Collaborative Innovation Center of Henan Province for Green
Manufacturing of Fine Chemicals, School of Chemistry and
Chemical Engineering, Henan Normal University
Xinxiang, Henan 453007 (P. R. China)
We envisioned that 4-ethylpyridine and ethyl chloroace-
tate work synergistically to increase the acidity of the
hydrogen atoms in the methylene group in polar solvents.
DFT calculations showed that the acidity of the methylene
E-mail: klzhuo@263.net
[**] This work was supported by the 973 Program (2012CB725302), the
NSFC (21390400, 21025206, 21103044, 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).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201409580.
Scheme 1. The copper-catalyzed selective oxidation of N-heterocyclic
compounds promoted by ethyl chloroacetate.
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hydrogens of 1-(2-ethoxy-2-oxoethyl)-4-ethylpyridin-1-ium in
the gas phase, in dimethylformamide (DMF), and in 1,4-
dioxane was largely enhanced compared to the acidity of the
methylene hydrogens of 4-ethylpyridine (for more details, see
the Supporting Information, SI). These results proved that the
À
formation of a covalent C N bond increased the acidity of the
hydrogen atoms of a methylene group at 4-alkylpyridine and
À
activated the aliphatic C H bond. To confirm our hypothesis,
we investigated the role of ethyl chloroacetate in the
oxidation of 4-ethylpyridine (SI, Table S1). Upon examina-
À
tion of the reaction, the formation of a covalent C N bond
À
was a key factor of activating the aliphatic C H bond. It was
found that ethyl chloroacetate was essential for the oxidation
of 4-ethylpyridine to form the desired product (SI, Table S1,
entries 1–3). However, little was known about the effect of
ethyl chloroacetate in the copper-catalyzed oxidation of
À
benzylic C H bonds. Based on the above results, a small
number of a-halogen compounds was subjected to the
À
oxidation of the aliphatic C H bond, but no positive results
À
Scheme 2. Copper-catalyzed selective oxidation of the aliphatic C H
bond. Conditions: 1 (1.0 mmol), ethyl chloroacetate (1.0 mmol),
CuCl2·2H2O (10 mol%), DMF (3.0 mL), 1308C, 24 h, O2 balloon, yield
of isolated product. [a] 1,4-Dioxane (3.0 mL), 1008C, 24 h. [b] Acetyl-
acetone (10 mol%) was added, and the yield was determined by GC
analysis. [c] Ethyl chloroacetate (2.0 equiv).
were obtained (SI, Table S1, entries 4–7). Only by using
methyl chloroacetate and phenacyl chloride as the activating
group, 4-ethylpyridine was selectively oxidized to afford
a moderate yield of the desired product. Only traces were
obtained when CuI (10 mol%) and HOAc (1.0 equiv) served
as the catalyst (SI, Table S1, entry 8). A Brønsted acid could
À
be applied for the activation of pyridines, but the covalent C
N bond formed by HOAc and 4-ethylpyridine was not enough
smoothly to afford the desired products in 56–61% yield
(4a–d; Scheme 3). Furthermore, 2-ethyl-8-methylquinoline
and 8-chloro-2-ethylquinoline were also suitable for this
reaction (4e and 4 f). The methylene group of quinolines with
two substituents such as alkyl and chloro were only selectively
oxidized to afford the desired products in good yields (4g,
4h). In addition, 2-ethyl-8-phenylquinoline and 3-ethylben-
zo[f]quinolone reacted with molecular oxygen under the
standard conditions to afford the desired products in moder-
ate yields (4i, 4j). To our surprise, 2-isopropylquinoline could
also be utilized to prepare 1-(quinolin-2-yl)ethan-1-one in
63% yield (Scheme 4, 4k).
À
to oxidize the aliphatic C H bond.
With the optimized conditions in hand, various substituted
pyridines were subjected to the copper-catalyzed oxidation of
aliphatic C H bond to test the substrate scope and generality.
À
In the process of optimizing the reaction conditions, we have
found that 1,4-dioxane was the best solvent for the oxidation
of 4-substituted pyridines, and DMF was the better solvent for
all other substrates. As shown in Scheme 2, the reactions
proceeded from good to excellent yields in the presence of 4-
ethylpyridine, 3-ethylpyridine, and 2-ethylpyridine (2a, 2c,
and 2d). Then we tried to extend the protocol to long-chain
aliphatic pyridine. Intriguingly, the 4-propylpyridine was well
tolerated and 2b was obtained in 78% yield. This method was
also successfully applied to a variety of 2-ethylbenzo[d]thia-
zole derivatives, providing the corresponding products in
51% and 47% yields (2e and 2 f). It was worth noting that N-
heterocycles such as 2-ethyl-1H-benzo[d]imidazole and 2-
ethylquinoxaline could be applied to the oxidation of
To gain insight into the reaction mechanism, we per-
formed a labeling experiment. The reaction between 4-
À
aliphatic C H bonds and gave the corresponding ketones in
moderate to good yields (2g and 2h). The reactions of 2-
substituted pyridines with typical functional groups such as
benzyl and Cl at the 4-position of the benzene ring were
successfully employed in the benzylic oxidation (2i and 2j). In
addition, 4-substituted pyridines were similarly found to be
suitable substrates for the transformation and gave the
desired products in excellent yields (2k and 2l).
After the successful application of the oxidative reaction
of methylene, we tried to extend this process to build up
structurally important quinolones. The reaction with 2-
substituted quinolines bearing electron-withdrawing and
electron-donating groups, such as Cl, Me, MeO, and tert-
butyl at the 6-position of the benzene ring proceeded
À
Scheme 3. Copper-catalyzed selective oxidation of the aliphatic C H
bond of 2-substituted quinolines. Conditions: 3 (1.0 mmol), ethyl
chloroacetate (1.0 mmol), CuCl2·2H2O (10 mol%), DMF (3.0 mL),
1308C, 24 h, O2 balloon, yield of isolated product.
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followed by protonation releases the final product 2a and
ethyl acetate which was detected by MS analysis.
LC-MS analysis can provide important information about
the intermediates of the reaction. To our delight, a clear
spectrum was obtained when the reaction mixture was
investigated by LC-MS. The 1-(2-ethoxy-2-oxoethyl)-4-alkyl-
pyridin-1-ium chloride (I), which is formed by interaction
between the 4-alkylpyridine and ethyl chloroacetate, was
detected at m/z values of 194. Furthermore, the ketone
coordinated to ethyl chloroacetate (V) was detected at m/z
values of 208 by LC-MS analysis of the reaction mixture (for
more details, see SI). These results proved that intermediate I
and V participate in the catalytic cycle.
Scheme 4. Copper-catalyzed selective oxidation of 2-isopropylquino-
line.
ethylpyridine (1a) and ethyl chloroacetate in the presence of
18O2 afforded the 18O-labeled product 2a in 75% yield
(Scheme 5), demonstrating that the carbonyl oxygen atom
of the 4-acetylpyridine originated from dioxygen as we
initially assumed.
Scheme 5. 18O isotope labeling experiment.
When the reaction mixture was investigated by GC-MS,
ethyl chloroacetate was found to be converted to ethyl
acetate. Based on the above results and previous reports,[9,14]
a possible reaction pathway is proposed (Scheme 6). Initially,
Scheme 6. Proposed reaction mechanism.
4-alkylpyridine and ethyl chloroacetate work synergistically
to produce 1-(2-ethoxy-2-oxoethyl)-4-alkylpyridin-1-ium
chloride. Formation of the pyridinium activates the methyl-
II
À
ene C H bonds and intermediate I is directly oxidized by Cu
to afford the radical species II. As a result, CuI and H+ are
generated. Subsequently, intermediate II easily combines
with molecular oxygen to form the peroxy radical species III.
Then, radical species III is reduced by the copper(I) catalyst
followed by protonation to generate intermediate IV. Inter-
mediate IV eliminates a molecule of H2O to produce the
Figure 1. The 2D kinetic profiles of the oxidation of heterobenzylic
methylenes. Reaction conditions: a) 4-ethylpyridine (1.0 mmol), ethyl
chloroacetate (1.0 mmol), and CuCl2·2H2O (0.10 mmol) successively
added to 1,4-dioxane (3.0 mL) at 1008C. b) 4-Benzylpyridine
(1.0 mmol), ethyl chloroacetate (1.0 mmol), and CuCl2·2H2O
(0.10 mmol) successfully added to 1,4-dioxane (3.0 mL) at 1008C.
À
oxidation product V. Due to the fact that the covalent C N
bond showed a strongly oxidizing ability, a subsequent
reduction of intermediate V by a lower valent Cu species
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The reactions were also monitored by in situ IR spectros-
copy in the absence of ethyl chloroacetate (Figure 1). The
kinetic profile clearly shows that 4-acetylpyridine and phe-
nyl(pyridin-4-yl)methanone could not be observed without
ethyl chloroacetate. Additionally, the two peaks of the
valuable information for the further design of additives for
selective copper-catalyzed direct oxidation and functionaliza-
À
tion reactions of Csp3 H bonds.
product at 1713 cmÀ1 and 1675 cmÀ1 were observed. These Experimental Section
General procedure: CuCl2·2H2O (17 mg, 0.10 mmol) was added to an
results indicate that 4-substituted pyridines were successfully
oxidized to the corresponding ketones under the standard
reaction conditions promoted by ethyl chloroacetate, and that
these reactions occurred without any inductive period as can
be seen from the results of operando IR.
To confirm that an organic radical species is involved in
the overall process, electron paramagnetic resonance (EPR)
experiments were conducted to gain insight into the catalytic
cycle. When ethyl chloroacetate in DMF and 4-ethylpyridine
in DMF were tested, no signals were observed (Figure 2a,b).
oven-dried Schlenk tube, which was sealed with a septum and fitted
with an oxygen balloon. Subsequently, ethyl chloroacetate
(1.0 mmol), 4-ethylpyridine (1.0 mmol), and DMF (3.0 mL) were
injected using a syringe or microsyringe. Finally, the Schlenk tube was
allowed to stir at 1308C for 24 h. After completion, the reaction was
quenched with water and the mixture was extracted with ethyl acetate
(4 ꢀ 40 mL). The organic layers were combined and dried over sodium
sulfate. The pure product was obtained by flash column chromatog-
raphy on silica gel. The desired product was isolated as a colorless oil
1
in 65% yield. H NMR (400 MHz, CDCl3) d = 8.79 (d, J = 4.0, 2H),
7.70 (dd, J = 4.0, 8.0 Hz, 2H), 2.61 ppm (s, 3H). 13C NMR (101 MHz,
CDCl3) d = 197.3, 150.9, 142.6, 121.2, 26.6 ppm. ESI-MS: 121(M)
Received: September 28, 2014
Revised: November 1, 2014
Published online: && &&, &&&&
Keywords: copper catalysis · ethyl chloroacetate ·
.
N-heterocycles · selective oxidations
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À
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À
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Communications
Selective Oxidations
J. Liu, X. Zhang, H. Yi, C. Liu, R. Liu,
H. Zhang, K. Zhuo,*
A. Lei*
&&&& — &&&&
Chloroacetate-Promoted Selective
Oxidation of Heterobenzylic Methylenes
under Copper Catalysis
Molecular oxygen can be used for the
N-heterocyclic compounds were well tol-
erated. Preliminary mechanistic investi-
gations indicated that organic radical
species were involved in the overall
process.
À
selective oxidation of C H bonds of N-
heterocyclic compounds to the corre-
sponding ketones with a copper catalyst
and ethyl chloroacetate as a promoter. In
this transformation, various substituted
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