Ruthenium(II)-Catalyzed C?H Difluoromethylation of Ketoximes: Tuning the Regioselectivity from the meta to the para Position

Article abstract of DOI:10.1002/anie.201711221

A highly para-selective C_Ar?H difluoromethylation of ketoxime ethers under ruthenium catalysis has been developed. A wide variety of ketoxime ethers are compatible with the reaction, which leads to the corresponding para-difluoromethylated products in moderate to good yield. A mechanistic study clearly showed that chelation-assisted cycloruthenation is the key factor in the para selectivity of the difluoromethylation of ketoxime ethers. Density functional theory was used to gain a theoretical understanding of the para selectivity.#.

Full text of DOI:10.1002/anie.201711221

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Accepted Article
Title: Ruthenium(II)-catalyzed C-H Difluoromethylation of Ketoxime:
Tuning the Regioselectivity from meta to para Position
Authors: Chunchen Yuan, Lei Zhu, Runsheng Zeng, Yu Lan, and
Yingsheng Zhao
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10.1002/anie.201711221
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COMMUNICATION
Ruthenium(II)-catalyzed C-H Difluoromethylation of Ketoxime:
Tuning the Regioselectivity from meta to para Position
+
+
Chunchen Yuan, Lei Zhu, Runsheng Zeng, Yu Lan* and Yingsheng Zhao*
Abstract:
A
highly para-selective CAr-H difluoromethylation of
Because fluorine-containing compounds, especially those
containing difluoromethylene (CF2) groups, have great application
in agrochemicals, pharmaceuticals, and life science, we set out to
expand the difluoromethylation reactions to the acetophenone-
containing structural units. Inspired by the previously reported
ruthenium complex enabled meta-selective C-H functionalization
reactions (Scheme 1a),7-11 we initially treated PMP protected
acetophenone imine or acetophenone with bromodifluoroacetate
in the presence of a ruthenium catalyst and potassium carbonate.
A mixture of the meta- and para-difluoromethylated ketone
products was obtained (Scheme 2, 3a-b). When substrate 1c was
subjected to the standard reaction conditions, only a trace amount
of the desired difluoromethyalted product was obtained. To our
great delight, when phenyl ketoxime ether was used, the para-
selective difluoromethylated product 3d was isolated in 37% yield,
along with recovered 55% starting material. When substrates 1e,
1f and 1g were further tested, the para-difluoromethylated ketone
products were observed. It is highly likely that an ester will not be
stable under the reaction conditions and will lead to the
decomposed ketone product. To get insight into these results,
substrates bearing a chloride substituent on the pyridine were
ketoxime ether using a ruthenium catalyst has been developed. A
wide variety of ketoxime ethers are compatible in the reaction, leading
to the corresponding para-selective difluorometylated products in
moderate to good yield. A mechanistic study clearly shows that
chelation-assisted cycloruthenation is the key factor in achieving the
para-selective difluoromethylation of ketoxime ethers. The density
functional theory (DFT) method was used to gain a theoretical
understanding of the para-selectivity.
Recently, para-selective CAr-H functionalization has undergone
groundbreaking development.1-6 For example, electronic-
controlled,1 bulky substituted arenes2 or arenes with a D-shaped
directing group3 can be selectively functionalized at the para-
position. A major breakthrough was realized by of Zhang4, Nakao5
and Ye6 groups, respectively, who developed a para-selective
alkylation, arylation and borylation of mono-substituted arenes,
including alkyl benzenes, alkoxylbenzenes, halobenzenes,
benzamides and aromatic ketones. Despite these important
accomplishments, these methodologies usually suffer from a
narrow substrate scope and poor regioselectivity, which greatly
hinder their application in pharmaceutical and natural product
synthesis. Herein, we report the development of a ruthenium(II)-
induced reaction of ketoxime ethers with bromodifluoroacetate to
provide difluoromethylated ketoxime ether derivatives with high
para-selectivity (Scheme 1, b).
tested. As expected,
a
mixture of meta- and para-
difluoromethylated products were obtained (3h, For more details
see SI.), which was different from the ruthenium enabled meta
selective C-H difluoromethylation reaction (3i). The clear reason
for this para-selectivity result was unclear, however, we could
speculate that the weak coordination ability of the oxime may
greatly reduce the para-directing ability of the Ru-C sigma bond,
leading to the reaction center changing to the position meta to the
Ru-C bond.
Scheme 1. The ruthenium-enabled difluoromethylation reaction.
Scheme 2. Preliminary study of the Ru(II)-catalyzed
difluoromethylation reaction.
[*]
C-C. Yuan, R.-S. Zeng, Prof. Dr. Y. Zhao
Key Laboratory of Organic Synthesis of Jiangsu Province, College
of Chemistry, Chemical Engineering and Materials Science
Soochow University, Suzhou 215123 (PR China)
E-mail: yszhao@suda.edu.cn
L. Zhu, Prof. Dr. Y. Lan
School of Chemistry and Chemical Engineering,
Chongqing University
Chongqing 40030, P. R. China
Email: lanyu@cqu.edu.cn
These authors contributed equally to this work.
Further studies showed that a satisfactory yield of 3d was
achieved when Na₂CO₃ was used as the base and N-Ac-L-Iso as
the ligand (See SI, Scheme 2S). With the optimized reaction
conditions in hand, a wide range of ketone oximes were treated
with 2 to examine the functional group tolerance of this ruthenium-
enabled para-selective CAr-H difluoromethylation reaction.
[+]
Supporting information for this article is given via a link at the end of
the document.
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Oxime-protected phenones were all well tolerated, providing the
para-difluoromethylated products in moderate to good yield (3d, j-
n). Substrate 1n was decomposed to the corresponding ketone,
resulting in a lower yield of the difluoromethylated product 3n.
Ortho-substituted acetophenone oxime derivatives gave the
corresponding para-difluoromethylated products in moderate to
good yield (3o–q). To our great delight, meta-substituted
acetophenone oxime derivatives provided their corresponding
difluoromethylated products at the sterically hindered para-
position in moderate to good yield (3r–t). These results are
different to the ruthenium-catalyzed meta-selective alkylation and
difluoromethylation reactions where the meta-substituted
substrates are less reactive than their ortho or para-substituted
analogues. It is worth mentioning that ortho- or meta-methoxy-
substituted acetophenone oxime derivatives only generated the
para-difluoromethylated products (3p, s) while the other
difluoromethylated regioisomer was not observed. However,
meta-trifluoro-substituted acetophenone was unreactive with only
trace amounts of the difluoromethylated product observed in the
reaction (3u). Disubstituted acetophenone oxime derivatives all
performed well in the reaction, affording the corresponding
products in good yield (3v-x).
Ketoprofen was first protected as the oxime and then subjected to
the standard reaction conditions. Gratifyingly, the para-selective
difluoromethylation selective happened at the less hindered
phenyl ring, providing the difluoromethylated ketoprofen product
7 in 41% yield, along with deprotected ketoprofen in 35% yield
(Scheme 4). Moreover, para-C-H monofluoromethylation was
also compatible under otherwise identical reaction conditions
(Scheme 5), highlighting the synthetic utility of this new protocol.
Table 2. Scope of the ketoxime ethers.a
Table 1. Scope of the ketoxime ethers.a
[a] 4 (0.20 mmol, 1.0 equiv) was used. Isolated yield after chromatography.
[b] Gram scale reaction.
Scheme 4. Synthesis of Ketoprofen derivative.
Scheme 5. Ru-enabled para-C-H monofluoromethylation.
[a] 1 (0.20 mmol, 1.0 equiv) was used. Isolated yield after chromatography.
[b] Recovered 4-oxo-4-phenylbutanoate.
To further understand the pathway of this ruthenium-enabled
para-selective difluoromethylation reaction, several reactions
were performed (Scheme 6). For example, when oxime protected
2, 6-dimethyl-substituted acetophenone was subjected to the
standard reaction conditions, only the starting material 1y was
recovered (Scheme 6a). This result may indicate that the initial
ortho-cycloruthenation is a key intermediate in achieving para-C-
H functionalization. Oxime protected 1z was further investigated
under the standard reaction condition. The result clearly reveals
the para-difluoromethylation reaction selectively occurred on the
benzoyl group rather than the non-activated phenyl ring. This
shows that the arylruthmuim complex13 was more inclined to react
with the difluoromethyl radical than the arene ring itself (Scheme
We next surveyed the scope and limitation of the aromatic
ketones using the oxime as the coordination center.
Benzoquinone and diphenylketone all proceed smoothly under
the standard reaction conditions to provide the para-
difluoromethylated products in moderate to good yields (5a-m).
However, oxime-protected 4-benzoylpyridine was totally
unreactive, with only starting material recovered. It is probable
that the pyridine can directly coordinate with the ruthenium
catalyst, shutting down the reaction completely.
The synthetic importance of this newly developed para-
selective difluoromethylation reaction can be demonstrated by the
synthesis of
a
fluorine-containing ketoprofen derivative12.
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10.1002/anie.201711221
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6b). A variety of known-ruthenium(II) complexes were further
prepared according to Jeganmohan’s procedure14. Complex A
can be used as the catalyst instead of [Ru(p-cymene)Cl2]2,
affording the difluoromethylated product 3a in 80% yield (Scheme
depicted in Figure 1, two possible transition states TS-para and
TS-meta were located by the DFT calculations, which lead to the
formation
of
the
corresponding
para-
and
meta-
difluoromethylated products, respectively. Meanwhile, the
intermolecular radical addition of ·CF2CO2Et to the C3 position of
intermediate I via transition state TS-para leads to the generation
of the para-difluoromethylated product with a free energy barrier
of 15.2 kcal/mol. Alternatively, radical addition to the C4 position
of intermediate I via transition state TS-meta could afford the
meta-substituted isomer. The computational results showed that
the relative free energy of transition state TS-meta was 1.7
kcal/mol higher than that of transition state TS-para. This
energetic discrepancy indicates that the para-difluoromethylated
product will be observed as the major product formed in this
system, which is consistent with the experimental results.
6c). Next, complex
A
was directly treated with
bromodifluoroacetate 2 and difluoromethylated acetophenone
was obtained with high para-selectivity (Scheme 6 d). In contrast,
when substrate 1a was subjected to the reaction conditions in
which a difluoromethyl free radical can be generated, a mixture of
para- and meta-difluoromethylated products was obtained in less
than 15% yield15 (Scheme 6e). Based on these experimental
results, we can speculate that reaction intermediates bearing Ru-
C bonds are responsible for the para-C-H functionalization
reaction.
Scheme 6. Mechanistic studies.
Scheme 7. Plausible catalytic cycle.
A series of deuterated experiments were performed to gain
insight into the reaction pathway (See SI, Scheme 3s). An isotopic
labeling
experiment
suggested
that
the
ortho-C-H
cycloruthenation step was reversible, whereas the para-C-H
activation was not. A kinetic isotope effect of 1.74 was obtained,
implying that the ortho-CAr-H activation step was the kinetically
relevant step. This result also explained why the amino acid type
ligand, which is usually applied in accelerating C-H activation, was
needed in the reaction. No product 3a was obtained in the
Figure 1. Energetics and geometry information of transition states TS-para and
TS-meta for the radical addition step. The bond lengths are given in angstroms.
reaction mixture when
a radical scavenger TEMPO was
employed in the reaction which was similar to that disclosed by
Ackermann.10a This result suggests a free radical pathway was
involved in this para-selective difluoromethylation reaction.
To understand the regioselectivity for the ruthenium catalyzed
CAr-H difluoromethylation reaction, the density functional theory
(DFT) method was employed to investigate the mechanism and
regioselectivity of this reaction.16 Based on the aforementioned
experimental observations, aryl ruthenium(II) complex I was
verified to be an active intermediate. Thus, we focused on the
subsequent radical addition step, which is considered to be the
step that determines the regioselectivity of this transformation. As
Figure 2. Calculated frontier molecular orbital (FMO) diagram for intermediate
I .
In order to understand the intrinsic preference for the
regioselectivity in this difluoromethylation reaction, we initially
considered the electronic effect of the benzene ring moiety in
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intermediate I. We calculated the electrostatic potential (ESP) of
intermediate I (Figure S2). The results indicate the electronic
density distribution at the C3 and C4 position is nearly identical,
which proved that the ·CF2CO2Et radical addition position was
independent of the electron density in this case. Furthermore, we
calculated the frontier molecular orbitals (FMOs) of intermediate I
(Figure 2b). The lowest unoccupied molecular orbital (LUMO) of
intermediate I mainly locates at the C1, C3 and C5 positions in
the reacting phenyl moiety. On the contrary, the corresponding
HOMO majorly appears at C2, C4 and C6 carbons. The
calculated HOMO and LUMO energy levels of intermediate I are
-5.36 and -1.56 eV, respectively, while the SOMO energy level
of ·CF2CO2Et radical is determined to be -2.91 eV. The
computational energy level of molecular orbitals clearly showed
that the energy level of·CF2CO2Et radical SOMO is closed to that
of the LUMO of intermediate I, which suggests that SOMO/LUMO
interaction would be more predominant than SOMO/HOMO
interaction in this case. Therefore, the distribution of the LUMO of
intermediate I revealed that C3 position should exhibit enhanced
addition, distortion/interaction analysis showed that the distortion
energy differences between TS-para and TS-meta result in the
para-selectivity.
Acknowledgements
We gratefully acknowledge financial support from the Natural
Science Foundation of China (NO. 21772139, 21572149,
21372266, and 21772020), Young National Natural Science
Foundation of China (NO. 21402133, 21403148) and the
Prospective Study Program of Jiangsu (BY2015039-08). The
PAPD Project are also gratefully acknowledged.
Keywords: ketoxime ethers • difluoromethylated • ruthenium •
para-selectivity • DFT calculation
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distortion/interaction model was also employed to clarify the origin
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[4]
[5]
‡
Figure 1 show that the distortion energy controlled the reactivity
because of the same trend in the activation free energy. The
calculated geometry information revealed a larger distortion of
reacting carbon in TS-meta (DC2-C3-C4-H2, from 180o to 163.0o)
compared with TS-para (DC1-C2-C3-H1, from 180o to 168.5o). It
means, when the radical addition takes place at C4 position, the
phenyl moiety should distorted further to capture the radical,
which leads to a late transition state. This is also in accordance
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state TS-meta is 2.09 Å, which is 0.07 Å shorter than the
correspond value (C3-C7) in transition state TS-para. All these
results lead to the higher activation free energy of transition state
TS-meta, indicating the subdued reactivity of C4 position. Based
on our experimental results and a previous report7l-n, a plausible
reaction pathway was proposed. Complex I will be formed via the
combination of [Ru(p-cymene)Cl2]2 and substrate 1 in the
presence of Na2CO3 and N-Ac-L-Iso. A free radical of ·CF2CO2Et
derived from 2-bromo-2,2-difluoroacetate was formed via a
single-electron-transfer process with the ruthenium catalyst.
The ·CF2CO2Et radical may be trapped by complex I, followed by
oxidation, aromatization and generation of the product (Scheme
7).
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In conclusion, we have developed a ruthenium-enabled para-
selective C-H difluoromethylation reaction of ketoxime ethers.
The site selectivity can be altered from the meta- to the para-
position by modifying the coupling partners, which gives an insight
into the ruthenium-enabled remote C-H activation process. Our
mechanistic study clearly implies that chelation-assisted
cycloruthenation is the key factor in achieving the para-selective
difluoromethylation of ketoxime ethers. The DFT calculation
results reveal that the para-selectivity was controlled by the
differences in the frontier molecular orbital contributions. In
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Text for Table
of Contents
C-C. Yuan, L. Zhu, R.-S.
Zeng, Prof. Dr. Y. Lan*
and Prof. Dr. Y.-S. Zhao*
Ruthenium(II)-catalzyed
C-H Difluoromethylation
of Ketoxime: Tunning
the
Regioselectivity
from meta
Position
to para
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