Ruthenium(II)-catalyzed para-selective C[sbnd]H difluoroalkylation of aromatic aldehydes and ketones using transient directing groups

Article abstract of DOI:10.1016/j.cclet.2020.09.044

A Ru(II)-catalyzed para-difluoroalkylation of aromatic aldehydes and ketones with a transient directing group has been developed. It utilizes less expensive ruthenium catalysts and allows facile access to challenging difluoroalkylated aldehydes. The mechanism studies suggest that the distinct coordination mode of ruthenium complex with imine moieties is responsible for para-selectivity.

Full text of DOI:10.1016/j.cclet.2020.09.044

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CCLET 5873 No. of Pages 6
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Contents lists available at ScienceDirect
Chinese Chemical Letters
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Communication
Ruthenium(II)-catalyzed para-selective C ÀÀ H difluoroalkylation of
aromatic aldehydes and ketones using transient directing groups
Yaohang Cheng , Yuhang He , Jie Zheng , Hui Yang , Jun Liu , Guanghui Ana,b,*,
a,1
a,1
a,1
a
a
a,
Guangming Li *
a
Key Laboratory of Functional Inorganic Material Chemistry (MOE), School of Chemistry and Materials Science, Heilongjiang University, Harbin 150080,
China
b
College of Materials Science and Chemical Engineering, Harbin Engineering University, Harbin 150001, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Received 31 July 2020
Received in revised form 9 September 2020
Accepted 24 September 2020
Available online xxx
A Ru(II)-catalyzed para-difluoroalkylation of aromatic aldehydes and ketones with a transient directing
group has been developed. It utilizes less expensive ruthenium catalysts and allows facile access to
challenging difluoroalkylated aldehydes. The mechanism studies suggest that the distinct coordination
mode of ruthenium complex with imine moieties is responsible for para-selectivity.
©
2020 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Keywords:
para-Selectivity
C ÀÀ H activation
Difluoroalkylation
Ruthenium catalysis
Fluorinated arenes, especially difluoroalkylated arenes, remain
privileged moieties for drug discovery and development owing to
gem-difluoromethylene group’s unique stability, and isosteric
properties as an ethereal oxygen atom or a carbonyl group, as
well as a lipophilic hydrogen-bond donor [1]. Accordingly, various
approaches to direct difluoroalkylation of aromatic rings have been
explored extensively in the last few decades [2]. Although
heteroarenes can afford site-selective products due to their
intrinsic electronic effects and photo-redox-catalyzed ortho-
difluoroalkylation of anilines have been achieved [3], general
aromatic compounds usually suffer from poor site selectivity for
remote C ÀÀ H difluoroalkylation. Until recently, meta-selective
C ÀÀ H difluoroalkylation of 2-arylpyridine derivatives [4] and
purine [5] has successfully been achieved by groups of Ackermann
and Wang. Following these remote C ÀÀ H difluoroalkylations, para-
selective counterparts have been demonstrated viable to several
aromatic rings, such as aniline derivatives [6], oximes [7], ketones
owing to the weak coordination of oxygen and ruthenium, the
direct para-selective difluoroalkylation of aromatic aldehydes,
ketones or benzoate derivatives employing less expensive
ruthenium catalysts still remains unsolved and challenging [11].
Aldehydes as the directing group (DG) in the C ÀÀ H activation
normally suffer from their weak coordinating ability, susceptibility
toward oxidation, and undesired metal insertion into acyl C ÀÀ H
bond. To overcome these limitations, Yu and others recently
introduced the transient directing group (TDG) concept and
successfully achieved diverse ortho-C–H functionalization of
aromatic aldehydes using amines as TDGs [12]. We envisioned
that introduction of TDG in para-difluoroalkylation of aromatic
aldehydes would enable the formation of strong coordinating
imine moiety which can benefit substrate-ruthenium coordina-
tion. Herein, we report the first transient directing group promoted
para-difluoroalkylation of aromatic aldehydes. This protocol
employs less expensive ruthenium catalysts and allows the rapid
access to both difluoroalkylated aromatic aldehydes and ketones.
We commenced our initial investigation by the reaction of
benzaldehyde 1a and bromodifluoroacetate 2a using [Ru(p-
[
8], aldehydes [9] and benzoate derivatives [10] (Scheme 1).
However, given that the formation of cycloruthenation between
oxygen-containing directing group and ruthenium is sluggish
2 2
cymene)Cl ] as catalyst with diverse TDGs (Scheme 2, Table S1
in Supporting information). When subjected to the model
reactions, the reported bidentate TDGs previously employed for
ortho-C–H functionalization of aldehydes afforded low yields in
this remote C–H difluoroalkylation (TDG1-TDG7) [12b–e,12k,12l].
Aniline type monodentate TDGs did not improve the reaction
efficiency (TDG8 and TDG9) [12h,12m]. To our delight, aliphatic
*
Corresponding authors at: Key Laboratory of Functional Inorganic Material
Chemistry (MOE), School of Chemistry and Materials Science, Heilongjiang
University, Harbin 150080, China.
E-mail addresses: chemagh@163.com (G. An), gmli@hlju.edu.cn (G. Li).
These three authors contributed equally to this work.
1
https://doi.org/10.1016/j.cclet.2020.09.044
1001-8417/© 2020 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article as: Y. Cheng, Y. He, J. Zheng et al., Ruthenium(II)-catalyzed para-selective C ÀÀ H difluoroalkylation of aromatic aldehydes
and ketones using transient directing groups, Chin. Chem. Lett., https://doi.org/10.1016/j.cclet.2020.09.044

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Y. Cheng, Y. He, J. Zheng et al. / Chinese Chemical Letters xxx (2019) xxx–xxx
Scheme 1. The remote C ÀÀ H difluoroalkylation of arenes.
Scheme 2. Transient directing group screening. Standard conditions: 1a (0.2 mmol), 2a (0.6 mmol), [Ru(p-cymene)Cl
2
]
2
(5 mol%), Na
2
CO
3
(2 equiv.), AgTFA (2 equiv.),
ꢀ
N-acetyl-
L
-isoleucine (30 mol%), TDG (0.5 equiv.), DCE (1 mL), 155 C, 36 h, under Ar. Isolated yields.
Please cite this article as: Y. Cheng, Y. He, J. Zheng et al., Ruthenium(II)-catalyzed para-selective C ÀÀ H difluoroalkylation of aromatic aldehydes
and ketones using transient directing groups, Chin. Chem. Lett., https://doi.org/10.1016/j.cclet.2020.09.044

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3
Table 1
a
Optimization of reaction conditions .
Entry
Deviation from the standard conditions
Yield (%)b
1
2
3
4
5
6
7
8
9
–
68
0
Pd(PPh
3
)
4
instead of [Ru(p-cymene)Cl
2
]
2
2
Ru
Ru(DMSO)
RuCl instead of [Ru(p-cymene)Cl
Ru(bpy) (PF instead of [Ru(p-cymene)Cl
N-Acetylglycine instead of N-Ac- -Iso
1-Ad-OH instead of N-Ac- -Iso
t-BuCOOH instead of N-Ac-
MesCOOH instead of N-Ac-
AgNTf instead of AgTFA
Ag O instead of AgTFA
AgF instead of AgTFA
AgSbF instead of AgTFA
AgOAc instead of AgTFA
3
(CO)12 instead of [Ru(p-cymene)Cl
2
]
33
12
15
15
33
43
38
40
60
54
58
42
30
28
32
57
50
43
51
9
4
2 2 2
Cl instead of [Ru(p-cymene)Cl ]
3
2 2
]
3
6
)
2
2 2
]
L
L
L
-Iso
1
0
L
-Iso
1
1
2
1
2
2
1
3
1
4
6
1
5
1
6
AgNO
AgBF
NaH
NaHCO
NaOAc instead of Na
CO instead of Na
Dioxane instead of DCE
O instead of DCE
3
instead of AgTFA
instead of AgTFA
1
7
4
1
8
2
PO
4
instead of Na
instead of Na
CO
CO
2
CO
3
1
9
3
2
CO
3
2
0
2
3
2
1
K
2
3
2
3
2
2
2
3
H
2
30
a
Standard conditions: 1a (0.2 mmol, 1.0 equiv.), 2a (0.6 mmol, 3.0 equiv.),
(5 mol%), Na CO (0.4 mmol, 2.0 equiv.), AgTFA (0.4 mmol, 2.0
-isoleucine (30 mol%), TDG10 (0.1 mmol, 0.5 equiv.), DCE (1.0 mL),
[
Ru(p-cymene)Cl
equiv.), N-acetyl-
2
]
2
2
3
L
ꢀ
1
55 C, 36 h, under Ar.
b
Isolated yields.
primary amine TDG10 could significantly enhanced the reaction
outcome, delivering the para-product 3a in 68% (Table 1, entry 1).
Other amines, such as 2-methylpropan-1-amine and 2-methyl-
butan-2-amine, gave lower chemical yields.
Further survey of other ruthenium catalysts [7] and previous
3 4
employed Pd(PPh ) [8] showed lower catalytic efficiency (Table 1,
entries 2–6). Besides, the use of N-acetylglycine, 1-adamantane
carboxylic acid (1-Ad-OH), pivalic acid (t-BuCOOH) and 2,4,6-
trimethylbenzoic acid (MesCOOH) instead of N-acetyl-L-isoleucine
decreased the efficiency of difluoroalkylation and regioselectivity
Scheme 3. Reaction scope. Standard conditions:
0.6 mmol, 3.0 equiv.), [Ru(p-cymene)Cl (5 mol%), Na
-isoleucine (30 mol%), TDG10 (0.1 mmol, 0.5
equiv.), DCE (1.0 mL), 155 C, 36 h, under Ar; Isolated yields. Cannot be separated
from aryl impurities.
1
(0.2 mmol, 1.0 equiv.),
2
(Table 1, entries 7–10). Further screening of diverse silver salts
(
2
]
2
2
CO
3
(0.4 mmol, 2.0 equiv.),
demonstrated AgTFA as the optimal choice (Table 1, entries 11–17).
A thorough investigation of bases and solvents revealed the
combination of Na CO and 1,2-dichloroethane (DCE) led to the
2 3
AgTFA (0.4 mmol, 2.0 equiv.), N-acetyl-
L
ꢀ
a
best chemical yields (Table 1, entries 18–23).
With optimal conditions, we treated different benzaldehydes
with 2a to examine the functional-group tolerance (Scheme 3).
Difluoroalkylation of benzaldehyde derivatives with ortho sub-
stituents proceeded smoothly to furnish the corresponding para-
difluoroalkylated products 3b-3e. Pleasingly, meta-substituted
benzaldehyde derivatives provided the corresponding products
BrCF CONMe (2b) and heteroaryl difluoromethyl bromide (2d)
2
2
with benzaldehyde, providing 3m and 3n in good yields. Although
1
19
H and F NMR of 3n is in agreement with literature [13], it was
containment with aryl impurities and can not be further purified.
Unfortunately, cyclic amides, difluoromethyl halides (HCF X),
2
difluoroalkyl halides, BrCF PO(OEt) and BrCFHCO Et didnot react
2
2
2
3
f-3i difluoroalkylated at the sterically hindered para-position in
with aldehydes to provide desired products. Further extension of
this protocol to aromatic ketones successfully furnished corre-
sponding para-difluoroalkylated products as well (Scheme 3). The
acetophenone derivatives performed well under the optimal
conditions (4a-4d). Other alkyl aromatic ketones were compatible
with the difluoroalkylation, providing the corresponding products
4e-4g in moderate to good yields. The diphenyl ketones afforded
monodifluoromethylation products 4h and 4i. 9-Fluorenone, the
important intermediate for organic synthesis and materials
science, also provided the mono-para-difluoroalkylated product
moderate to good yield. This reactivity is different to that observed
in previous meta-selective alkylation and difluoroalkylation
reactions [8], in which meta-substituted substrates are less
reactive than their ortho- or para-substituted analogues. Notably,
previous uninvestigated 2-naphthaldehyde only generated the
meta-difluoroalkylated product 3j. Heteroarenes, such as furan-2-
carbaldehyde and thiophene-2-carbaldehyde, are also viable
substrates, providing 3k and 3l in moderate yields. The current
methodology can be easily extended to the coupling of
Please cite this article as: Y. Cheng, Y. He, J. Zheng et al., Ruthenium(II)-catalyzed para-selective C ÀÀ H difluoroalkylation of aromatic aldehydes
and ketones using transient directing groups, Chin. Chem. Lett., https://doi.org/10.1016/j.cclet.2020.09.044

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Y. Cheng, Y. He, J. Zheng et al. / Chinese Chemical Letters xxx (2019) xxx–xxx
Scheme 4. Transformations of 3a.
4
j. 1-Tetralone and chromanone reacted smoothly with bromodi-
difluoroalkylated ketoprofen derivative (4n) and octabenzone
derivative (4o) were successfully obtained by this transformation.
Although H and F NMR of 4o is in agreement with literature [9a],
it was containment with aryl impurities and can not be further
purified.
Further conversion of difluoralkylated products can also be
achieved via transient directing group strategy. ortho-C–H
Methylation[12e], fluorination [12e], chlorination [12i] and
fluoroacetate to afford the corresponding para-difluoroalkylated
products 4k and 4l in 56% and 53% yields, respectively. Substrates
of 4m provided single difluoroalkylated products with high
selectivity at the para-position of the benzoyl ring rather than
the electronically rich aromatic ring. Directly introducing fluorine-
containing functional groups into bioactive compounds is an
effective method for new drug development. To our delight, the
1
19
Scheme 5. Preliminary mechanistic study.
Please cite this article as: Y. Cheng, Y. He, J. Zheng et al., Ruthenium(II)-catalyzed para-selective C ÀÀ H difluoroalkylation of aromatic aldehydes
and ketones using transient directing groups, Chin. Chem. Lett., https://doi.org/10.1016/j.cclet.2020.09.044

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5
possibility, cross-over H/D exchange experiment was carried
out, which substrates [D8]-1d and 1e were recovered without
H/D exchange (Scheme 5d). These results indicate the cyclo-
ruthenation cannot be obtained from coordination of A with Ru
catalysts under our conditions and is not responsible for para-
selectivity. When substrate 1a was subjected to the difluoroalkyl
radical generated conditions without Ru catalysts [16], a mixture of
para- and meta-difluoroalkylated products was obtained in
5
% yield (Scheme 5e). Therefore, we hypothesized para-selectivity
could be controlled by the steric and electronic feature of
complex B, which is similar to Zhou’s reports [17].
Based on these experiments, a mechanism is proposed for para-
selective difluoroalkylation of aromatic aldehydes and ketones
(Scheme 7). First, the TDG10 reacts with the 1a to form imine
intermediateA. SubsequentcoordinationofAandFaffordscomplex
B. A radical C, derived from 2-bromo-2,2-difluoroacetate via a
single-electron-transfer process [7], is trapped by B to generate D,
which releases product 3a, TDG10 and catalysis specices F.
In summary, we have developed a general transient directing
group strategy for para-selective C ÀÀ H difluoroalkylation of
aromatic aldehydes and ketones. The protocol can be performed
by using an inexpensive ruthenium catalyst, and allows the rapid
access to challenging para-difluoroalkylated aldehydes. Mecha-
nism investigation suggests that the distinct coordination of
ruthenium complex with imine moieties is responsible for para-
selectivity.
Scheme 6. Plausible coordinationmodeofruthenium complex withiminemoieties.
Declaration of competing interest
The authors report no declarations of interest.
Acknowledgments
The authors gratefully acknowledge support from the Univer-
sity Nursing Program for Young Scholars with Creative Talents in
Heilongjiang Province (No. UNPYSCT-2017124). Dr. Guijie Mao was
acknowledged for her help in the NMR spectrum.
Appendix A. Supplementary data
Supplementary material related to this article can be
found, in the online version, at doi:https://doi.org/10.1016/j.
cclet.2020.09.044.
Scheme 7. Proposed catalytic cycle.
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Please cite this article as: Y. Cheng, Y. He, J. Zheng et al., Ruthenium(II)-catalyzed para-selective C ÀÀ H difluoroalkylation of aromatic aldehydes
and ketones using transient directing groups, Chin. Chem. Lett., https://doi.org/10.1016/j.cclet.2020.09.044