Ruthenium-Catalyzed Difluoroalkylation of 8-Aminoquinoline Amides at the C5-Position

Article abstract of DOI:10.1002/ejoc.201701150

A ruthenium-catalyzed highly selective difluoromethylation of 8-aminoquinoline amides at the C5 position has been developed. It tolerates a broad range of functional groups, providing the corresponding difluoromethylated products in moderate to good yields. Preliminary experimental results indicate that the tricoordinate ruthenium intermediate is the key factor in achieving the C5-position selectivity.

Full text of DOI:10.1002/ejoc.201701150

DOI: 10.1002/ejoc.201701150
Communication
C–H Difluoroalkylation | Very Important Paper |
Ruthenium-Catalyzed Difluoroalkylation of 8-Aminoquinoline
Amides at the C5-Position
Changpeng Chen,[a] Runsheng Zeng,[b] Jingyu Zhang,*[a] and Yingsheng Zhao*[b]
Abstract: A ruthenium-catalyzed highly selective difluoro- moderate to good yields. Preliminary experimental results indi-
methylation of 8-aminoquinoline amides at the C5 position has cate that the tricoordinate ruthenium intermediate is the key
been developed. It tolerates a broad range of functional groups, factor in achieving the C5-position selectivity.
providing the corresponding difluoromethylated products in
Introduction
arylation of aromatic amides aided by a bidentate directing
group.[9] Later, the group of Ackermann disclosed a ruthenium-
catalyzed direct C–H arylation of aromatic amides employing a
triazole directing group.[10] Inspired by the recent advances in
ruthenium-catalyzed C–H-alkylation reactions,[11] we speculated
that the ortho-C–H difluoromethylation of benzoic acid can be
performed efficiently with a ruthenium catalyst and the assist-
ance of an 8-aminoquinoline auxiliary. To our surprise, the C–
H-functionalization reaction did not occur at the ortho position
of benzoic acid, but at the C5 position of 8-aminoquinoline.
Although carbon–heteroatom and C–C bond formations at the
C5 position of quinolines have been well explored (Scheme 1,
a),[12] the direct C–H difluoroalkylation at the C5-position of
quinolines (Scheme 1, b) has rarely been reported.[13] The group
of Wang reported a nickel-catalyzed C5-functionalized difluoro-
methylation of 8-aminoquinoline with good to excellent yields
and good tolerance of a broad substrate scope of 8-aminoquin-
oline scaffolds. However, the reaction requires very high tem-
peratures and expensive phosphorus ligands. Hence, there is
still room for development of a more convenient C5-position-
selective difluoromethylation. Herein, we report an example of
a ruthenium-catalyzed direct C–H difluoroalkylation at the C5
position of quinolines under mild conditions (Scheme 1, c).
Fluorinated organic compounds are widespread in medicinal
chemistry, agrochemicals, and materials sciences because of
their unique properties such as their high stability, high solubil-
ity, and biological properties.[1] In the past decades, direct
derivatization with a trifluoromethyl or fluorine functional
group has been extensively investigated.[2] However, the ap-
proach to the synthesis of difluoromethylated aromatic arenes
is still limited. In the past decades, transition-metal-catalyzed
difluoromethylation of prefunctionalized substrates has pro-
vided a convenient approach to achieving these organic mol-
ecules, as described by the groups of Hartwig, Zhang, Wang,
and others.[3] Because site-selective C–H functionalizations pro-
vide an efficient approach to the formation of C–C and carbon–
heteroatom bonds, it is of great importance in difluoromethyl-
ation through direct C–H functionalizations.[4] For example, the
group of Yamakawa developed a direct difluoromethylation of
various aromatic compounds by using Fenton's reagent as
catalyst in DMSO.[5] The direct difluoromethylation of arenes by
visible-light photoredox catalysis was reported by Liu and co-
workers.[4b] The group of Wang developed a Pd0-catalyzed
intramolecular aryldifluoromethylation of alkenes under mild
conditions.[6]
In recent years, ruthenium complexes have been shown to
display super-reactivity in promoting C–H functionalizations.[7]
There are a few reports of ruthenium-catalyzed C–H-activation
reactions assisted by bidentate directing groups.[8] In 2013,
Chatani and co-workers reported a ruthenium-catalyzed direct
[a] College of Physics, Optoelectronics and Energy & Collaborative Innovation
Center of Suzhou Nano Science and Technology, Soochow University,
Suzhou 215006, China
E-mail: jyzhang@suda.edu.cn
[b] Key Laboratory of Organic Synthesis of Jiangsu Province,
College of Chemistry, Chemical Engineering and Materials Science,
Soochow University,
Suzhou 215123, China
E-mail: yszhao@suda.edu.cn
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201701150.
Scheme 1. Ruthenium-catalyzed C–H functionalization of 8-aminoquinolines.
6947 © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communication
Results and Discussion
tuted quinoline at C2 position was also compatible and pro-
vided the corresponding product 3ac in 51 % yield. To our great
delight, the quinoline substituted at C3-position afforded the
difluoromethylated products (3ad–3af) in good yields. Notably,
the functional groups Br and I, which are easily transformed
into other functional groups, were well tolerated by the di-
fluoromethylation.
At the outset of this study, we used N-(quinolin-8-yl)benzamide
(1a) as the model substrate. The reaction of 1a (0.1 mmol) with
ethyl 2-bromo-2,2-difluoroacetate (BrCF2CO2Et, 2, 0.3 mmol) in
the presence of the catalyst [{RuCl2(p-cymene)}2] (5 mol-%) and
the base Na2CO3 (0.20 mmol) in DCE (0.5 mL) at 120 °C for 48 h
gave the difluoromethylated product 3a in 68 % yield (Table 1,
entry 1). The bases were then extensively screened. To our de-
light, the yield of the desired product 3a was dramatically im-
proved from 68 % to 81 % relative to that of other bases when
K2CO3 was applied in the reaction (Table 1, entry 2). Further
optimization showed that the choice of base also significantly
affected the reaction (Table 1, entries 1–8). Compound 3a was
not obtained without K2CO3 (Table 1, entry 9). A control experi-
ment confirmed that the Ru catalyst is essential for the difluoro-
methylation (Table 1, entry 10). Several other catalysts such as
FeCl3, Cu(OAc)2, and Pd(OAc)2 were screened under standard
reaction conditions. However, all these catalysts failed to give
3a but instead yielded the starting material (Table 1, entries
11–13).
Table 2. Substrate scope of 8-aminoquinolines.[a]
.
Table 1. Optimization studies.[a]
Entry
Catalyst
Base
Yield(3a)%
1
2
3
4
5
6
–
–
–
–
–
–
Na2CO3
K2CO3
Cs2CO3
NaHCO3
KHCO3
KOAc
68
81
35
21
42
0
7
8
9
–
–
–
K2HPO4
K3PO4
none
36
27
0
10
11
12
13
none
FeCl3
Cu(OAc)2
Pd(OAc)2
K2CO3
K2CO3
K2CO3
K2CO3
0
0
0
0
[a] Reaction conditions: 1 (0.2 mmol), 2 (0.6 mmol), [{RuCl2(p-cymene)}2]
(5 mol-%), K2CO3 (0.2 mmol), DCE (0.5 mL), 120 °C, 48 h. Isolated yields.
[a] Reaction conditions: 1a (0.1 mmol), 2a (0.3 mmol), [{RuCl2(p-cymene)}2]
(5 mol-%), base (0.1 mmol), solvent (0.25 mL), 120 °C,48 h. Yield was deter-
mined by using GC with tridecane as the internal standard.
Subsequently, a variety of functionalized difluoromethyl
bromides were investigated (Table 3). Various 2-bromo-2,2-di-
fluoroamides were well tolerated under the optimal reaction
conditions (4a–h). Importantly, methoxyamide was compatible
and gave the corresponding product in acceptable synthetic
yields (4b). Further screening revealed that all reactions with
dialkylamine, indoline, morpholine, and thiomorpholine pro-
ceeded well to afford the corresponding products in moderate
to good yields (4c–h). However, a secondary amide showed no
activity (4i). The specific reason for this inactivity is unclear,
probably the amide coordinated with the ruthenium catalyst
which inhibited the reaction completely.
Upon establishment of the optimal reaction conditions, we
explored the scope of 8-aminoquinoline amides. The results
clearly show that the electron-donating and withdrawing func-
tional groups substituting benzoic acid have no effect on the
ruthenium-catalyzed C5-position difluoromethylation (Table 2).
The reaction tolerated various functional groups well, such as
Me, MeO, tBu, F, Cl, Br, CF3, NMe2, and CHO to afford the corre-
sponding products in moderate to good yields (3a–3t). Reac-
tion of the several benzo-annelated heterocycles and hetero-
cyclic amides also gave moderate yields (3u–3x). We next ex-
To demonstrate the utility of the protocol, a gram-scale reac-
plored the substituent effects on the quinoline moiety. All reac- tion was carried out. Gratifyingly, the difluoromethylated prod-
tions with 6-methoxyl-8-aminoquinoline amides and 6-methyl- uct 3o was obtained in 79 % yield (Scheme 2, a). A series of
8-aminoquinoline amides proceeded well to afford the difluoro- experiments were performed to investigate the possible reac-
methylated products (3aa–3ab) in good yields. A methyl-substi- tion pathway. First, 2,2,6,6-tetramethyl-1-piperidinyloxy, a free-
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Table 3. Scope of difluoromethyl bromides.[a]
.
group-assisted ruthenium-catalyzed C–H activation is reversible
(Scheme 2, c). The difluoromethylated product 3y was not
formed when 2y was subjected to optimal reaction conditions,
and the isotope-labeling experiment was carried out with 1a-
D5. A kinetic isotope effect (kH/kD = 1.9) was observed. These
results indicate that the C–H cleavage step is a kinetically rele-
vant step.
On the basis of the above mechanistic studies and the rele-
vant literature,[3]
a plausible catalytic cycle is proposed
(Scheme 3).[9,13] First, 8-aminoquinoline amide 1a coordinates
to the Ru center to give ruthenium complex II; this is followed
by C–H activation, which affords complex III. The free radical
·CF2CO2Et is generated through single-electron transfer by the
ruthenium catalyst. CF2CO2Et is trapped by complex III to form
complex IV, which then undergoes oxidation by the RuIII com-
plex to afford 3a. Finally, ligand exchange of complex I with 1a
gives the product and regenerates complex II for the next cycle.
[a] Reaction conditions: 1 (0.2 mmol), 2 (0.6 mmol), [{RuCl2(p-cymene)}2]
(5 mol-%), K2CO3 (0.2 mmol), DCE (0.5 mL), 120 °C, 48 h. Isolated yields.
radical scavenger was added (Scheme 2, b). The difluoromethyl-
ation reaction was completely stopped, and the starting mate-
rial was recovered. This result suggests that the reaction in-
volves a free-radical pathway. When 2c was treated with
[{RuCl2(p-cymene)}2] and AcOD (10 equiv.) in DCE, significant
H/D scrambling at the ortho-position of 2-methoxybenzoic acid
was observed. This result indicates that the bidentate-directing-
Scheme 3. Plausible catalytic cycle.
Conclusion
We have developed an efficient ruthenium-catalyzed direct
C–H difluoroalkylation of 8-aminoquinoline amides at the C5
position under mild conditions. The difluoromethyl source ethyl
2-bromo-2,2-difluoroacetate is inexpensive. K2CO3 was found to
be the best base, and DCE is a good solvent. The reaction toler-
ates a wide range of substituents and gives corresponding
products in moderate to good yields.
Experimental Section
General Procedure for Ru-Catalyzed Difluoroalkylation of 8-
Aminoquinoline Amides: A mixture of 1 (0.2 mmol), [RuCl2(p-cym-
ene)2]2 (5 mol-%), 2 (0.6 mmol), K2CO3 (0.2 mmol) and DCE (0.5 mL)
in a 25 mL glass vial (sealed with PTFE cap) was heated at 120 °C
for 48 h. The reaction mixture was cooled to room temperature and
Scheme 2. Large-scale synthesis and mechanistic studies.
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Acknowledgments
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (No. 21572149), the Young
National Natural Science Foundation of China (Nos. 21402133
and 21403148), and the Prospective Study Program of Jiangsu
(BY2015039-08). The PAPD Project is also gratefully acknowl-
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Received: August 16, 2017
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