Copper-Catalyzed Direct C-5 Fluorination of 8-Aminoquinolines by Remote C-H Activation

Article abstract of DOI:10.1055/s-0037-1610130

A convenient method was developed for direct regioselective fluorination of 8-aminoquinolines at the C-5 position by copper-catalyzed remote C-H activation using Selectfluor as the electrophile fluorinating reagent. With this method, diverse fluorinated quinoline derivatives were facilely obtained under mild conditions with moderate yields.

Full text of DOI:10.1055/s-0037-1610130

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–E
letter
A
en
S.-S. Luo et al.
Letter
Synlett
Copper-Catalyzed Direct C-5 Fluorination of 8-Aminoquinolines
by Remote C–H Activation
Si-Si Luoa
Lan-Jun Sua
Yue Jianga
Xiao-Bao Lib
Zheng-Hui Lia
Huan Sun*a
Ji-Kai Liu*a
Cl
F
O
O
N
2BF4
Cu(OAc)2
MeOH, 80 °C
"F"
N
R
N
H
R
N
H
F
N
N
Selectfluor
16 examples
22–45% yield
R= alkyl, aryl, heterocycle
a School of Pharmaceutical Sciences, South-Central University
for Nationalities, Wuhan, 430074, P. R. of China
sunh15@163.com
Copper-catalyzed remote C-H fluorination
Mild reaction conditions
Excellent regioselectivity
jkliu@mail.kib.ac.cn
b Department of Civil and Environmental Engineering, North-
western University, Evanston, IL, 60060, USA
Received: 02.02.2018
Accepted after revision: 06.04.2018
Published online: 16.05.2018
tBu
O
O
HN
N
DOI: 10.1055/s-0037-1610130; Art ID: st-2018-w0070-l
N
O
Abstract A convenient method was developed for direct regioselec-
tive fluorination of 8-aminoquinolines at the C-5 position by copper-
catalyzed remote C–H activation using Selectfluor as the electrophile
fluorinating reagent. With this method, diverse fluorinated quinoline
derivatives were facilely obtained under mild conditions with moderate
yields.
N
O
Et
OH
F
Camptothecin
Insecticide
O
X
Et
R
N
N
Key words fluorination, copper-catalyzed, 8-aminoquinolines, Select-
fluor, remote C–H activation
M
N
N
I
Et
Electronic effect of AQ
in C-H activation
Ethyl Red
The quinolines are among the most abundant and im-
portant nitrogen-containing heterocycles found in natural
products, pharmaceuticals, and functional materials.1 The
distinctive fluorescence characteristics of quinoline2 lead to
the extensive application of quinolines in pH indicators, flu-
orescent probes, and colorants.3 Quinoline was demonstrat-
ed as a critical core in antitumoral, antifungal, anti-asth-
matic, and immune-depressing activities.4 In the past de-
cade, directed inert C–H functionalization offered span-
new insight on rapidly increasing molecular complexity of
quinoline (Figure 1). Aminoquinoline is a representative of
strong bident chelating DGs to facilitate diverse C–H func-
tionalizations pioneered by Daugulis.5 Recent work illus-
trated that the electronic property of the quinoline rings
could deeply influence the directing ability.6 Therefore,
functionalization of the quinoline core to enrich the struc-
tural motifs diversity is of great importance and value. Gen-
erally, the modification mainly focuses on C-2, C-3, C-4, C-8
position via Minisci reaction or metal-catalyzed C–C cou-
pling.7,8 The modification of C-5 position was not accessible
until Stahl reported the first chlorination example in 2013.9
Since then, more attention has been devoted to C-5 posi-
tion. Various transition metals (copper, iron, nickel, cobalt,
Figure 1 Selective molecules containing quinoline scaffolds
etc.) can be used to facilitate the C–H transformations in-
cluding halogenation,10 nitration,11 sulfonylation,12 azida-
tion,13 alkylation,14 phosphonation,15 etc. and to enormous-
ly enhance the structure diversity of quinolines.
Fluorine-containing functional group is another im-
portant class of building blocks of quinoline, which has
been constantly applied in drug design, agrochemicals, and
organic functional materials, due to their unique physical,
chemical, and biological properties.16 Consequently, inten-
sive research has been directed toward the development of
methods for effective incorporation of fluorine-containing
functional groups to quinoline.17 For these developed meth-
ods for fluorine introduction, transition-metal-catalyzed C–
H functionalization is an indispensable strategy, with
which Csp2–H bond and even inert Csp3–H bond can be
smoothly converted into the corresponding C–CF3, C–F, or
C–CHF2.18 However, the reaction site was mostly limited to
the ortho- or β- position of the directing group via an or-
ganometallic intermediate. Generally, the remote inert C–H
bond remained untouched and inaccessible without the di-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

B
S.-S. Luo et al.
Letter
Synlett
recting auxiliary. Accordingly, the direct incorporation of
fluorinated groups to the quinolines at C-5 position was rel-
atively rare. Trifluoromethylation was firstly achieved at C-
5 position using CuCl as the catalyst.19 Afterwards, perfluo-
ralkylated quinoline was obtained through a radical-based
approach under visible-light-induced or oxidant atmo-
sphere (Scheme 1, a).20 In spite of these successes of C-5 fluo-
rination, the direct C–F bond formation at the C-5 position
was scarce, except for an unique example using nickel as the
catalyst and NFSI as the fluorine source, which, however,
was limited by the relative high reaction temperature and
substrate compatibility (Scheme 1, b).21 Due to such limita-
tions in existing approaches, a methodology that allows a
more effective selective fluorination at C-5 position is
necessary. Here, we reported a copper-catalyzed 5-posi-
tion-selective C–H fluorination of 8-aminoquinolines with
broad functional group tolerance under mild conditions
(Scheme 1, c).
Table 1 Screening Reaction Conditions for Fluorination of 8-Amino-
quinolinea
F
O
O
20 mol% [M]
1.5 equiv "F"
N
N
H
H
solvent, 80 °C
N
N
Me
Me
1a
2a
Entry Catalyst
‘F’
Additive
Solvent
Yield (%)b
1
2
Ni(OAc)2
Selectfluor
–
–
–
–
–
–
–
–
–
–
–
–
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
DCE
22
Cu(OAc)2
CoF2
Selectfluor
Selectfluor
Selectfluor
Selectfluor
NFSI
30
3
23
4
NiCl2
20
5
Mn(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
NR
6
trace
trace
trace
22
7
A
8
B
a) Trifluoromethylation and perfluoralkylation of quinolines at C-5 position
9
C
Togni reagent
or
CF3
O
10
11
12
13
14
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
NR
CF3SO2Na
R
N
H
[Cu]
CH3CN
DMF
NR
N
O
trace
35
TMSCnF2n+1
PhI(TFA)2
CnF2n+1
R
N
H
O
KH2PO4
MeOH
MeOH
N
R
N
H
CnF2n+1
I
KH2PO4
Na2SO4
45
N
visible light
b) Nickel-catalyzed C-F formation at C-5 position
F
O
O
Cl
N
F
Cl
–
N
N
F
NFSI
–
–
BF4
BF4
BF4
R
N
H
R
N
H
F
NiSO4, DCE, 110 °C
N
N
A
B
C
c) This work
a Reaction conditions: 1a (0.1 mmol), ‘F’ source (0.15 mmol, 1.5 equiv),
transition-metal catalyst (0.02 mmol, 0.2 equiv), additive (0.2 mmol, 2.0
equiv), solvent (1 mL), 80 ℃, 12 h.
F
O
O
Cu(OAc)2
Selectfluor
b Isolated yield.
R
N
H
R
N
H
MeOH, 80 °C
N
N
MeOH was most appropriate, compared with DCE, MeCN,
DMF, etc. Increasing the amount of Selectfluor and reaction
temperature did not make a great difference. Further,
bases and additives were well studied and optimized with
KH2PO4, Na2SO4 selected for high yield.
Scheme 1 Incorporation of fluorinate-containing functional groups to
C-5 position of quinolines
8-Aminoquinoline derivative 1a was chosen as the
model substrate for reaction conditions development (Table
1). A variety of transition metals were attempted and
Selectfluor was used as the fluorine source at 80 ℃. Among
the transition metals, Cu(OAc)2demonstrated the highest
activity, giving 30% yield. CoF2, Ni(OAc)2 also accelerated the
reaction smoothly but at lower yield compared to Cu(OAc)2,
however, when NiCl2 was used, the chlorination product at
C-5 position was obtained as byproduct.
Diverse electrophile fluorinating reagent, such as NFSI,
1-fluoro-pyridine salts, were also investigated. Among
these reagents, Selectfluor offered the most satisfying yield.
Moreover, the screening of reaction solvents indicated that
With the optimized conditions in hand, we then exam-
ined the scope of functional group tolerance. As shown in
Scheme 2, a variety of 8-aminoquinoline derivatives were
smoothly converted into the desired fluorinated product
with moderate yields. Aromatic substrates with a broad
substitution pattern and of different electronic nature were
well tolerated. Halogen, no matter bromide or chloride, did
not interfere the transition-metal-catalyzed process.
Arenes bearing para-, meta-, or disubstituted groups afford-
ed the desired fluorinated product successfully. Steric hin-
drance from the ortho substitution showed little impact on
the fluorination. Substrates with strong electron-with-
drawing groups, such as NO2 and CN, showed unsatisfying
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

C
S.-S. Luo et al.
Letter
Synlett
F
20 mol% Cu(OAc)2
1.5 equiv Selectfluoro
O
O
R
N
H
R
N
H
2.0 equiv KH2PO4
Na2SO4, MeOH, 80 °C
N
N
1
2
F
F
F
F
O
Me
OMe
Cl
N
N
N
N
H
HN
HN
HN
N
O
O
O
2a, 45%
2b, 42%
2c, 28%
2d, 35%
F
F
F
F
Me
Cl
F
Br
N
N
N
N
HN
HN
HN
HN
O
O
O
O
2e, 32%
2f, 30%
2g, 38%
2h, 31%
F
F
F
F
N
N
HN
F
O
R
S
N
N
HN
O
F
HN
HN
O
MeO
OMe
O
F
F
2k, R = CN, < 5%
2l, R = NO2, < 5%
F
2i, 34%
2j, 23%
2m, 25%
F
F
F
F
N
N
N
N
Me
Me
Me
HN
HN
HN
HN
O
O
Cl
Me
O
O
2n, 41%
2o, 34%
2p, 36%
2q, 30%
Scheme 2 Substrate scope for the fluorination of quinoline at C-5 position
yields. Heterocycles and alkyl substrates, on the other hand,
demonstrated well tolerance under the fluorinated condi-
tions.
organometallic heterocycle A, which was then oxidized to
Cu(III) in the presence of Selectfluor, accompanied by fluo-
rine radical formation. Subsequently, a SET approach hap-
pened to afford the cationic quinoline radical intermediate
C. The C-5 position of intermediate C was attacked by fluo-
rine radical to generate intermediate D. A concerted proton
transfer/demetallation step provided the final fluorination
product and released the Cu(OAc)2 for a new catalytic cycle.
As previous reported, hydrolysis of amide bond always
requires harsh conditions, such as strong bases or acids and
high temperature.21 However, under our fluorination condi-
tions, hydrolysis of the amide bond occurred simultaneous-
ly to afford the fluorinated 8-amino quinoline, which offers
more opportunities for further transformation (Scheme 3).
However, considering the difluorinated product as byprod-
uct, further reaction modification was necessary and un-
derway.
F
20% Cu(OAc)2
O
1.5 equiv Selectfluoro
Me
N
H2N
2.0 KH2PO4, Na2SO4
MeOH, 80 °C
H
N
N
Based on the related reports,19,21 the plausible mecha-
nism that involves a single-electron transfer (SET) approach
was proposed (Scheme 4). Initially, the coordination of
substrate 1 with Cu(II) generated the five-membered
2r, 22%
Scheme 3 Hydrolysis of amide bond to afford the fluorinated 8-amino
quinoline
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

D
S.-S. Luo et al.
Letter
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O
R
N
CuII
O
Selectfluor
N
AcO
R
N
H
OAc
A
N
1
Cu(OAc)2
F
O
O
R
N
CuIII
F
R
N
H
N
Proton
transfer
N
AcO
OAc
2
B
H
O
N
F
R
SET
CuII
N
AcO
OAc
D
O
Radical
coupling
R
N
CuII
N
AcO
OAc
C
Scheme 4 Proposed mechanism
In conclusion, we successfully developed an efficient
and practical method for the direct C-5 fluorination of
quinoline scaffolds by making use of cheap and readily
available Cu(OAc)2 as the catalyst and Selectfluor as the effi-
cient fluorine source.22 An excellent regioselectivity and
good functional group tolerance were demonstrated. For
this transformation, a single-electron transfer approach
was proposed, and further mechanistic studies are under-
way in our group.
Primary Data
for this article are available online at https://doi.org/10.1055/s-0037-
1610130 and can be cited using the following DOI: 10.4125/pd0098th.
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References and Notes
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Funding Information
The authors gratefully acknowledge funding from National Natural
Science Foundation of China (81561148013, 31560010, 21502239),
Key Projects of Technological Innovation of Hubei Province (No.
2016ACA138), Hubei Provincial Natural Science Foundation of China
(2018CFB222), "the Fundamental Research Funds for the Central
Universities", South-Central University for Nationalities (CZQ17008).
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610130.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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N-(5-Fluoroquinolin-8-yl)-4-methylbenzamide (2a)
45% yield, white solid. 1H NMR (600 MHz, chloroform-d): δ =
10.52 (s, 1 H), 8.94–8.85 (m, 2 H), 8.47 (dd, J = 8.4, 1.7 Hz, 1 H),
8.01–7.94 (m, 2 H), 7.56 (dd, J = 8.4, 4.2 Hz, 1 H), 7.40–7.33 (m, 2
H), 7.30–7.27 (m, 1 H), 2.46 (s, 3 H). 13C NMR (151 MHz, chloro-
form-d): δ = 165.48 , 153.87 (d, J = 250.7 Hz), 149.22, 142.55,
139.09 (d, J = 3.0 Hz), 132.28, 131.35 (d, J = 3.0 Hz), 129.98 (d, J =
3.0 Hz), 129.62, 127.37, 121.87 (d, J = 3.0 Hz), 119.00 (d, J = 3.0
Hz), 116.09 (d, J = 7.6 Hz), 110.72 (d, J = 19.6 Hz), 21.71. 19F NMR
(565 MHz, chloroform-d): δ = –129.22. HRMS (ESI): m/z calcd
for C17H14ON2F [M + H]+: 281.1090; found: 281.1086.
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4-Fluoro-N-(5-fluoroquinolin-8-yl)benzamide (2g)
38% yield, white solid. 1H NMR (600 MHz, chloroform-d): δ =
10.50 (s, 1 H), 8.91 (dd, J = 4.2, 1.6 Hz, 1 H), 8.87 (dd, J = 8.6, 5.3
Hz, 1 H), 8.48 (dd, J = 8.4, 1.7 Hz, 1 H), 8.12–8.06 (m, 2 H), 7.57
(dd, J = 8.4, 4.2 Hz, 1 H), 7.30–7.23 (m, 3 H). 13C NMR (151 MHz,
chloroform-d): δ = 165.83, 164.23, 164.16, 153.89 (d, J = 252.2
Hz), 149.16, 138.92 (d, J = 3.0 Hz), 131.16 (d, J = 3.0 Hz), 130.96
(d, J = 4.5 Hz), 129.95 (d, J = 4.5 Hz), 129.64 (d, J = 9.1 Hz), 121.82
(d, J = 1.5 Hz), 118.90 (d, J = 18.1 Hz), 116.07 (d, J = 9.1 Hz),
115.97 (d, J = 22.6 Hz), 110.59 (d, J = 19.6 Hz). 19F NMR (565
MHz, chloroform-d): δ = –107.51, –128.74. HRMS (ESI): m/z
calcd for C16H11ON2F2 [M + H]+: 285.0839; found: 285.0833.
N-(5-Fluoroquinolin-8-yl)-2,6-dimethoxybenzamide (2i)
34% yield, white solid. 1H NMR (600 MHz, chloroform-d): δ =
10.10 (s, 1 H), 8.99 (dd, J = 7.6, 1.3 Hz, 1 H), 8.78 (dd, J = 4.2, 1.7
Hz, 1 H), 8.18 (dd, J = 8.2, 1.7 Hz, 1 H), 7.61 (t, J = 7.9 Hz, 1 H),
7.56 (dd, J = 8.3, 1.4 Hz, 1 H), 7.45 (dd, J = 8.2, 4.2 Hz, 1 H), 7.14
(dd, J = 11.2, 9.1 Hz, 1 H), 6.64 (dd, J = 9.2, 3.3 Hz, 1 H), 4.01 (d,
J = 1.9 Hz, 3 H), 3.83 (s, 3 H). 13C NMR (151 MHz, chloroform-d):
δ = 162.92 (d, J = 3.0 Hz), 153.18 (d, J = 3.0 Hz), 150.80 (d, J =
241.6 Hz), 148.35, 145.77 (d, J = 12.1 Hz) 138.60, 136.44, 134.76,
128.10, 127.60, 121.97, 121.73, 117.79 (d, J = 21.1 Hz), 117.01,
106.10 (d, J = 7.6 Hz), 62.32 (d, J = 4.5 Hz), 56.49. 19F NMR (565
MHz, chloroform-d): δ = –139.30, –139.33. HRMS (ESI): m/z
calcd for C18H16O3N2F [M + H]+: 327.1145; found: 327.1140.
2,3,4,5,6-Pentafluoro-N-(5-fluoroquinolin-8-yl)benzamide (2j)
23% yield, white solid. 1H NMR (600 MHz, chloroform-d): δ =
10.19 (s, 1 H), 8.87 (ddd, J = 4.7, 3.0, 1.7 Hz, 1 H), 8.83 (ddd, J =
8.9, 5.3, 3.8 Hz, 1 H), 8.48 (ddd, J = 8.4, 4.2, 1.7 Hz, 1 H), 7.58
(ddd, J = 8.5, 4.2, 2.9 Hz, 1 H), 7.32–7.27 (m, 1 H). 13C NMR (151
MHz, chloroform-d): δ = 155.23, 154.61 (d, J = 253.7 Hz),
149.49, 145.35 (m), 143.66 (m), 141.81 (m), 138.65 (m), 136.98
(m), 130.07 (m), 122.08, 118.90 (dd, J = 18.4, 3.6 Hz), 116.99 (d,
J = 9.1 Hz), 116.94 (m), 110.51(dd, J = 19.6, 2.8 Hz). 19F NMR
(565 MHz, chloroform-d): δ = –126.79, –139.92 (d, J = 19.0 Hz),
–149.94 (d, J = 20.9 Hz), –149.99, –159.64 (t, J = 19.2 Hz). HRMS
(ESI): m/z calcd for C16H7ON2F6 [M + H]+: 357.0463; found:
357.0457.
(20) (a) Chen, H.; Li, P. H.; Wang, M.; Wang, L. Org. Lett. 2016, 18,
4794. (b) Xu, J.; Qiao, L.; Ying, B.; Zhu, X.; Shen, C.; Zhang, P. Org.
Chem. Front. 2017, 4, 1116. (c) Arockiam, P.; Guillemard, L. Adv.
Synth. Catal. 2017, 359, 2571.
(21) Ding, J.; Zhang, Y.; Li, J. Org. Chem. Front. 2017, 4, 1528.
(22) Fluorinated Product 2a–t, General Procedure
8-Aminoquinoline derivatives 1 (0.1 mmol, 1.0 equiv), Cu(OAc)2
(0.02 mmol, 0.2 equiv), Selectfluor (0.15 mmol, 1.5 equiv),
KH2PO4 (0.2 mmol, 2.0 equiv), and Na2SO4 (50 mg) were
weighed into an oven-dried Schlenk tube, and MeOH (1 mL) was
added. The reaction vessel was capped and vacuum-flushed
with N2 three times. The reaction was stirred under N2 atmo-
sphere at 80 °C, and the progress of the fluorination was moni-
tored by TLC. Upon complete consumption of 1, the reaction
was cooled to room temperature. Volatile solvent and reagents
were removed by rotary evaporation, and the residue was puri-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E