Transition-Metal-Free Regioselective C–H Bond Fluorination of 8-Amidoquinolines with Selectfluor

Article abstract of DOI:10.1002/ejoc.201800389

A simple and efficient transition-metal-free protocol for the regioselective C–H bond fluorination of 8-aminoquinoline scaffolds with Selectfluor was developed. The reaction has a broad substrate scope and provides facile access to the corresponding C-5 f

Full text of DOI:10.1002/ejoc.201800389

A Journal of
Accepted Article
Title: Regioselective C−H Bond Fluorination of 8-Amidoquinolines
with Selectfluor on the C5-Position under Transition-Metal-Free
Conditions
Authors: Lei Wang, Hao Chen, Pinhua Li, and Min Wang
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800389
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800389
Supported by

10.1002/ejoc.201800389
European Journal of Organic Chemistry
FULL PAPER
Regioselective C−H Bond Fluorination of 8-Amidoquinolines with
Selectfluor on the C5-Position under Transition-Metal-Free
Conditions
Hao Chen,a Pinhua Li,*a Min Wang,a and Lei Wang*a,b
Abstract: A simple and efficient protocol for the regioselective C−H
bond fluorination of 8-aminoquinoline scaffolds with Selectfluor
under transition-metal-free conditions was developed. The reaction
has a broad substrate scope and provides a facile and useful access
to the corresponding C5-fluorinated quinolines in good yields.
aminoquinoline and picolinic acid auxiliaries (Scheme 1a-II).[13]
Despite these remarkable advances in the directed fluorination
of aromatic C(sp2)−H bonds, developing new routes to C(sp2)–F
formation from readily available precursors under mild and
environmentally friendly reaction conditions is highly desirable.
Directing
Me
Fluorination of Arenes:
(a)
Group-Assisted
Introduction
Me
Me
F
Fluorinated organic molecules are prevalent in pharmaceuticals,
agrochemicals and imaging materials.[1] In recent years, the
selective introduction of fluorine atoms into small organic
molecules has emerged as a new strategy for modulating the
properties of chemical leads in drug discovery.[2] Although a
variety of methods for the C−F bond formation have been
developed in the past few decades, the fact that C−F bond
construction remains a challenging project, particularly for the
synthesis of aryl fluorides.[3] Classical methods for preparation of
fluoroaromatics framework include the conversion of amines via
the aryldiazonium salt with HBF4,[4] the fluorination of Grignard
reagents with electrophilic N-fluorinated reagents,[5] palladium-
mediated fluorination of arylboronic acids,[6] copper-mediated
fluorination of aryl iodides and arylboronate esters,[7] as well as
the transformation of aryl triflates with simple fluoride salts.[8]
However, most of the existing methods require either harsh
reaction conditions or highly specialized reagents, which is a
great disadvantage in the preparation of complex fluoroarenes.
Transition-metal-catalyzed C−H bond fluorination has
emerged as a highly efficient strategy for the rapid construction
of fluorinated organic molecules.[9] In 2006, Sanford and co-
workers reported a pioneering study on the Pd(II)-catalyzed
ortho-C−H fluorination directed by pyridyl groups using
Pd(OAc)2
+
N
F
(I)
Me
N
N
H
BF4
Me
O
O
CuI
+
N
H
N
H
AgF
(II)
N
N
H
F
Selective C-H Fluorination of
(b)
(c)
Pyridines:
CH3CN
rt, 1 h
+
R
R
AgF2
N
N
H
F
This Work:
Fluorination:
KHCO3
C5
Regioselective
H
F
O
O
+
Selectfluor
R
N
R
N
Transition-Metal-Free
H
H
N
N
Scheme 1. Approaches for aryl C(sp2)−H bond fluorination.
In the past few years, the C5-functionalization of quinolines
has been achieved considerable attention via transition-metal-
catalyzed
remote
C−H
functionalizations,
and
their
halogenation,[14] allylation,[15] chalcogenation,[16] sulfonylation,[17]
amination,[18] nitration[19] and phosphonation[20] on the C5-
positions of quinolines have been developed. Most recently, a
Ni-catalyzed C5-fluorination of 8-aminoquinolines with NFSI was
realized.[21] It is worth to note that the remote oxidative C–H
functionalization of 8-acylaminoquinolines on the C5-position
under metal-free conditions has also received much attention in
the past two years.[22] In view of the synthetic utility for the
functionalization of quinolines, the development of the new
synthetic methodology on their frameworks is essential. As a
part of ongoing efforts on C−H functionalization of 8-
acylaminoquinolines on the C5-position,[23] herein we
demonstrate the fluorination of 8-aminoquinoline scaffolds on
their C5-positions with Selectfluor via the direct C−H
functionalization under transition-metal-free conditions (Scheme
1c).[24] This method proceeded under simple reaction conditions
and showed good air and moisture tolerance and functional
group compatibility.
electrophilic
fluorinating
reagents
(Scheme
1a-I).[10]
Subsequently, Yu et al developed the Pd(II)-catalyzed
fluorination of aromatic C(sp2)−H bonds of triflamide-protected
benzylamines and N-perfluoroaryl benzamides.[11] In 2013,
Hartwig’s group presented an applicable and safe method for
thesite-selective fluorination of a single C−H bond in pyridines
and diazines using commercially available silver(II) fluoride
(Scheme 1b).[12] Meanwhile, Daugulis demonstrated the copper-
catalyzed fluorination of C(sp2)–H bonds assisted by 8-
[a]
[b]
H. Chen, Prof. P. Li, Prof. M. Wang, Prof. Dr. L. Wang
Department of Chemistry, Huaibei Normal University
Huaibei 235000 Anhui (P. R. China)
E-mail: pphuali@126.com, leiwang@chnu.edu.cn.
Prof. Dr. L. Wang
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032(P. R. China)
Supporting information and the ORCID identification number for the
author of this article can be found under:
Results and Discussion
https://doi.org/10.1002/chem.xxxxx.
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10.1002/ejoc.201800389
European Journal of Organic Chemistry
FULL PAPER
Initially, N-(quinolin-8-yl)benzamide (1a) and N-chloromethyl-N'-
fluorotriethylenediammoniumbis(tetrafluoroborate) (Selectfluor,
2a) were chosen as model substrates for optimization of the
reaction conditions, and the results are outlined in Table 1.
When the reaction was carried out in ethyl alcohol at 120 °C for
12 h in the presence of K2CO3 as a base, the remote C5-
fluorination proceeded and delivered a sole product 3a in 5%
yield (Table 1, entry 1).The structure of 3a was characterized by
1H and 13C NMR. An improved yield (33%) of 3a was obtained
when KHCO3 was used as a base, while NaHCO3 was found to
be less effective. However, other bases, such as Na2CO3,
Cs2CO3,
diazabicyclo[5.4.0]undec-7-ene),
aminopyridine) failed in this reaction (Table 1, entries 2−10).
Further screening showed that Ni(dppf)Cl2, Cu(OAc)2 and
Fe(OTf)2 were no longer the effective catalyst for the reaction
K3PO4,
K2HPO4,
KF,
DMAP
DBU
(1,8-
(4-dimethyl
n
(Table 1, entry 11). Among the examined solvents, BuOH was
the best of choice (Table 1, entries 12−20). Other fluorinating
reagents, including NSFI, Selectfluor II were also examined,
both of them failed in this transformation (Table 1, entries 21 and
-
H
F
2BF4
O
O
KHCO
Cl
equiv)
3 (2.0
120 o 12 h
N
+
R1
N
R1
N
N+
nBuOH
R2
R2
C,
H
(2 mL),
H
N
N
F
Table 1. Optimized reaction conditions.[a]
2a
3
1
F
-
H
O
2BF4
O
Base
equiv)
(2.0
Cl
+
N
Ph
N
---------------------------------------------------------------------------------
120 o 12 h
Ph
N
N+
Solvent
C,
H
(2.0 mL),
H
N
N
F
F
F
F
O
O
O
3a
1a
2a
N
N
N
H
H
H
N
N
N
H3CO
H3C
Entry
Base
Solvent
Yield (%)[b]
3a
3b
3c 71%
70%
73%
,
,
,
F
F
F
1
2
3
4
5
6
7
8
9
10
K2CO3
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
5
O
O
O
KHCO3
Na2CO3
33
N
N
N
H
H
H
N
N
N
Ph
X
F3C
Trace
14
=
=
3e
X
X
,
Cl,
Br, 55%
50%
3d
3g
61%
,
68%
,
3f
,
NaHCO3
Cs2CO3
K3PO4
K2HPO4
KF
F
F
F
O
O
O
Trace
Trace
Trace
Trace
N. R.
N. R.
Cl
Cl
O
N
N
N
H
H
H
N
N
N
3j
64%
,
3h 57%
,
3i
68%
,
F
F
F
O
O
O
S
DBU
N
N
N
H
H
N
H
N
N
DMAP
3m
, 50%
3k 57%
3l
,
, 59%
38[c], 37[d],
F
F
11
KHCO3
EtOH
F
31[e]
O
O
O
N
N
N
H
12
13
14
15
16
17
18
19
20
21
22
23
24
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
nPrOH
nBuOH
tBuOH
45
H
H
N
N
N
70
3n
64%
,
3o
50%
,
3p 71% CH3
,
36
F
F
F
O
O
O
1-Pentanol
1-Hexanol
DMF
41
CH3
C2H
N
H
N
N
H
H
25
N
N
N
Ph
3s 60%
,
N. R.
N. R.
N. R.
15
N. R.[f]
Trace[g]
45[h], 68[i]
48[j], 70[k]
3r
3q
65%
,
, 52%
DMSO
DCE
CH3
OCH3
F
F
F
O
O
O
Cl
N
N
H
N
H
H
Toluene
nBuOH
nBuOH
nBuOH
nBuOH
N
N
N
3u
3v
60%
,
63%
3t
,
53%
,
H3C
HN
F
F
O
F
O
CH3
N
H
CH3
N
H
N
N
O
N
CH3
Cl
[a] Reaction Conditions: 1a (0.25 mmol), 2a (0.50 mmol), base (0.50 mmol,
3y 55%
,
3w
48%
,
3x
63%
,
[b]
2.0 equiv), solvent (2.0 mL), 120 °C, 12 h. Isolated yield. [c] Ni(dppf)Cl2 (5
[d]
[e]
mol%) was added. Cu(OAc)2 (5 mol%) was added. Fe(OTf)2 (5 mol%)
[f]
Scheme 2. Substrate scope of amides [Reaction conditions: 1 (0.25
mmol), 2a (0.50 mmol), KHCO3 (0.50 mmol, 2.0 equiv), n-butyl alcohol
(2.0 mL), 120 °C, 12 h; isolated yield of the product].
was added.
Selectfluor.
NFSI (N-Fluorobenzenesulfonimide) was instead of
[g]
Selectfluor
II
{1-Fluoro-4-methyl-1,4-
was instead of
Selectfluor. [h] 110 °C. [i] 130 °C. [j] 8h. [k] 16 h. N. R. = No Reaction.
diazoniabicyclo[2.2.2]octanebis-(tetrafluoroborate)}
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10.1002/ejoc.201800389
European Journal of Organic Chemistry
FULL PAPER
22). The reaction temperature and the reaction time were
optimized, also shown in Table 1 (entries 23−24).
oxidation was captured, and the corresponding adduct D was
detected by HRMS (Scheme 4a and Supporting Information). It
is indicated that the radical process might be involved in the
reaction. Moreover, when C5-position hydrogen of 1a was
substituted by a chlorine atom, no desired product was obtained
and the starting materials were recovered (Scheme 4b).
With the optimized reaction conditions in hand, we
subsequently explored the substrate scope with respect to 8-
aminoquinoline amides, and the results are illustrated in Scheme
2. It can be seen from Scheme 2 that the protecting groups on
amino moiety have no obvious influence on the reaction.
Aromatic amides with a variety of substituted groups including
electron-donating groups (Me, MeO) and electron-withdrawing
groups (Ph, Cl, Br, CF3) on the benzene rings exhibited high
reactivity to Selectfluor (2a), and the desired products (3a−g)
were obtained in high yields. In addition, the structure of 3c was
further confirmed by X-ray single crystal analysis.[25] It should be
noted that disubstituted (3,4-dichloro)benzamide, 2-naphthamide
and heterocyclic amides (furan-2-carboxamide and thiophene-2-
carboxamide) could also afford the corresponding C5-fluorinated
products (3h−k) in moderate to good yields. Furthermore, the
reaction scope is beyond aromatic amides, aliphatic amides
including methacrylamide, cinnamamide, pivalamide and
cyclohexanecarboxamide have a good suitability for the reaction
with 2a, providing the desired products (3l−o) in moderate yields.
We next explored the applicability of the present protocol for
diverse 8-aminoquinoline scaffolds. The results indicated that
this reaction is not sensitive to the electron density on the
quinoline rings. The quinoline scaffolds bearing both electron-
donating groups and electron-withdrawing groups were well
tolerated under the standard reaction conditions and the desired
products (3p−w) were generated in moderate to good yields.
The reaction of disubstituted 8-aminoquinoline could also
undergo to give the desired products (3x−y) in moderate yields.
To further explore the scope of substrate, a series of
analogous of quinolones was investigated, which are listed in
Scheme 3. Under the optimized reaction conditions, the reaction
of N-methyl-N-(quinolin-8-yl)benzamide (4) with 2a failed to
generate the C5-fluorinated product and the starting materials
were recovered. Moreover, quinolin-8-ylbenzoate (5), N-
(quinolin-8-yl)benzenesulfon-amide (6), 8-aminoquinoline (7)
and its derivative N,N-dimethyl-8-aminoquinoline (8) were all
ineffective in the reaction.
mmol)
SelectFluor
KHCO
(0.50
equiv)
3a 0%
,
O
3 (2.0
tBu
OH
Ph
N
H
nBuOH
(a)
O
120 o
C
N
BHT
(2 equiv),
Ph
N
1a
H
N
tBu
detected
HRMS!
by
Cl
mmol)
SelectFluor
KHCO
O
(0.50
equiv)
1z
99%
,
3 (2.0
no
occurred!
reaction
Ph
N
H
(b)
the starting materials
recoveried!
nBuOH
120 o 12 h
N
1a
0%
,
1z
C,
Scheme 4. Control experiments.
Although the exact mechanism remains unclear up till now, on
the basis of our experimental results and the literature,[26]
mechanistic hypothesis for the transition-metal free
a
regioselective C−H fluorination of 8-aminoquinoline amide is
proposed, as shown in Scheme 5. The initial step involves a
proton-coupled electron transfer (PCET)[27] process via the
transfer of a single electron (single-electron transfer, SET) and a
single proton (deprotonation step) in the presence of a base
(KHCO3), converting 8-aminoquinoline amide (1a) into an
intermediate A, along with the generation of free radical
intermediate B. Then 8-aminoquinoline radical C is generated in
situ from A through a resonance. The subsequent step is a
fluorine atom transfer between the radical C and intermediate B
to generate the desired product 3a. Further investigation is being
conducted to afford evidence for the proposed mechanism.
Cl
N
-
N+
2BF4
-
BF4
F
O
O
Cl
rocess
N
N
PCET p
+
+
F
Ph
N
Ph
N
H
ase
B
N
N
F
A
B
a
1
H
O
O
O
O
-
S
2BF4
N
N
O
OH
H
Cl
N
t
t
u
N
CH3
N
N
u
B
B
N
4
5
6
F
B
F
O
O
-
a om rans er
F
t
t
f
BHT
Ph
N
Ph
N
H3C
O
H
H
N
H2N
N
N
-
BF4
C
Ph
N
H
CH3
N
N
a
3
D
7
8
Cl
N
N
N
e ec e
d by HRMS!
d
t
t
Scheme 5. Plausible mechanism.
Scheme 3. Ineffective C5-fluorination of substrates (4−8).
In order to gain insight into the reaction mechanism, some
control experiments, including free radical inhibition and trapping
experiments were performed. It was found that the remote C−H
fluorination was completely inhibited in the presence of 2,6-di-
tert-butyl-4-methylphenol (BHT) as a free radical scavenger.
Meanwhile, the 8-aminoquinoline C5 radical (C, shown in
Scheme 5) generated in situ from 1a through a single electron
Conclusions
In summary, we have established a green and convenient
method for C5-fluorination of 8-aminoquinoline scaffolds under
transition-metal-free conditions. The reaction system shows
tolerance toward numerous 8-aminoquinoline amides, giving the
corresponding products in good yields. On the basis of
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10.1002/ejoc.201800389
European Journal of Organic Chemistry
FULL PAPER
experimental investigations,
a free radical cross-coupling
3.6 Hz), 129.05, 127.25, 121.62 (d, J = 2.5 Hz), 118.75 (d, J = 18.2
Hz), 115.77 (d, J = 7.5 Hz), 113.97, 110.46 (d, J = 19.4 Hz), 55.41.
HRMS (ESI) ([M+H]+) Calcd. For C17H14FN2O2: 297.1034, Found:
297.1032.
pathway underlying the reaction mechanism is proposed.
Further explorations for fluorination of other heteroarene
systems under transition-metal free conditions are currently
underway in our laboratory.
N-(5-Fluoroquinolin-8-yl)-4-methylbenzamide (3c). White solid
(49.7 mg, 71% yield), m.p. 135–137 °C. 1H NMR (400 MHz, CDCl3) δ:
10.50 (s, 1H), 8.91−8.88 (m, 2H), 8.45 (dd, J1 = 1.4 Hz, J2 = 8.4
Hz,1H), 7.97 (d, J = 8.1 Hz, 2H), 7.54 (dd, J1 = 4.3 Hz, J2 = 8.4 Hz,
Experimental Section
General remarks
1
All H NMR and 13C NMR spectra were recorded on a 400 MHz
1H), 7.35 (d, J = 8.0 Hz, 2H), 7.27 (t, J = 8.8 Hz, 1H), 2.46 (s, 3H); 13
C
Bruker FT-NMR spectrometers (400 MHz or 100 MHz,
respectively). All chemical shifts are given as δ value (ppm) with
reference to tetramethylsilane (TMS) as an internal standard. The
peak patterns are indicated as follows: s, singlet; d, doublet; t,
triplet; m, multiplet; q, quartet. The coupling constants, J, are
reported in Hertz (Hz). High resolution mass spectroscopy data of
the product were collected on a Waters Micromass GCT
instrument. High resolution mass spectroscopy data of the
product were collected on an Agilent Technologies 6540 UHD
Accurate-Mass Q-TOF LC/MS (ESI).
The chemicals and solvents were purchased from commercial
suppliers either from Aldrich (USA) or Shanghai Chemical
Company (China) without further purification. All the solvents
were dried and freshly distilled prior to use. All the reactions were
carried out under air atmosphere. Products were purified by flash
chromatography on 100–200 mesh silica gels, SiO2.
NMR (100 MHz, CDCl3) δ: 165.29, 152.92 (d, J = 249.5 Hz), 149.05,
142.35, 139.00 (d, J = 3.1 Hz), 132.24, 131.27 (d, J = 4.1 Hz), 129.79
(d, J = 3.7 Hz), 129.45, 127.24, 121.66 (d, J = 2.6 Hz), 118.82 (d, J =
18.1 Hz), 115.96 (d, J = 7.6 Hz), 110.50 (d, J = 19.5 Hz), 21.50.
HRMS (ESI) ([M+H]+) Calcd. For C17H14FN2O: 281.1085, Found:
281.1084.
N-(5-Fluoroquinolin-8-yl)-[1,1'-biphenyl]-4-carboxamide
(3d).
1
White solid (58.2 mg, 68% yield), m.p. 222–224 °C. H NMR (400
MHz, CDCl3) δ: 10.60 (s, 1H), 8.95−8.91 (m, 2H), 8.48 (dd, J1 = 1.6
Hz, J2 = 8.4 Hz, 1H), 8.17−8.15 (m, 2H), 7.80−7.78 (m, 2H),
7.69−7.67 (m, 2H), 7.57 (dd, J1 = 4.3 Hz, J2 = 8.4 Hz, 1H), 7.53−7.49
(m, 2H), 7.44−7.41 (m, 1H), 7.29 (t, J = 9.1 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ: 165.01, 153.02 (d, J = 249.8 Hz), 149.12, 144.68,
140.00, 139.01 (d, J = 3.0 Hz), 133.66, 131.17 (d, J = 4.2 Hz), 129.84
(d, J = 3.6 Hz), 128.95, 128.06, 127.76, 127.46, 127.23, 121.73 (d, J
= 2.3 Hz), 118.84 (d, J = 17.9 Hz), 116.07 (d, J = 7.5 Hz), 110.52 (d, J
= 19.6 Hz). HRMS (ESI) ([M+H]+) Calcd. For C22H16FN2O: 343.1241,
Found: 343.1244.
General procedure for the C5-fluorination of 8-aminoquinolines
8-Aminoquinoline amide (1a, 0.25 mmol), Selectfluor (2a, 0.50
mmol), KHCO3 (0.50 mmol) and nBuOH (2.0 mL) was added to a 15
mL Schlenk tube, and the reaction mixture was stirred in an oil
bath at 120 °C for 12 h. Then the reaction mixture was cooled
down to room temperature and the reaction solution was
concentrated under reduced pressure to yield crude product,
which was purified by flash chromatography (silica gel, petroleum
ether/ethyl acetate = 15:1) to give the desired product 3a in 70 %
yield as a white solid.
4-Chloro-N-(5-fluoroquinolin-8-yl)benzamide (3e). White solid
(37.5 mg, 50% yield), m.p. 145–146 °C. 1H NMR (400 MHz, CDCl3) δ:
10.45 (s, 1H), 8.87 (dd, J1 = 1.6 Hz, J2 = 4.2 Hz, 1H), 8.83 (dd, J1 =
5.4 Hz, J2 = 8.6 Hz, 1H), 8.43 (dd, J1 = 1.6 Hz, J2 = 8.4 Hz, 1H),
7.99−7.96 (m, 2H), 7.53 (dd, J1 = 4.2 Hz, J2 = 8.4 Hz, 1H), 7.51–7.49
(m, 2H), 7.23 (t, J = 9.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ:
164.02, 153.05 (d, J = 250.0 Hz), 149.10, 138.83 (d, J = 3.0 Hz),
138.12, 133.28, 130.80 (d, J = 4.1 Hz), 129.80 (d, J = 3.4 Hz), 129.00,
128.58, 121.72 (d, J = 2.4 Hz), 118.74 (d, J = 18.0 Hz), 116.05 (d, J =
7.6 Hz), 110.41 (d, J = 19.6 Hz). HRMS (ESI) ([M+H]+) Calcd. For
C16H11ClFN2O: 301.0538, Found: 301.0542.
Characterization data for all products
N-(5-Fluoroquinolin-8-yl)benzamide (3a). White solid (46.6 mg,
70% yield), m.p. 133–134 °C. 1H NMR (400 MHz, CDCl3) δ: 10.53 (s,
1H), 8.91−8.88 (m, 2H), 8.45 (dd, J1 = 1.6 Hz, J2 = 8.4 Hz, 1H),
8.09−8.06 (m, 2H), 7.60−7.53 (m, 4H), 7.27 (t, J = 8.8 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ: 165.26, 152.97 (d, J = 249.6 Hz), 149.08,
138.94 (d, J = 3.0 Hz), 134.98, 131.84, 131.10 (d, J = 4.1 Hz), 129.78
(d, J = 3.6 Hz), 128.78, 127.19, 121.70 (d, J = 2.6 Hz), 118.78 (d, J =
17.9 Hz), 116.00 (d, J = 7.5 Hz), 110.46 (d, J = 19.6 Hz). HRMS (ESI)
([M+H]+) Calcd. For C16H12FN2O: 267.0928, Found: 267.0927.
4-Bromo-N-(5-fluoroquinolin-8-yl)benzamide (3f). White solid
(47.3 mg, 55% yield), m.p. 193–194 °C. 1H NMR (400 MHz, CDCl3) δ:
10.46 (s, 1H), 8.88 (dd, J1 = 1.6 Hz, J2 = 4.2 Hz, 1H), 8.84 (dd, J1 =
5.4 Hz, J2 = 8.6 Hz, 1H), 8.44 (dd, J1 = 1.6 Hz, J2 = 8.4 Hz, 1H),
7.93−7.90 (m, 2H), 7.68−7.66 (m, 2H), 7.54 (dd, J1 = 4.2 Hz, J2 = 8.4
Hz, 1H), 7.25 (t, J = 9.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ:
164.17, 153.08 (d, J = 250.1 Hz), 149.13, 138.87 (d, J = 3.2 Hz),
133.78, 132.00, 130.81 (d, J = 3.9 Hz), 129.83 (d, J = 3.6 Hz), 128.77,
126.61, 121.75 (d, J = 2.5 Hz), 118.78 (d, J = 17.9 Hz), 116.10 (d, J =
7.6 Hz), 110.44 (d, J = 19.5 Hz). HRMS (ESI) ([M+H]+) Calcd. For
C16H11BrFN2O: 345.0033, Found: 345.0031.
N-(5-Fluoroquinolin-8-yl)-4-methoxybenzamide (3b). White solid
1
(54.0 mg, 73% yield), m.p. 137−139 °C. H NMR (400 MHz, CDCl3)
δ: 10.45 (s, 1H), 8.89−8.85 (m, 2H), 8.43 (dd, J1 = 1.6 Hz, J2 = 8.4
Hz,1H), 8.05−8.02 (m, 2H), 7.53 (dd, J1 = 4.2 Hz, J2 = 8.4 Hz,1H),
7.25 (t, J = 9.3 Hz, 1H), 7.05−7.01 (m, 2H), 3.89 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ: 164.80, 162.51, 152.79 (d, J = 249.4 Hz),
148.98, 138.90 (d, J = 2.9 Hz), 131.27 (d, J = 4.0 Hz), 129.74 (d, J =
N-(5-Fluoroquinolin-8-yl)-4-(trifluoromethyl)benzamide
White solid (50.9 mg, 61% yield), m.p. 140–141 °C. H NMR (400
(3g).
1
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800389
European Journal of Organic Chemistry
FULL PAPER
MHz, CDCl3) δ: 10.51 (s, 1H), 8.87 (dd, J1 = 1.6 Hz, J2 = 4.2 Hz,1H),
8.83 (dd, J1 = 5.4 Hz, J2 = 8.6 Hz,1H), 8.42 (dd, J1 = 1.6 Hz, J2 = 8.4
Hz, 1H), 8.14 (d, J = 8.1 Hz, 2H), 7.79 (d, J = 8.2 Hz, 2H), 7.53 (dd,
J1= 4.3 Hz, J2 = 8.4 Hz, 1H), 7.23 (t, J = 8.9 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ: 163.70, 153.20 (d, J = 250.3 Hz), 149.19, 138.84 (d,
J = 3.0 Hz), 138.15, 133.45 (q, J1 = 32.4 Hz, J2 = 65.1 Hz), 130.61 (d,
J = 4.1 Hz), 129.82 (d, J = 3.6 Hz), 127.61, 125.79 (q, J1 = 3.6 Hz, J2 =
7.3 Hz), 123.66 (q, J1 = 270.8 Hz, J2 = 541.8 Hz), 121.79 (d, J = 2.4
Hz), 118.75 (d, J = 18.2 Hz),116.22 (d, J = 7.8 Hz), 110.38 (d, J =
19.7 Hz). HRMS (ESI) ([M+H]+) Calcd. For C17H11F4N2O: 335.0802,
Found: 335.0799.
CDCl3) δ: 159.86, 152.99 (d, J = 249.5 Hz), 149.14, 139.84, 138.67,
130.92, 130.81 (d, J = 4.0 Hz), 129.83 (d, J = 3.6 Hz), 128.38, 127.85，
121.76 (d, J = 2.5 Hz), 118.78 (d, J = 18.1 Hz), 115.98 (t, J = 7.7 Hz),
110.51 (d, J = 19.6 Hz). HRMS (ESI) ([M+H]+) Calcd. For
C14H10FN2OS: 273.0492, Found: 273.0490.
N-(5-Fluoroquinolin-8-yl)methacrylamide (3l). White solid (33.9
1
mg, 59% yield), m.p. 115–116 °C. H NMR (400 MHz, CDCl3) δ:
10.15 (s, 1H), 8.86 (dd, J1 = 1.6 Hz, J2 = 4.2 Hz,1H), 8.78 (dd, J1 = 5.4
Hz, J2 = 8.6 Hz, 1H), 8.43 (dd, J1 = 1.6 Hz, J2 = 8.4 Hz, 1H), 7.52 (dd,
J1 = 4.2 Hz, J2 = 8.4 Hz, 1H), 7.22 (t, J = 8.9 Hz, 1H), 6.04 (s, 1H),
5.56 (s, 1H), 2.19 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 166.26,
152.91 (d, J = 249.7 Hz), 149.04, 140.60, 138.86, 130.98 (d, J = 3.7
Hz), 129.72 (d, J = 3.7 Hz), 121.63, 120.56, 118.73 (d, J = 18.1 Hz),
115.91 (d, J = 7.5 Hz), 110.40 (d, J = 19.6 Hz), 18.62. HRMS (ESI)
([M+H]+) Calcd. For C13H12FN2O: 231.0928, Found: 231.0927.
3,4-Dichloro-N-(5-fluoroquinolin-8-yl)benzamide (3h). White
1
solid (47.6 mg, 57% yield), m.p. 181–183 °C. H NMR (400 MHz,
CDCl3) δ: 10.45 (s, 1H), 8.91 (d, J = 2.9 Hz, 1H), 8.82 (dd, J1 = 5.4 Hz,
J2 = 8.6 Hz, 1H), 8.47 (d, J = 8.3 Hz, 1H), 8.14 (d, J = 1.7 Hz, 1H),
7.88−7.85 (m, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.57 (dd, J1 = 4.2 Hz, J2 =
8.4 Hz, 1H), 7.26 (t, J = 9.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ:
162.88, 153.26 (d, J = 250.5 Hz), 149.27, 138.87 (d, J = 3.2 Hz),
136.35, 134.76, 133.39, 130.80, 130.57 (d, J = 3.9 Hz), 129.92 (d, J
= 3.6 Hz), 129.49, 126.18, 121.86 (d, J = 2.5 Hz), 118.82 (d, J = 18.2
Hz), 116.29 (d, J = 7.6 Hz), 110.46 (d, J = 19.7 Hz). HRMS (ESI)
([M+H]+) Calcd. For C16H10Cl2FN2O: 335.0149, Found: 335.0151.
N-(5-Fluoroquinolin-8-yl)cinnamamide (3m). White solid (36.5 mg,
1
50% yield), m.p. 156–158 °C. H NMR (400 MHz, CDCl3) δ: 9.80 (s,
1H), 8.88−8.85 (m, 2H), 8.43 (dd, J1 = 1.6 Hz, J2 = 8.4 Hz, 1H), 7.82
(d, J =15.5 Hz, 1H), 7.62−7.59 (m, 2H), 7.53 (dd, J1 = 4.2 Hz, J2 = 8.4
Hz, 1H), 7.44–7.38 (m, 3H), 7.23 (t, J = 9.4 Hz, 1H), 6.77 (d, J = 15.5
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 163.93, 152.93 (d, J = 249.6
Hz), 148.93, 142.09, 138.61 (d, J = 2.8 Hz), 134.72, 131.14 (d, J =
4.1 Hz), 129.89, 129.77 (d, J = 3.7 Hz), 128.82, 127.98, 121.65 (d, J
= 2.2 Hz), 121.33, 118.71 (d, J = 18.1 Hz), 116.28 (d, J = 7.6 Hz),
110.49 (d, J = 19.6 Hz). HRMS (ESI) ([M+H]+) Calcd. For C18H14FN2O:
293.1085, Found: 293.1082.
N-(5-Fluoroquinolin-8-yl)-2-naphthamide (3i). White solid (53.7
1
mg, 68% yield), m.p. 158–160 °C. H NMR (400 MHz, CDCl3) δ:
10.64 (s, 1H), 8.94–8.90 (m, 2H), 8.55 (s, 1H), 8.43 (dd, J1 = 1.6 Hz,
J2 = 8.4 Hz, 1H), 8.10–8.08 (m, 1H), 8.03–8.00 (m, 1H), 7.98–7.96
(m, 1H), 7.91−7.89 (m, 1H), 7.61–7.56 (m, 2H), 7.53 (dd, J1 = 4.3 Hz,
J2 = 8.5 Hz, 1H), 7.26 (t, J = 9.1 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ: 165.28, 152.99 (d, J = 249.6 Hz), 149.11, 138.97 (d, J = 2.9 Hz),
134.91, 132.72, 132.17, 131.16 (d, J = 4.0 Hz), 129.79 (d, J = 3.5 Hz),
129.15, 128.67, 127.87, 127.84, 127.76, 126.79, 123.58, 121.70 (d,
J = 2.2 Hz), 118.80 (d, J = 18.0 Hz), 116.07 (t, J = 7.6 Hz), 110.49 (d,
J = 19.5 Hz). HRMS (ESI) ([M+H]+) Calcd. For C20H14FN2O: 317.1085,
Found: 317.1087.
N-(5-Fluoroquinolin-8-yl)pivalamide (3n). White solid (39.4 mg,
1
64% yield), m.p. 71–72 °C. H NMR (400 MHz, CDCl3) δ: 10.07 (s,
1H), 8.87 (dd, J1 = 1.6 Hz, J2 = 4.2 Hz, 1H), 8.75 (dd, J1 = 5.5 Hz, J2 =
8.7 Hz, 1H), 8.43 (dd, J1 = 1.6 Hz, J2 = 8.4 Hz, 1H), 7.52 (dd, J1 = 4.3
Hz, J2 = 8.5 Hz, 1H), 7.21 (t, J = 9.0 Hz, 1H), 1.43 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ: 177.05, 152.70 (d, J = 248.8 Hz), 149.01,
138.95 (d, J = 2.8 Hz), 131.23 (d, J = 3.9 Hz), 129.69 (d, J = 3.6 Hz),
121.54 (d, J = 2.3 Hz), 118.70 (d, J = 18.1 Hz), 115.63 (d, J = 7.6 Hz),
110.37 (d, J = 19.4 Hz), 40.23, 27.68. HRMS (ESI) ([M+H]+) Calcd.
N-(5-Fluoroquinolin-8-yl)furan-2-carboxamide (3j). White solid
(41.0 mg, 64% yield), m.p. 200–201 °C. 1H NMR (400 MHz, CDCl3) δ: For C14H16FN2O: 247.1241, Found: 247.1244.
10.57 (s, 1H), 8.93 (dd, J1 = 1.6 Hz, J2 = 4.2 Hz, 1H), 8.82 (dd, J1 =
N-(5-Fluoroquinolin-8-yl)cyclohexanecarboxamide (3o). White
5.4 Hz, J2 = 8.6 Hz, 1H), 8.44 (dd, J1 = 1.6 Hz, J2 = 8.4 Hz, 1H),
7.63−7.62 (m, 1H), 7.55 (dd, J1 = 4.3 Hz, J2 = 8.4 Hz, 1H), 7.31–7.30
(m, 1H), 7.24 (t, J = 9.4 Hz, 1H), 6.59 (dd, J1 = 1.8 Hz, J2 = 3.5 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ: 156.21, 153.06 (d, J = 250.0 Hz),
149.20, 148.18, 144.49, 138.80, 130.67 (d, J = 4.1 Hz), 129.71 (d, J
= 3.6 Hz), 121.72 (d, J = 2.2 Hz), 118.77 (d, J = 18.1 Hz), 116.08 (t, J
= 7.8 Hz), 115.10, 112.43, 110.42 (d, J = 19.6 Hz). HRMS (ESI)
([M+H]+) Calcd. For C14H10FN2O2: 257.0721, Found: 257.0723.
1
solid (34.0 mg, 50% yield), m.p. 112–114 °C. H NMR (400 MHz,
CDCl3) δ: 9.69 (s, 1H), 8.86 (dd, J1 = 1.6 Hz, J2 = 4.2 Hz, 1H), 8.75
(dd, J1 = 5.5 Hz, J2 = 8.6 Hz, 1H), 8.42 (dd, J1 = 1.6 Hz, J2 = 8.4 Hz,
1H), 7.51 (dd, J1 = 4.2 Hz, J2 = 8.4 Hz, 1H), 7.20 (t, J = 9.0 Hz, 1H),
2.50–2.42 (m, 1H), 2.10–2.07 (m, 2H), 2.50–2.42 (m, 1H), 1.91–
1.87 (m, 2H), 1.78–1.72 (m, 1H), 1.69–1.59 (m, 2H), 1.42–1.34 (m,
2H), 1.33–1.26 (m, 1H); 13C NMR (100 MHz, CDCl3) δ: 174.62,
152.67 (d, J = 248.9 Hz), 148.88, 138.68 (d, J = 2.9 Hz), 131.19 (d, J
= 4.0 Hz), 129.71 (d, J = 3.7 Hz), 121.53 (d, J = 2.4 Hz), 118.69 (d, J
= 18.0 Hz), 115.84 (d, J = 7.4 Hz), 110.38 (d, J = 19.5 Hz), 46.79,
29.73, 25.75, 25.72. HRMS (ESI) ([M+H]+) Calcd. For C16H18FN2O:
273.1398, Found: 273.1402.
N-(5-Fluoroquinolin-8-yl)thiophene-2-carboxamide (3k). White
1
solid (38.8 mg, 57% yield), m.p. 167–169 °C. H NMR (400 MHz,
CDCl3) δ: 10.39 (s, 1H), 8.91 (dd, J1 = 1.6 Hz, J2 = 4.2 Hz, 1H), 8.80
(dd, J1 = 5.4 Hz, J2 = 8.6 Hz, 1H), 8.46 (dd, J1 = 1.5 Hz, J2 = 8.4 Hz,
1H), 7.83 (dd, J1 = 1.0 Hz, J2 = 3.7 Hz, 1H), 7.60 (dd, J1 = 1.0 Hz, J2 =
5.0 Hz, 1H), 7.56 (dd, J1 = 4.2 Hz, J2 = 8.4 Hz, 1H), 7.26 (t, J = 9.4 Hz,
1H), 7.20 (dd, J1 = 3.8 Hz, J2 = 4.9 Hz, 1H); 13C NMR (100 MHz,
N-(5-Fluoro-2-methylquinolin-8-yl)benzamide (3p). White solid
(49.7 mg, 71% yield), m.p. 115–116 °C. 1H NMR (400 MHz, CDCl3) δ:
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800389
European Journal of Organic Chemistry
FULL PAPER
10.58 (s, 1H), 8.85 (dd, J1 = 5.5 Hz, J2 = 8.6 Hz, 1H), 8.32 (d, J = 8.5
Hz, 1H), 8.08−8.06 (m, 2H), 7.60−7.54 (m, 3H), 7.40 (d, J = 8.6 Hz,
1H), 7.18 (t, J = 9.4 Hz, 1H), 2.79 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ: 165.12, 158.29, 153.25 (d, J = 249.2 Hz), 138.52, 135.16, 131.75,
130.43 (d, J = 3.8 Hz), 129.82 (d, J = 3.3 Hz), 128.79, 127.16, 122.50
(d, J = 2.4 Hz), 116.83 (d, J = 18.1 Hz), 116.00 (d, J = 7.8 Hz), 109.48
(d, J = 19.5 Hz), 25.45. HRMS (ESI) ([M+H]+) Calcd. For C17H14FN2O:
281.1085, Found: 281.1083.
(44.1 mg, 63% yield), m.p. 221–223 °C. 1H NMR (400 MHz, CDCl3) δ:
10.45 (s, 1H), 8.79−8.77 (m, 2H), 8.35 (dd, J1 = 1.6 Hz, J2 = 8.4 Hz,
1H), 8.07−8.05 (m, 2H), 7.58−7.52 (m, 3H), 7.46 (dd, J1 = 4.2 Hz, J2
= 8.4 Hz, 1H), 2.48 (d, J = 2.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ:
165.08, 150.31 (d, J = 246.7 Hz), 147.96, 137.63, 134.95, 131.75,
130.35 (d, J = 3.6 Hz), 129.11 (d, J = 4.2 Hz), 128.72, 127.13, 121.58,
120.27 (d, J = 15.9 Hz), 119.13 (d, J = 4.4 Hz), 118.55 (d, J = 18.8
Hz), 14.69 (d, J = 3.3 Hz). HRMS (ESI) ([M+H]+) Calcd. For
C17H14FN2O: 281.1085, Found: 281.1083.
N-(5-Fluoro-2-phenylquinolin-8-yl)benzamide (3q). Yellow solid
(44.5 mg, 52% yield), m.p. 164–166 °C. 1H NMR (400 MHz, CDCl3) δ: N-(5-Fluoro-6-methoxyquinolin-8-yl)benzamide (3v). White solid
10.68 (s, 1H), 8.87 (dd, J1 = 5.4 Hz, J2 = 8.6 Hz, 1H), 8.46 (d, J = 8.7
Hz, 1H), 8.17−8.14 (m, 2H), 8.10−8.08 (m, 2H), 7.97 (d, J = 8.7 Hz,
1H), 7.62−7.57 (m, 4H), 7.55−7.53 (m, 2H), 7.22 (t, J = 9.1 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ: 164.93, 155.88, 153.13 (d, J = 249.6
Hz), 138.66 (d, J = 3.0 Hz), 138.52, 135.09, 131.84, 131.08 (d, J =
3.8 Hz), 130.73 (d, J = 3.2 Hz), 129.97, 129.00, 128.86, 127.33,
127.06, 119.30 (d, J = 2.4 Hz), 117.49 (d, J = 18.1 Hz), 116.26 (d, J =
7.7 Hz), 110.25 (d, J = 19.6 Hz). HRMS (ESI) ([M+H]+) Calcd. For
C22H16FN2O: 343.1241, Found: 343.1237.
(44.4 mg, 60% yield), m.p. 125–126 °C. 1H NMR (400 MHz, CDCl3) δ:
10.57 (s, 1H), 8.96 (d, J = 8.5 Hz, 1H), 8.71 (dd, J1 = 1.6 Hz, J2 = 4.2
Hz, 1H), 8.35 (dd, J1 = 1.5 Hz, J2 = 8.5 Hz, 1H), 8.07−8.05 (m, 2H),
7.60−7.53 (m, 3H), 7.47 (dd, J1 = 4.2 Hz, J2 = 8.5 Hz, 1H), 4.10 (s,
3H); 13C NMR (100 MHz, CDCl3) δ: 165.26, 146.63, 143.45 (d, J =
9.4 Hz), 140.53 (d, J = 248.5 Hz),134.74, 133.31, 131.96, 131.51 (d,
J = 3.9 Hz), 128.82, 128.45 (d, J = 4.2 Hz), 127.15, 122.03 (d, J = 2.7
Hz), 119.30 (d, J = 14.9 Hz), 106.08, 57.20. HRMS (ESI) ([M+H]+)
Calcd. For C17H14FN2O2: 297.1034, Found: 297.1038.
N-(5-Fluoro-4-methylquinolin-8-yl)benzamide (3r). White solid
N-(5-Fluoro-7-methylquinolin-8-yl)benzamide (3w). White solid
(45.5 mg, 65% yield), m.p. 178–179 °C. 1H NMR (400 MHz, CDCl3) δ: (33.6 mg, 48% yield), m.p. 149–152 °C. 1H NMR (400 MHz, CDCl3) δ:
10.67 (s, 1H), 8.86 (dd, J1 = 5.0 Hz, J2 = 8.7 Hz, 1H), 8.66 (d, J = 4.4
Hz, 1H), 8.08−8.05 (m, 2H), 7.60−7.52 (m, 3H), 7.25−7.19 (m, 2H),
2.85 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 165.15,
154.67 (d, J = 251.1 Hz), 148.52, 144.32 (d, J = 4.1 Hz), 139.51,
135.09, 131.72, 131.37 (d, J = 4.0 Hz), 128.72, 127.17, 123.91,
118.83 (d, J = 13.5 Hz), 115.88 (d, J = 8.3 Hz), 111.36 (d, J = 22.7
Hz), 22.50 (d, J = 11.0 Hz). HRMS (ESI) ([M+H]+) Calcd. For
C17H14FN2O: 281.1085, Found: 281.1088.
9.39 (s, 1H), 8.81 (dd, J1 = 1.6 Hz, J2 = 4.2 Hz, 1H), 8.37 (dd, J1 = 1.6
Hz, J2 = 8.4 Hz, 1H), 8.09−8.07 (m, 2H), 7.59−7.56 (m, 1H),
7.52−7.49 (m, 2H), 7.41 (dd, J1 = 4.2 Hz, J2 = 8.4 Hz, 1H), 7.18 (d, J =
10.6 Hz, 1H), 2.54 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 165.96,
154.91 (d, J = 252.0 Hz), 149.95, 142.91 (d, J = 3.8 Hz), 134.52,
134.32 (d, J = 8.1 Hz), 131.82, 129.39 (d, J = 3.6 Hz), 128.62, 128.07
(d, J = 4.2 Hz), 127.72, 120.66 (d, J = 2.4 Hz), 117.34 (d, J = 17.8 Hz),
113.39 (d, J = 19.5 Hz), 20.37 (d, J = 1.1 Hz). HRMS (ESI) ([M+H]+)
Calcd. For C17H14FN2O: 281.1085, Found: 281.1087.
N-(4-Ethyl-5-fluoroquinolin-8-yl)benzamide (3s). White solid (44.1
1
mg, 60% yield), m.p. 112–115 °C. H NMR (400 MHz, CDCl3) δ:
N-(5-Fluoro-2,4-dimethylquinolin-8-yl)benzamide (3x). Yellow
1
10.73 (s, 1H), 8.88 (dd, J1 = 5.0 Hz, J2 = 8.6 Hz, 1H), 8.72 (d, J = 4.5
Hz, 1H), 8.09−8.06 (m, 2H), 7.59−7.52 (m, 3H), 7.30 (d, J = 4.5 Hz,
1H), 7.24 (dd, J1 = 8.7 Hz, J2 = 12.8 Hz, 1H), 3.27−3.21 (m, 2H),
1.39−1.35 (m, 3H); 13C NMR (100 MHz, CDCl3) δ: 165.17, 154.31 (d,
J = 251.2 Hz), 150.26 (d, J = 5.0 Hz), 148.66 (d, J = 1.2 Hz), 139.72
(d, J = 3.0 Hz), 135.14, 131.72, 131.56 (d, J = 4.1 Hz), 128.72,
127.19, 122.14, 118.12 (d, J = 13.3 Hz), 115.82 (d, J = 8.7 Hz),
111.57 (d, J = 23.4 Hz), 28.61 (d, J = 10.9 Hz), 14.93 (d, J = 4.1 Hz).
HRMS (ESI) ([M+H]+) Calcd. For C18H16FN2O: 295.1241, Found:
295.1242.
solid (46.3 mg, 63% yield), m.p. 157–159 °C. H NMR (400 MHz,
CDCl3) δ: 10.73 (s, 1H), 8.81 (dd, J1 = 5.1 Hz, J2 = 8.6 Hz, 1H),
8.07−8.04 (m, 2H), 7.59−7.53 (m, 3H), 7.16−7.11 (m, 2H), 2.78 (d, J
= 6.3 Hz, 3H), 2.69 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 164.97,
157.59, 154.91 (d, J = 250.5 Hz), 144.08 (d, J = 4.1 Hz), 139.19 (d, J
= 2.8 Hz), 135.25, 131.64, 130.67 (d, J = 4.0 Hz), 128.73, 127.12,
124.56, 116.94 (d, J = 13.4 Hz), 115.85 (d, J = 8.6 Hz), 110.37 (d, J =
22.7 Hz), 25.01, 22.31 (d, J = 10.5 Hz). HRMS (ESI) ([M+H]+) Calcd.
For C18H16FN2O: 295.1241, Found: 295.1240.
N-(2-Chloro-5-fluoro-4-methylquinolin-8-yl)benzamide
White solid (43.2 mg, 55% yield), m.p. 222–223 °C. H NMR (400
(3y).
1
N-(4-Chloro-5-fluoroquinolin-8-yl)benzamide (3t). White solid
(39.8 mg, 53% yield), m.p. 168–169 °C. 1H NMR (400 MHz, CDCl3) δ: MHz, CDCl3) δ: 10.22 (s, 1H), 8.90 (dd, J1 = 5.0 Hz, J2 = 8.8 Hz, 1H),
10.52 (s, 1H), 8.92 (dd, J1 = 4.7 Hz, J2 = 8.7 Hz, 1H), 8.66 (d, J = 4.7
Hz, 1H), 8.04 (d, J = 7.1 Hz, 2H), 7.59−7.53 (m, 4H), 7.32−7.28 (m,
1H); 13C NMR (100 MHz, CDCl3) δ: 165.19, 152.53 (d, J = 255.5 Hz),
8.06−8.03 (m, 2H), 7.61−7.54 (m, 3H), 7.27−7.21 (m, 2H),
2.84−2.82 (m, 3H); 13C NMR (100 MHz, CDCl3) δ: 165.23, 154.66 (d,
J = 251.6 Hz), 150.01, 147.92 (d, J = 4.2 Hz), 138.93 (d, J = 3.0 Hz),
148.06 (d, J = 1.8 Hz), 140.32, 140.14 (d, J = 2.0 Hz), 134.78, 131.92, 134.81, 131.94, 130.70 (d, J = 3.9 Hz), 128.85, 127.19, 124.31,
131.51 (d, J = 4.5 Hz), 128.78, 127.16, 123.95, 117.07, 116.99,
113.13 (d, J = 22.1 Hz). HRMS (ESI) ([M+H]+) Calcd. For
C16H11ClFN2O: 301.0538, Found: 301.0540.
117.50 (d, J = 8.6 Hz), 112.13 (d, J = 22.6 Hz), 22.39 (d, J = 11.1 Hz).
HRMS (ESI) ([M+H]+) Calcd. For C17H13ClFN2O: 315.0695, Found:
315.0699.
N-(5-Fluoro-6-methylquinolin-8-yl)benzamide (3u). White solid
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Acknowledgements
We gratefully acknowledge the National Natural Science
Foundation of China (21772062, 21572078) and the Natural
Science Foundation of Anhui Province (170808J02,
KJ2015ZD34) for financial support of this work.
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Conflict of Interest
The authors declare no conflict of interest.
Keywords: regioselective C−H activation • fluorination • 8-
amidoquinolines • Selectfluor • synthetic method
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Metal-Free-Fluorination of Quinolines!
Hao Chen, Pinhua Li*, Min Wang and
Lei Wang*
-
H
2BF4
F
O
O
KHCO
Page No. – Page No.
Cl
equiv)
3 (2
N
+
R1
N
R1
N
N+
nBuOH
120 o 12
R2
H
R2
h
C,
H
(2 mL),
Regioselective C−H Bond
Fluorination of 8-Amidoquinolines
with Selectfluor on the C5 Position
under Transition-Metal-Free
Conditions
N
N
F
A simple and efficient protocol for the C5-selective fluorination of 8-aminoquinoline
scaffolds with Selectfluor under transition-metal free conditions was developed.
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