C5-selective trifluoromethylation of 8-amino quinolines via photoredox catalysis

Article abstract of DOI:10.1016/j.jfluchem.2018.12.011

A new protocol for C5-selective C–H trifluoromethylation of 8-aminoquinolines via photoredox catalysis was developed. It allows rapid access to various C5-trifluoromethyl 8-amino quinoline derivatives in MeCN/H₂O enabled by Eosin Y as photocatalysts.

Full text of DOI:10.1016/j.jfluchem.2018.12.011

Accepted Manuscript
Title: C5-Selective Trifluoromethylation of 8-Amino
quinolines via Photoredox Catalysis
Authors: Chao Tian, Li-Ming Yang, Hai-Tao Tian, Guang-Hui
An, Guang-Ming Li
PII:
S0022-1139(18)30391-9
DOI:
Reference:
https://doi.org/10.1016/j.jfluchem.2018.12.011
FLUOR 9273
To appear in:
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Received date:
Revised date:
Accepted date:
30 September 2018
24 December 2018
24 December 2018
Please cite this article as: Tian C, Yang L-Ming, Tian H-Tao, An G-Hui, Li G-Ming,
C5-Selective Trifluoromethylation of 8-Amino quinolines via Photoredox Catalysis,
Journal of Fluorine Chemistry (2018), https://doi.org/10.1016/j.jfluchem.2018.12.011
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C5-Selective Trifluoromethylation of 8-Amino
quinolines via Photoredox Catalysis
Chao Tian,a Li-Ming Yang,a Hai-Tao Tian,a Guang-Hui Ana,b,*
and Guang-Ming Lia,*
a
Key Laboratory of Functional Inorganic Material Chemistry (MOE) School of Chemistry and
Materials Science Heilongjiang University No. 74, Xuefu Road, Nangang District, Harbin 150080 (P.R.
China).
b
College of Materials Science and Chemical Engineering Harbin Engineering University Harbin,
150001 (P.R. China).
*Corresponding authors.
E-mail addresses: chemagh@163.com (G.-H. An); gmli@hlju.edu.cn (G.-M. Li)

Graphical abstarct
Highlights
 A
trifluoromethylation protocol was achieved.
transition-metal
free,
site-selective,
visible-light
mediated
 The reaction was carried in environmental benign solvent enabled by organo
photocatalyst.
A R T I C L E I N F O
A B S T R A C T
A new protocol for C5-selective C–H trifluoromethylation of 8-aminoquinolines via photoredox
catalysis was developed. It allows rapid access to various C5-trifluoromethyl 8-amino quinoline
derivatives in MeCN/H2O enabled by Eosin Y as photocatalysts.
Keywords:
Trifluoromethylation
8-Aminoquinolines
Photoredox catalysis
para-selective C-H activation
1. Introduction
The developed of methods that introduce fluorine-containing functional groups into the
organic molecule has attract increasing attentions in organic synthesis [1]. Among these moieties,
trifluoromethyl groups are important core structures in many drugs, agrochemicals, and organic
functional materials [2]. Among various trifluoromethylation strategies, regioselective C–H
trifluoromethylation reactions has proved to be an efficient and prime method for introducing
trifluoromethyl group(s) into organic molecules. In the case of 6-membered heteroaromatic
compounds, especially quinoline derivatives, as an important structure in natural products and
pharmaceuticals [3], received extensive attention. The regioselectivity is difficult to control, and
mixtures of regioisomers are usually formed. Thus, great efforts have been devoted to
regioselective C–H trifluoromethylation at the 2- [4], 4- [5], and benzylic-positions [6] of
quinoline derivatives. In contrary, C–H trifluoromethylation at the remote C5 position of
quinolines remains chanllenging [7]. In 2016, a single case has been disclosed for the copper
catalyzed C5-trifluoromethylation [8]. After that, copper-catalyzed C5 CH trifluoromethylation
with Togni’s reagent [9] and supported copper-catalyzed version have been reported [10].
Additionally, hypervalent iodinium reagents combing with suitable additives have been reported
as efficient oxidants for metal free C5-trifluoromethylation [11]. Despite these advances, the
existing approaches typically required transition metal catayst or complicated oxidant-additive

combination. Recently, a photocatalyst free version with fine-tune wavelength LED lights has
been disclosed by Wang and Li’s group [12]. Recently, Xia and co-workes have been successfully
achieved C5 CH trifluoromethylation by using Ru as photocatalyst, hypervalent iodine(III)
reagents that contain perfluoroalkanoate as trifluoromethylation reagent. [13] To achieve a
practical C5-selective trifluoromethylation of 8-amino quinolines under mild conditions, an
alternative protocol via photoredox catalysis is still highly demanding. Along our interest in para
selective C-H activation of arenes [14], we envisioned that development of an approach with
readily available conditions in metal free manner would be meaningful for both organic chemistry
and medicine chemistry. Herein, we reported a photoredox catalyzed 5-position-selective C–H
trifluoromethylation of 8-aminoquinoline derivatives enabled by Eosin Y. The protocol underwent
smoothly in the environmental benign solvents, allowing rapid access various 8-amino quinoline
derivatives.
Scheme 1. Overview of trifluoromethylation of 8-aminoquinolines
2. Results and discussion
We commenced our optimization studies by reacting 8-aminoquinolines with CF3SO2Na,
employing various catalysts (Table 1, entries 1-6). Among various catalysts, Eosin Y showed
highest activity, providing desired C5-trifluoromethyl 8-aminoquinoline derivative 3a in 57%
yield and 24% of 1a was recovered (75% yield based on conversion, Table 1, entry 1). Moreover,
20% of the products were produced without photocatalyst (Table 1, entry 6). Based on previous
literature, Wang and Li's group observed that the products formed in this reaction can act as
photosensitisers [12]. However, when adding 20 mol% 3a as photosensitisers without any
photocatalyst in the reaction, 18% yield of product can be obtained after remove the amount of
pre-added products, indicating the product didn’t promote the reaction. (Table 1, entry 7) To confirm
the selectivity of the reaction, we checked the product distribution before purification. It showed that
the reaction afforded mainly C5-selective trifluoromethylation products. Further survey of different

oxidants, such as persulfate, hypervalent iodium reagents were carried out, resulting in no
significant increase in the reactivity (Table 1, entries 8-11 vs entry 1). No product was observed
when the reaction was carried out in the absence of either an oxidant or visible light irradiation,
indicating the crucial role of both oxidant and lights to the trifluoromethylation (Table 1, entry 12
and 13). Screening of the solvents such as CH2Cl2, CH3CH2OH and CH3CN, didn’t increase the
reaction outcome (Table 1, entries 15-17). The mixture solvent (CH3CN/H2O=3:1) gave the
optimal yields for this transformation (Table 1, entry 14). The reaction was not affected when the
reaction was performed under an argon atmosphere (Table 1, entry 18), and the decrease of
reaction time led to the decrease of reaction product (Table 1, entry 19).
Table 1
The optimization of reaction conditions.a
Entry
1
Catalyst
Eosin Y
Oxidant
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
K2S2O8
Solvent
Yield (%)b
CH3CN/H2O=1:1
CH3CN/H2O=1:1
CH3CN/H2O=1:1
CH3CN/H2O=1:1
CH3CN/H2O=1:1
CH3CN/H2O=1:1
CH3CN/H2O=1:1
CH3CN/H2O=1:1
CH3CN/H2O=1:1
CH3CN/H2O=1:1
CH3CN/H2O=1:1
CH3CN/H2O=1:1
CH3CN/H2O=1:1
CH3CN/H2O=3:1
CH3CH2OH
57 (75)
55
30
12
40
20
18
53
49
40
42
0
.
2
Ru(bpy)3Cl2 6H2O
3
[Ru(p-cymene)2]2
Ru3(CO)12
Ru(DMSO)4Cl2
-
4
5
6
7c
-
8
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Eosin Y
9
(NH4)2S2O8
PhI(OAc)2
PhI(TFA)2
-
10
11
12
13d
14
15
16
17
18e
19f
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
0
60 (80)
0
CH3CN
59
0
DCE
CH3CN/H2O=3:1
CH3CN/H2O=3:1
60
45
a
Reaction conditions: 1a (0.2 mmol), 2 (3.0 equiv), catalyst (5 mol%), oxidant (2.0 equiv.),
solvent (2.0 mL), 63 W blue LEDs as light source (see the Supporting Information (SI) for details),
b
under air; isolated yield of the product. Isolated yields based on conversion are described in
c
e
f
parentheses. Add 20 mol% 3a in the reaction. d Without light. Ar atmosphere. React 12 h.
DCE=ClCH2CH2Cl

Scheme 2. Substrate scope of photocatalytic trifluoromethylation of aminoquinolines.a,b
a Reactions conditions: 1 (0.2 mmol), CF3SO2Na (3 equiv.), Eosin Y (5 mol%), Na2S2O8 (2 equiv.),
solvent (2 mL), 63 W blue LEDs as light source (see the SI for details), air, 20 h; isolated yield of
the product. b Isolated yields based on conversion are described in parentheses.
With the optimized reaction conditions in hand, we explored the generality of the present
trifluoromethylation protocol and examined a number of 8-aminoquinoline derivatives (Scheme 2).
8-Aminoquinoline amides with an electron-donating or electron-withdrawing group in the para-
meta- or ortho-position of benzene rings in benzamides successfully delivered the desired
products (3a-3i) in moderate to good yields. Steric effect didn’t lead to significant decrease of
outcome in the substrates bearing motifs at ortho-position of benzene rings in benzamides (3d).
However, multisubstituted benzamides resulted in decreasing yield of 3d. Further transformable
groups, such as chloro, bromo and iodo, were tolerated, overriding the potential decomposition of
halobenzenes (3e-3i). Aliphatic amides could provide the corresponding products 3j–3l in 44–59%

yields. In addition, the heterocyclic amide also successfully underwent trifluoromethylation
reaction, delivering the product 3m in reasonable yield. Moreover,
4-methyl-N-(quinolin-8-yl)benzenesulfonamide was also compatible in this reaction, giving 57%
yield of the desired product 3n. Further application to substrates bearing substituents on quinolines
was also viable, leading to the desired trifluoromethylated products. The substrates bearing a
methyl (Me) group in the 2-position and a methoxyl (MeO) group in the 6-position of quinoline
rings could afford the desired products (3o–3p) in 60% and 58% yields.
Scheme 3. Control experiments.
To understand this transformation clearly, a series of control experiments were conducted. When
the radical scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was added to the reaction,
the trifluoromethylation of aminoquinolines was inhibited and allows 95% recovery of 1a,
implying a single electron transfer (SET) process for the reaction (Scheme 3a). When the product
3a reacted with CF3SO2Na under the standard reaction conditions, no reaction was observed and
3a was recovered in 99% yield (Scheme 3b), indicating that no other reactions will occur when the
C-5 position existed with substituents. In addition, the trifluoromethyl radical was trapped using
1,1-diphenylethylene (4) in the presence of CF3SO2Na (see the SI), implying the formation of a
trifluoromethyl radical in the reaction (Scheme 3c).
Scheme 4. Proposed mechanism.
Given literature reports [8-11] and our control experiments, a plausible mechanism was proposed
in Scheme 4. Upon photoirradiation of Eosin Y, Eosin Y* was formed [15]. The reaction of Eosin

•-
•-
Y* with Na2S2O8 gave Eosin Y•+ and SO4 . SO4 then oxidized CF3SO2Na via a single electron
•
•
transfer (SET) process to generate CF3 radical. The obtained CF3 reacted with substrate A to
afford the intermediate B, which further reacts with Eosin Y•+ to afford C and recovery of the
photocatalyst. Finally, C undergoes a proton-transfer (PT) process to afford product D.
3. Conclusions
In summary, we have developed
a visible light-mediated Eosin Y catalyzed
trifluoromethylation of 8-amino quinoline derivatives. Compared with the existing procedures for
the synthesis of 5-trifluoromethyl- 8-aminoquinolines, this protocol has several advantages
including the use of environmental benign solvent and simple operation at room temperature and
under an air atmosphere. The mechanism investigation revealed a trifluoromethyl radical involved
pathway. Further application of this radical generation protocol to other trifluoromethylation
reactions is under investigation.
4. Experimental section
4.1. General information
Unless otherwise noted, all reagents were obtained from commercial suppliers and used
without further purification. The reaction product was isolated by column chromatography on a
silica gel (236–400 mesh) column using petroleum ether (PE) with a boiling range from 60 to
90 °C and EtOAc. 1H, 13C and 19F NMR spectra were recorded on 400, 101, 376 MHz NMR
1
13
19
spectrometers using CDCl3 as solvent. Data for H NMR, C NMR and F NMR were recorded
as follows: chemical shift (δ, ppm), multiplicity (s=singlet, d=doublet, t=triplet, m=multiplet,
q=quartet, coupling constant (s) in Hz). In addition, 1H and 13C NMR spectra used
tetramethylsilane as the internal standard and fluorine chemical shifts are reported relative to
trifluoroacetic acid (δ −76.55 ppm) as an external reference. Infrared (IR) spectra were recorded
on a Fourier transform infrared spectrophotometer. HRMS were made by means of ESI. Unless
otherwise noted, all reagents were weighed and handled in air, and all reactions were carried out in
air.
4.2. General procedure for the synthesis of compounds.
To a vial equipped with a magnetic stir bar, 8-amino quinoline amides 1 (0.2 mmol, 1 equiv.),
CF3SO2Na (3 equiv.), Eosin Y (5 mol%), Na2S2O8 (2 equiv.) and solvent (CH3CN/H2O = 3/1, 2
mL) was added sequentially and the vial was irradiated with 63 W Blue LED lamps (Kessil
A360WE LED Aquarium Light) for 20 hours and the vial temperature remained 46 °C. After
completion, the solvent was evaporated under reduced pressure and the residue was diluted with
EtOAc, and washed with brine. The water phase was extracted with EtOAc (2 × 30 mL) and the
combined organic phase was dried over Na2SO4. The solvent was evaporated in vacuo and the
residue was purified by column chromatography on silica gel to give the pure product.
4.3. Compound data of the trifluoromethylation products

N-(5-(trifluoromethyl)quinolin-8-yl)benzamide (3a): After column chromatography (PE to
1
PE/EtOAc 9:1) a yellow solid was obtained. 60% yield. H NMR (400 MHz, CDCl3) δ 9.96 (s,
1H), 8.87 (d, J = 3.2 Hz, 1H), 8.78 (d, J = 8.2 Hz, 1H), 8.50 (d, J = 8.7 Hz, 1H), 7.90 (d, J = 8.2
Hz, 2H), 7.59 (dd, J = 8.7, 4.2 Hz, 1H), 2.37 (s, 4H). 13C NMR (101 MHz, CDCl3) δ 165.70,
148.75, 138.59, 138.12, 134.61, 133.29 (q, J = 2.0 Hz), 132.29, 128.94, 127.39, 126.66 (q, J = 5.0
Hz), 125.63, 124.34 (q, J = 271.3 Hz), 122.92, 119.87, 114.22 (q, J = 31.5 Hz). 19F NMR (376
MHz, CDCl3) δ -59.13. IR (KBr, ν/cm−1) 3370, 3081, 1672, 1578, 1530, 1508, 1491, 1090, 868,
781, 704, 682. HRMS (ESI) m/z calcd for C17H12F3N2O+ [M+H]+: 317.0896; found: 317.0898.
4-methyl-N-(5-(trifluoromethyl)quinolin-8-yl)benzamide (3b): After column chromatography
1
(PE to PE/EtOAc 9:1) a yellow solid was obtained. 54% yield. H NMR (400 MHz, CDCl3) δ
10.89 (s, 1H), 9.07 – 8.75 (m, 2H), 8.65 – 8.39 (m, 1H), 7.97 (t, J = 8.1 Hz, 3H), 7.61 (dd, J = 8.7,
4.2 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 2.46 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 165.68, 148.69,
142.88, 138.61, 138.26, 133.27 (q, J = 2.0 Hz), 131.83, 129.59, 127.41, 126.68 (q, J = 5.0 Hz),
19
125.67, 124.34 (q, J = 271.3 Hz), 122.85, 119.70 (q, J = 30.3 Hz), 114.14, 21.59. F NMR (376
MHz, CDCl3) δ -59.12. IR (KBr, ν/cm−1) 3339, 2922, 1676, 1613, 1579, 1533, 1511, 1392, 1093,
845, 784, 742, 669. HRMS (ESI) m/z calcd for C18H14F3N2O+ [M+H]+: 331.1053; found:
331.1054.
4-methoxy-N-(5-(trifluoromethyl)quinolin-8-yl)benzamide
(3c):
After
column
1
chromatography (PE to PE/EtOAc 4:1) a yellow solid was obtained. 57% yield. H NMR (400
MHz, CDCl3) δ 10.85 (s, 1H), 8.94 (d, J = 8.1 Hz, 2H), 8.53 (d, J = 8.6 Hz, 1H), 8.06 (d, J = 8.7
Hz, 2H), 7.96 (d, J = 8.2 Hz, 1H), 7.61 (dd, J = 8.6, 4.2 Hz, 1H), 7.05 (d, J = 8.7 Hz, 2H), 3.90 (s,
3H). 13C NMR (101 MHz, CDCl3) δ 165.20, 162.86, 148.65, 138.58, 138.32, 133.26 (q, J = 2.0
Hz), 129.33, 126.87, 126.70 (q, J = 5.1 Hz), 124.34 (q, J = 271.3 Hz), 122.85, 119.54 (q, J = 31.5
Hz), 119.23, 114.12, 114.01, 55.52. 19F NMR (376 MHz, CDCl3) δ -59.10. IR (KBr, ν/cm−1) 3371,
2941, 1666, 1601, 1574, 1530, 1512, 1388, 1263, 1094, 847, 790, 763, 658. HRMS (ESI) m/z
+
calcd for C18H14F3N2O2 [M+H]+: 347.1002; found: 347.1003.
2,4,6-trimethyl-N-(5-(trifluoromethyl)quinolin-8-yl)benzamide
(3d):
After
column
1
chromatography (PE/EtOAc 9:1) a yellow solid was obtained. 35% yield. H NMR (400 MHz,
CDCl3) δ 10.08 (s, 1H), 9.00 (d, J = 8.1 Hz, 1H), 8.93 – 8.65 (m, 1H), 8.54 (dt, J = 8.5, 1.6 Hz,
1H), 7.99 (d, J = 8.2 Hz, 1H), 7.61 (dd, J = 8.7, 4.2 Hz, 1H), 7.05 (s, 1H), 6.95 (s, 1H), 2.52 (d, J
= 3.1 Hz, 6H), 2.39 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 169.47, 148.69, 139.14, 138.38,
137.99, 134.56, 133.18 (q, J = 2.3 Hz), 132.24, 128.56, 126.59 (q, J = 5.0 Hz), 124.37, 124.00 (q,
J = 271.3 Hz), 122.84, 119.36 (q, J = 31.5 Hz), 114.35, 21.16, 19.41. 19F NMR (376 MHz, CDCl3)
δ -59.19. IR (KBr, ν/cm−1) 3345, 2919, 1679, 1611, 1514, 1476, 1383, 1093, 846, 837, 788, 686.
HRMS (ESI) m/z calcd for C20H18F3N2O+ [M+H]+: 359.1366; found: 359.1369.
2-chloro-N-(5-(trifluoromethyl)quinolin-8-yl)benzamide (3e): After column chromatography
(PE/EtOAc 9:1) a yellow solid was obtained. 50% yield. 1H NMR (400 MHz, CDCl3) δ 10.72 (s,
1H), 8.98 (d, J = 8.2 Hz, 1H), 8.88 (dd, J = 4.1, 1.4 Hz, 1H), 8.54 (dt, J = 8.6, 1.6 Hz, 1H), 7.98 (d,
J = 8.2 Hz, 1H), 7.84 (dd, J = 7.4, 1.9 Hz, 1H), 7.61 (dd, J = 8.7, 4.2 Hz, 1H), 7.58 – 7.35 (m, 3H).
13C NMR (101 MHz, CDCl3) δ 165.15, 148.83, 138.52, 137.95, 135.27, 133.20 (q, J = 2.0 Hz),
131.91, 131.21, 130.66, 130.29, 127.28, 126.56 (q, J = 5.6 Hz), 124.32 (q, J = 270.6 Hz), 124.06,
122.91, 120.20 (q, J = 30.3 Hz), 114.63. 19F NMR (376 MHz, CDCl3) δ -59.21. IR (KBr, ν/cm−1)
3313, 2924, 1680, 1582, 1536, 1501, 1471, 1093, 849, 791, 737, 723, 675. HRMS (ESI) m/z calcd
for C17H11ClF3N2O+ [M+H]+: 351.0507; found: 351.0510.

2-iodo-N-(5-(trifluoromethyl)quinolin-8-yl)benzamide (3f): After column chromatography
(PE/EtOAc 9:1) a yellow solid was obtained. 45% yield. 1H NMR (400 MHz, CDCl3) δ 10.34 (s,
1H), 8.96 (d, J = 8.1 Hz, 1H), 8.87 (dd, J = 4.1, 1.2 Hz, 1H), 8.61 – 8.41 (m, 1H), 7.99 (dd, J = 8.1,
2.2 Hz, 2H), 7.63 (td, J = 8.9, 2.9 Hz, 2H), 7.50 (t, J = 7.2 Hz, 1H), 7.22 (td, J = 7.7, 1.6 Hz, 1H).
13C NMR (101 MHz, CDCl3) δ 167.67, 148.81, 141.79, 140.44, 138.41, 137.78, 133.23 (q, J = 2.1
Hz), 131.75, 128.52, 128.42, 126.54 (q, J = 5.7 Hz), 125.35 (q, J = 271.0 Hz), 124.35, 122.95,
119.96 (q, J = 31.6 Hz), 114.61, 92.57. 19F NMR (376 MHz, CDCl3) δ -59.22. IR (KBr, ν/cm−1)
3291, 2922, 1684, 1580, 1523, 1500, 1453, 1102, 847, 794, 750, 731, 668. HRMS (ESI) m/z calcd
for C17H11F3IN2O+ [M+H]+: 442.9863; found: 442.9866.
3-chloro-N-(5-(trifluoromethyl)quinolin-8-yl)benzamide (3g): After column chromatography
(PE/EtOAc 9:1) a yellow solid was obtained. 47% yield. 1H NMR (400 MHz, CDCl3) δ 10.88 (s,
1H), 9.10 – 8.88 (m, 2H), 8.56 (dt, J = 8.7, 1.6 Hz, 1H), 8.07 (t, J = 1.8 Hz, 1H), 8.01 – 7.84 (m,
2H), 7.65 (dd, J = 8.7, 4.2 Hz, 1H), 7.59 (ddd, J = 8.0, 1.9, 1.0 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H).
13C NMR (101 MHz, CDCl3) δ 164.27, 148.87, 138.54, 136.39, 136.13, 135.20, 133.35 (q, J = 2.8
Hz), 132.30, 130.21, 127.80, 126.59 (q, J = 5.7 Hz), 125.34, 124.23 (q, J = 269.9 Hz), 123.00,
119.94 (q, J = 30.1 Hz), 114.43. 19F NMR (376 MHz, CDCl3) δ -59.19. IR (KBr, ν/cm−1) 3350,
2924, 1681, 1578, 1543, 1505, 1472, 1029, 862, 790, 732, 680. HRMS (ESI) m/z calcd for
C17H11ClF3N2O+ [M+H]+: 351.0507; found: 351.0509.
4-chloro-N-(5-(trifluoromethyl)quinolin-8-yl)benzamide (3h): After column chromatography
(PE/EtOAc 9:1) a yellow solid was obtained. 58% yield. 1H NMR (400 MHz, CDCl3) δ 10.89 (s,
1H), 9.06 – 8.80 (m, 2H), 8.55 (dt, J = 8.6, 1.6 Hz, 1H), 8.03 (d, J = 8.6 Hz, 2H), 7.97 (d, J = 8.2
Hz, 1H), 7.64 (dd, J = 8.7, 4.2 Hz, 1H), 7.54 (d, J = 8.6 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ
164.58, 148.81, 138.65, 138.54, 137.87, 133.33 (q, J = 2.0 Hz), 132.99, 129.22, 128.81, 126.59 (q,
J = 5.9 Hz), 124.36, 124.04 (q, J = 271.1 Hz), 122.97, 119.99 (q, J = 29.2 Hz), 114.32. 19F NMR
(376 MHz, CDCl3) δ -59.18. IR (KBr, ν/cm−1) 3348, 2921, 1677, 1598, 1579, 1530, 1506, 1094,
842, 745, 653. HRMS (ESI) m/z calcd for C17H11ClF3N2O+ [M+H]+: 351.0507; found: 351.0508.
4-bromo-N-(5-(trifluoromethyl)quinolin-8-yl)benzamide (3i): After column chromatography
(PE/EtOAc 9:1) a yellow solid was obtained. 43% yield. 1H NMR (400 MHz, CDCl3) δ 10.90 (s,
1H), 8.96 – 8.89 (m, 2H), 8.55 (dt, J = 8.7, 1.6 Hz, 1H), 7.97 (t, J = 8.6 Hz, 3H), 7.71 (d, J = 8.5
Hz, 2H), 7.64 (dd, J = 8.7, 4.2 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 164.71, 148.82, 138.55,
137.85, 133.46, 133.37 (q, J = 2.2 Hz), 132.21, 128.96, 127.14, 126.62 (q, J = 5.8 Hz), 124.34,
124.01 (q, J = 273.1 Hz), 122.98, 120.00 (q, J = 31.3 Hz), 114.34. 19F NMR (376 MHz, CDCl3) δ
-59.18. IR (KBr, ν/cm−1) 3342, 2922, 1684, 1590, 1580, 1536, 1501, 1100, 856, 843, 791, 739,
662. HRMS (ESI) m/z calcd for C17H11BrF3N2O+ [M+H]+: 395.0001; found: 395.0003.
N-(5-(trifluoromethyl)quinolin-8-yl)acetamide (3j): After column chromatography
1
(PE/EtOAc 2:1) a yellow solid was obtained. 59% yield. H NMR (400 MHz, CDCl3) δ 9.96 (s,
1H), 8.87 (d, J = 3.2 Hz, 1H), 8.78 (d, J = 8.2 Hz, 1H), 8.50 (d, J = 8.7 Hz, 1H), 7.90 (d, J = 8.2
Hz, 1H), 7.59 (dd, J = 8.7, 4.2 Hz, 1H), 2.37 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 169.13,
148.56, 147.13, 138.01, 133.21 (q, J = 2.4 Hz), 126.59 (q, J = 5.7 Hz), 125.60, 124.24 (q, J =
272.5 Hz), 122.81, 119.35 (q, J = 29.3 Hz), 114.04, 25.22. 19F NMR (376 MHz, CDCl3) δ -59.17.
IR (KBr, ν/cm−1) 3359, 3076, 1680, 1585, 1546, 1503, 1394, 1079, 863, 794, 635. HRMS (ESI)
m/z calcd for C12H10F3N2O+ [M+H]+: 255.0740; found: 255.0744.
N-(5-(trifluoromethyl)quinolin-8-yl)isobutyramide (3k): After column chromatography
(PE/EtOAc 9:1) a yellow solid was obtained. 44% yield. 1H NMR (400 MHz, CDCl3) δ 10.08 (s,

1H), 8.88 (d, J = 4.2 Hz, 1H), 8.81 (d, J = 8.2 Hz, 1H), 8.50 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 8.2
13
Hz, 1H), 7.59 (dd, J = 8.6, 4.2 Hz, 1H), 2.98 – 2.60 (m, 1H), 1.36 (d, J = 6.9 Hz, 6H). C NMR
(101 MHz, CDCl3) δ 176.11, 148.57, 138.28, 138.16, 133.20 (q, J = 2.0 Hz), 126.62 (q, J = 5.0
Hz), 124.26 (q, J = 271.1 Hz), 122.77, 119.19 (q, J = 29.2 Hz), 114.05, 37.21, 19.62. 19F NMR
(376 MHz, CDCl3) δ -59.78. IR (KBr, ν/cm−1) 3344, 2966, 1701, 1580, 1522, 1391, 1319, 1107,
846, 793, 725, 657. HRMS (ESI) m/z calcd for C14H14F3N2O+ [M+H]+: 283.1053; found:
283.1059.
N-(5-(trifluoromethyl)quinolin-8-yl)pivalamide (3l): After column chromatography
(PE/EtOAc 9:1) a yellow solid was obtained. 55% yield. 1H NMR (400 MHz, CDCl3) δ 10.44 (s,
1H), 8.89 (dd, J = 4.1, 1.3 Hz, 1H), 8.81 (d, J = 8.2 Hz, 1H), 8.51 (dt, J = 8.7, 1.6 Hz, 1H), 7.91 (d,
J = 8.2 Hz, 1H), 7.59 (dd, J = 8.7, 4.2 Hz, 1H), 1.43 (s, 9H). 13C NMR (101 MHz, CDCl3) δ
177.65, 148.65, 138.61, 138.25, 133.20 (q, J = 2.0 Hz), 126.64 (q, J = 5.7 Hz), 124.49 (q, J =
271.0 Hz), 122.96, 122.73, 119.30 (q, J = 31.3 Hz), 113.89, 40.52, 27.65. 19F NMR (376 MHz,
CDCl3) δ -59.12. IR (KBr, ν/cm−1) 3366, 2960, 1676, 1523, 1395, 1380, 1096, 843, 795, 679.
HRMS (ESI) m/z calcd for C15H16F3N2O+ [M+H]+: 297.1209; found: 297.1211.
N-(5-(trifluoromethyl)quinolin-8-yl)picolinamide (3m): After column chromatography
(PE/EtOAc 9:1) a yellow solid was obtained. 41% yield. 1H NMR (400 MHz, CDCl3) δ 12.44 (s,
1H), 9.10 – 8.98 (m, 2H), 8.85 – 8.73 (m, 1H), 8.54 (dt, J = 8.6, 1.6 Hz, 1H), 8.36 (d, J = 7.8 Hz,
1H), 8.04 – 7.91 (m, 2H), 7.63 (dd, J = 8.7, 4.2 Hz, 1H), 7.54 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H). 13C
NMR (101 MHz, CDCl3) δ 163.16, 150.09, 149.13, 148.65, 139.18, 138.08, 137.60, 133.04 (q, J =
2.5 Hz), 126.68, 126.49 (q, J = 5.8 Hz), 124.92, 124.02 (q, J = 269.9 Hz), 122.81, 122.69, 119.30
(q, J = 31.0 Hz), 114.45. 19F NMR (376 MHz, CDCl3) δ -59.14. IR (KBr, ν/cm−1) 3317, 3056,
1692, 1530, 1458, 1104, 867, 787, 742, 689. HRMS (ESI) m/z calcd for C16H11F3N3O+ [M+H]+:
318.0849; found: 318.0852.
4-methyl-N-(5-(trifluoromethyl)quinolin-8-yl)benzenesulfonamide (3n): After column
1
chromatography (PE/EtOAc 9:1) a yellow solid was obtained. 57% yield. H NMR (400 MHz,
CDCl3) δ 9.48 (s, 1H), 8.85 (d, J = 4.1 Hz, 1H), 8.43 (d, J = 8.7 Hz, 1H), 7.85 (d, J = 8.3 Hz, 2H),
7.79 (d, J = 3.3 Hz, 2H), 7.56 (dd, J = 8.7, 4.2 Hz, 1H), 7.22 (d, J = 8.2 Hz, 2H), 2.33 (s, 3H). 13C
NMR (101 MHz, CDCl3) δ 149.08, 144.34, 138.03, 137.58, 136.14, 133.16 (q, J = 2.0 Hz), 129.80,
127.28, 125.95 (q, J = 5.7 Hz), 125.43, 124.54 (q, J = 271.3 Hz), 123.22, 119.83 (q, J = 32.0 Hz),
111.46, 21.53. 19F NMR (376 MHz, CDCl3) δ -59.30. IR (KBr, ν/cm−1) 3433, 2920, 1582, 1511,
1472, 1378, 1315, 1166, 1110, 880, 731, 664. HRMS (ESI) m/z calcd for C17H14F3N2O2S+
[M+H]+: 367.0723; found: 367.0726.
N-(2-methyl-5-(trifluoromethyl)quinolin-8-yl)benzamide (3o): After column chromatography
(PE/EtOAc 9:1) a yellow solid was obtained. 60% yield. 1H NMR (400 MHz, CDCl3) δ 10.99 (s,
1H), 8.92 (d, J = 8.2 Hz, 1H), 8.63 – 8.28 (m, 1H), 8.08 (dd, J = 8.0, 1.4 Hz, 2H), 7.89 (d, J = 8.2
Hz, 1H), 7.59 (d, J = 7.4 Hz, 3H), 7.49 (d, J = 8.8 Hz, 1H), 2.81 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 165.58, 157.94, 138.09, 137.46, 134.81, 133.28 (q, J = 2.0 Hz), 132.18, 128.94, 127.33,
125.52 (q, J = 5.7 Hz), 124.61 (q, J = 271.0 Hz), 123.73, 122.44, 119.49 (q, J = 29.3 Hz), 114.23,
25.30. 19F NMR (376 MHz, CDCl3) δ -59.13. IR (KBr, ν/cm−1) 3318, 2922, 1677, 1615, 1582,
1529, 1490, 1393, 1087, 842, 798, 736, 692. HRMS (ESI) m/z calcd for C18H14F3N2O+ [M+H]+:
331.1053; found: 331.1059.
N-(6-methoxy-5-(trifluoromethyl)quinolin-8-yl)benzamide
(3p):
After
column
1
chromatography (PE/EtOAc 9:1) a yellow solid was obtained. 58% yield. H NMR (400 MHz,

CDCl3) δ 11.01 (s, 1H), 8.96 (s, 1H), 8.72 (dd, J = 4.1, 1.5 Hz, 1H), 8.57 (dt, J = 8.8, 1.4 Hz, 1H),
8.08 (d, J = 6.9 Hz, 2H), 7.60 (dd, J = 13.2, 7.3 Hz, 3H), 7.52 (dd, J = 8.9, 4.1 Hz, 1H), 4.11 (s,
3H). 13C NMR (101 MHz, CDCl3) δ 165.87, 158.27 (q, J = 1.7 Hz), 146.00, 139.30, 134.41, 133.98,
132.75 (q, J = 5.5 Hz), 132.40, 128.98, 127.34, 126.33, 125.20 (q, J = 269.9 Hz), 123.33, 121.33
(q, J = 30.3 Hz), 103.92, 57.03. 19F NMR (376 MHz, CDCl3) δ -52.50. IR (KBr, ν/cm−1) 3348,
3000, 1677, 1624, 1600, 1528, 1491, 1389, 1262, 1083, 860, 783, 740, 696. HRMS (ESI) m/z
+
calcd for C18H14F3N2O2 [M+H]+: 347.1002; found: 347.1006.
Acknowledgements
The authors gratefully acknowledge support from National Natural Science Foundation of China
(21502046), Natural Science Foundation of Heilongjiang Province (B2016008) and the University
Nursing Program for Young Scholars with Creative Talents in Heilongjiang Province
(UNPYSCT-2017124). The Fundamental Research Funds for the Central Universities from Harbin
Engineering University (HEUCFD1412, HEUCFJ161002, HEUCFJ 171006, and HEUCFJ181008)
were also acknowledged. 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
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