Copper-Catalyzed Electrochemical Selective Bromination of 8-Aminoquinoline Amide Using NH4Br as the Brominating Reagent

Article abstract of DOI:10.1021/acs.joc.9b03223

A simple and mild protocol for copper-catalyzed bromination of quinoline at the C5 site of quinoline by anodic oxidation was developed, affording the desired remote C-H activation products with isolated yields of up to about 90%. The reaction proceeds wit

Full text of DOI:10.1021/acs.joc.9b03223

Subscriber access provided by Imperial College London | Library
Article
Copper-Catalyzed Electrochemical Selective Bromination Of 8-
Aminoquinoline Amide Using NH4Br as the Brominating Reagent
Xiang Yang, Qi-Liang Yang, Xiang-Yang Wang, Haohan Xu, Tian-Sheng Mei, Yan Huang, and Ping Fang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03223 • Publication Date (Web): 31 Dec 2019
Downloaded from pubs.acs.org on January 3, 2020
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 13
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Copper-Catalyzed Electrochemical Selective Bromination Of 8-
Aminoquinoline Amide Using NH4Br as the Brominating Reagent
‡
Xiang Yang† , Qi-Liang Yang‡, Xiang-Yang Wang‡, Hao-Han Xu,† Tian-Sheng Mei*‡, Yan Huang*†
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
and Ping Fang*‡
†Key Laboratory of Oil & Gas Fine Chemicals, Ministry of Education & Xinjiang Uyghur Autonomous Region, College of
Chemistry and Chemical Engineering, Xinjiang University, Urumqi, Xinjiang 830046, China.
‡State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of
Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai
200032, China.
E-mail: xjuchem_2012@163.com; mei7900@sioc.ac.cn; pfang@sioc.ac.cn
Supporting Information Placeholder
ABSTRACT: A simple and mild protocol for copper-catalyzed bromination of quinoline at C5 site of quinoline by anodic oxida-
tion was developed, affording the desired remote C–H activation products with isolated yields of up to about 90%. The reaction
proceeds with low-cost NH4Br and shows a mild and green conditions (electricity as green oxidant; NH3 and H2 as byproducts). At
the same time, a gram-scale bromination reaction was also successfully fulfilled, showing its potential applicable value in organic
synthesis. Moreover the CV chart further demonstrated the proposed catalytic cycle.
Introduction
metric oxidant such as PhI(OAc)2, K2S2O8, Oxone, etc. (ii)
Some of reactions also use additives, such as PivOH,
NH2SO3H, NaHCO3 and CH3(CH2)5COOH. (iii) There was
usage of halide salts (LiX, NaX, KCl) or stoichiometric CuX
as halogenation reagents which generated metal salts as by-
product. (iv) Some of reactions require higher temperature and
inert atmosphere to progress. Accordingly, we still explore an
inexpensive and atom economical synthetic manners which is
in line with the green chemistry.
Aromatic and heterocyclic aromatic halids are an important
intermediate of natural products, medicine, dyestuff, ar-
grochemicals and pharmaceuticals.1 Meanwhile, they were
synthesized via electrophlic aromatic substitution,2 directed
ortho lithiation3 or Sandmeyer reaction.4 Although the above-
mentioned traditional ways are widely used in organic chemis-
try, there are still many limitions, including harsh reaction
conditions, poor functional group toluence and metal salts as
byproduct etc. Therefore it is of great scientific significance to
develop effective and universal strategies for the synthesis of
aromatic chlorides.
Scheme 2. Catalytic Bromination of 8-Aminoquinoline
Amide
Scheme 1. Structures of Some Biologically Active Com-
pounds Containing Quinoline Motifs
The quinoline and motified quinoline have attracted consid-
erable attentions during the past few years due their biological
and pharmacological activities,5 which exist in natural prod-
ucts and marketed drugs6 (Scheme 1). In the past few years,
Stahl, Zhang, Huang, etc reported C5 chlorination of 8-
aminoquinoline that is geomatically difficulted to afford7.
However, there are some limitions and drawbacks. For exam-
ple, (i) most of reactions need expensive and toxic stoichio-
The past decade has witnessed a renaissane in electro-
chemical organic synthesis and the study on electro-synthesis
has become one of the fascinating fields recently.8 The rise of
electrochemical synthesis has become a promising alternative
to traditional chemical oxidants because it uses electrons
ACS Paragon Plus Environment

The Journal of Organic Chemistry
which are safety, green, enviroment amity of reagents as oxi-
Page 2 of 13
Scheme 3. Evaluation of Analogous Substrates
1
2
3
4
5
6
7
8
dant or reductant more importantly. Meanwhile, we can
change the electricity and potential to control reaction rate and
chemoselectivity. In recent years, electronchemical bromina-
tion of arenes has been developed. For example, Thasan, Fach-
igami and Lei, etc reported electrochemical bromination of
aromatic compounds.9 In 2018, our group reported copper-
catalyzed electrochemical C−H amination of arenes with sec-
ondary amines which proceeded via a single-electron-transfer
(SET) process.10 Later, we described palladium-catalyzed elec-
trochemical C−H bromination with divided cell11 (Scheme 2a),
but the reaction device was complex and the reaction tempera-
ture was higher. So we assumed if we could realize the cop-
per-catalyzed regioselective bromination of 8-amidquinoline
amide under anodic oxidation using NH4Br as the brominating
source with undivided cell (Scheme 2b).
Table 2. Evaluation of 8-Aminoquinoline Amidea
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Reaction Optimization with Substrate 1aa
aReaction conditions: 1a (0.20 mmol), Cu(OAc)2 (10 mol %),
DMF (3 mL) NH4Br (0.8 M) in undivided cell with two plati-
num eletrodes (1.0×1.0 cm2), 3 mA, 60 °C, 30 h (16.8 F/mol).
1
bYield was determined by H NMR analysis with CH2Br2 as
the internal standard. cIsolated yield in parentheses.
Result and Discussion
we began our investivation with the electrochemical bro-
mination of arylation of 8-aminoquinoline amide (1a) under
various reaction conditions (Table 1, and see Tables S1–S6 in
the Supporting Information). Through a lot of research, the
results are shown in table 1. 99% yield of the desired product
(2a) could be obtained under constant-current electrolysis at
3.0 mA in the presence of 10 mol% Cu(OAc)2 and NH4Br in
DMF without other electrolyte at 60 °C with platinum elec-
trodes (entry 1). There is only 10% yield without catalyst (en-
aReaction conditions: the reactions were run on 1b–1z (0.20 mmol),
Cu(OAc)2 (10 mol %), DMF (3 mL), NH4Br (0.8 M) in undivided cell
with two platinum eletrodes (1.0×1.0 cm2), 3 mA, 60 °C, 30-40 h.
ACS Paragon Plus Environment

Page 3 of 13
The Journal of Organic Chemistry
try 2) and the CuI as catalyst give the worse yield (entry 3).
However, Cu(OTf)2 led to slightly reduced yield (entry 4).
Scheme 5. Preparation of quinoline derivatives
1
2
3
4
5
6
7
8
9
When we decreased or increased the amount of NH4Br, the
yields also redeced (entries 5 and 6) because increasing the
amount of NH4Br gave 5,7-dibrominated product. Different
solvents were examined and DMF afforded the best yield (en-
tries 7-8). Inorganic bromide salts including LiBr resulted in
good yields (entry 9). However, the n-Bu4NBr kept the reac-
tion from beginning (entry 10). Lower temperatures result in
lower yields (entry 11). Increasing the electric current gave
lower yield because of 5,7-dibrominated product as byprodruct
(entry 12). The use of C anode instead of Pt anode gave lightly
lower yield (entry 13). Electrical current was necessary for this
reaction on the basis of control experiments (entry 14).
With the optimized reaction conditions in hand, next, we
explored the analogous substrates (Scheme 3). Such as, none
of the substrates produced the corresponding products under
the standard conditions. In summary, the bidentate nitrogen
structure was very critical for the process and a free NH was
necessary.
Following, we proceeded to investigate the substrate scope
and limitation of the reaction. As shown in （Table 2）, di-
versified aryl substituted carboxamides were tested as sub-
strates Arenes substituted with a variety of functional groups
such as alkyl, fluoro, nitro, sulfonyl, bromo, phenyl, nitrile,
ester, trifluoromethyl, and Chloro were tolerated (2a-2p), af-
fording good to excellent yields. Meanwhile, multisubstituted
gropes also get good yields (2q, 2r). To our delight, the heter-
ocyclic amide could afford the brominated products in 90-94%
yields (2s, 2t). It was worth noting, aliphatic amides could also
afford the bromated products in higher yields (2u-2y). Re-
markablely, this bromination protocol could also be applied to
8-aminoquinoline protected by (Boc)2O (2z), affording bro-
minated product in excellent yields. Unexpected, the substrate
1aa give the dibrominated products 2aa.The structures of 2s
and 2aa were unambiguously confirmed by X-ray analysis.
Next, the scalability of this copper-catalyzed electrochemi-
cal C–H bromination furnished the desired product in 93%
isolated yield by using a reaction contioning 5.34 mmol of 1c,
which showcases the preparative utility of this electrochemical
C−H bromination (Scheme 4).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To gain more insight into the reaction, we compared the re-
actions with and without copper catalyst. It further proved that
copper is indispensable (Figure 1). Moreover, a kinetic iso-
tope effect (KIE) value of 1.07 was observed by comparing the
global reaction rates of 1a versus 1a−D2, which in indicated
that the C–H bond activation is not the rate-limiting step
(Scheme 6).
Figure 1.The Reaction Condition with or without Copper
100
without Cu(OAc)2
with Cu(OAc)2
80
60
40
20
0
0
5
10
15
20
25
30
35
40
Scheme 4. Gram-scale Experiment
Time (h)
Scheme 6. KIE Experiment
To further demonstrate the advantage of using this method
(Scheme 5), we found that the 5-brominated product also as a
new directing group, chlorination and bromination could be
achieved under palladium-catalyzed anodic oxidation condi-
tions. To our delight, the dibominated products were obtained
with substratecontaining two ortho C−H bonds in excellent
yields and the dichlorinated product showed moderated yields.
The structures of 3a were unambiguously confirmed by X-ray
analysis (see Supporting Information). Furthermore, remote
alkynylation of 8-aminoquinoline scaffolds at C5 position was
achieved in good yield (Sonogashira cross-coupling reaction).
At the same time, the amide bond could be easily hydrolyzed
into C5 brominated 8-aminoquinoline in 98% yield.
Studies were performed to obtain insight into the reaction
mechanism. We carried out cyclic voltammetry (CV) experi-
ments. individual components (Figure 2) showed that sub-
strate 1a (curve b, 1.71 V), NH4Br (curve c, 0.76 V, 1.12 V),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 13
which probably associated with with Br3−/Br− and Br3−/Br2
complex B. Then, the bromine radical attacked complex B and
redox couples,11,12 Cu(OAc)2 (curve d), no oxidation potentials.
Then we observed that there was no change when added sub-
strate 1a and NH4Br (Figure 3, curve b). To our delight, a new
oxidation wave is Ep = 1.0 V when mixed substrate 1a and
Cu(OAc)2 (Figure 3, curve c), which probably generated
complex A, fllowing the NH4Br added, the oxidation poten-
tials of NH4Br (Ep = 1.12 V) disappeared, it maybe formed
complex C. However, the wave of 1.0 v still exist (Figure 3,
curve c), which indicated Cu(II) complex still exist, so we
assumed that complex C quickly transformed into D under
anodic oxidation.
turned into complex C by single electron transfer (SET), fol-
lowed by the complex C transformed into D by anodic oxida-
tion. After generation of the intermediate E through the proton
transfer process (PT), finally metal dissociation to give prod-
uct, thereby completing the catalytic cycle.
1
2
3
4
5
6
7
8
Scheme 7. Proposed Catalytic Cycle
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2.0x10-4
a blank
b substrate 1a
c NH4Br
c
1.5x10-4
1.0x10-4
d Cu(OAc)2
b
a
1.71 V
0.76 V
d
1.12 V
5.0x10-5
0.0
0.0
0.5
1.0
1.5
2.0
Conclusion
E vs SCE/V
In conclusion, we have developed a simple, mild and envi-
ronmental-friendly protocol for the C5 bromination of 8-
aminoquinoline amides promoted by a dual catalysis of transi-
tion metal and electricity. Note that this method afforded C5
brominated 8-aminoquinoline amides with high regioselectivi-
ty. The strategy for the construction of C5 functionalized
quinolines also has a good application foreground. Moreover,
the CV chart further demonstrated the proposed catalytic cycle
in our laboratory.
Figure 2. Cyclic voltammograms recorded on a Pt electrode (area = 0.03
cm2): (a) DMF containing 0.1 M n-Bu4NPF6; (b) solution (a) after addition
of 5 mM substrate 1a; (c) solution (a) after addition of 5 mM NH4Br; (d)
solution (a) after addition of 5 mM Cu(OAc)2.
2.0x10-4
a blank
b substate 1a + NH4Br
EXPERIMENTAL SECTION
1.5x10-4
1.0x10-4
c substate 1a + Cu(OAc)2
1.66 V
b
d substate 1a + Cu(OAc)2 + NH4Br
c
General Experimental Section. All the electrochem-
ical oxidations were performed in an undivided cell
equipped with two platinum electrodes (1.0×1.0 cm2)
unless otherwise noted. Solvents and commercially
available reagents were used without purification. Col-
umn chromatography was performed using either 100-
200 Mesh or 300-400 Mesh silica gel. All commercial
reagents were purchased from Macklin, TCI, Sigma-
Aldrich, Adamas-beta of the highest purity grade. Cy-
clic voltammograms were recorded on a CHI 660E po-
tentiostat. 1H NMR and 13C NMR spectra were recorded
on Agilent AV 400, Varian Inova 400 (400 MHz and 100
MHz, respectively). 19F NMR spectra were recorded on
Agilent AV 400, Varian Inova 400 (376 MHz) instrument
and are reported relative to the CFCl3 as the internal
standard. The peaks were internally referenced to TMS
(0.00 ppm) or residual undeuterated solvent signal. The
following abbreviations were used to explain multiplici-
ties: s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, and br = broad. Infrared spectra were ob-
a
1.00 V
1.12 V
d
5.0x10-5
0.0
0.75 V
-5.0x10-5
0.0
0.5
1.0
1.5
2.0
E vs SCE/V
Figure 3. Cyclic voltammograms recorded on a Pt electrode (area = 0.03
cm2): (a) DMF containing 0.1 M n-Bu4NPF6; (b) solution (a) after addition
of 5 mM substrate 1a and 5 mM NH4Br; (c) solution (a) after addition of 5
mM substrate 1a and 5 mM Cu(OAc)2 ; (d) solution (c) after addition of 5
mM substrate NH4Br.
Based on our experimental results and previous work, a
plausible mechanism is presented for Cu-catalyzed electro-
chemical regioselective bromination of 8-amidquinolines
(Scheme 7). Substrate 1 and Cu(II)(OAc)2 generated the aryl-
Cu(II) complex A, which was deprotonated by AcO- to form
ACS Paragon Plus Environment

Page 5 of 13
The Journal of Organic Chemistry
8.84-8.80 (m, 1H), 8.25-8.19 (m, 2H), 8.17 (d, J = 8.4
tained on a Bio-Rad FTS-185 instrument. High resolu-
1
2
3
4
Hz, 1H), 8.12-8.07 (m, 2H), 7.60-7.53 (m, 2H), 7.47 (dd,
J = 8.2, 4.2 Hz, 1H), 3.10 (s , 3H). 13C{1H} NMR (100
MHz, CDCl3) 163.6, 148.6, 143.3, 140.0, 138.7, 136.6,
134.0, 128.4, 128.1, 127.4, 122.5, 122.0, 116.9, 44.5. IR
(neat): 3341, 2996, 1664, 1535, 1483, 1421, 1386, 1314,
1151, 968, 759, 734, 643, 629 cm-1. HRMS (ESI-TOF)
Calcd for C17H15N2O3S, [M+H]+: 327.0798, found
327.0796.
tion mass spectra were recorded at the Center for Mass
Spectrometry, Shanghai Institute of Organic Chemistry.
Analytical and spectral data of all those known com-
pounds are exactly matching with the reported values.
5
6
7
8
9
General Procedure for compounds 1a-1aa. To a so-
lution of mixture of 8-aminoquinoline (10 mmol, 1
equiv, 1.442 g) and Et3N (15 mmol, 1.5 equiv, 1.518 g) in
anhydrous CH2Cl2 (30 mL) at ice bath cooling, RCOCl
(11 mmol, 1.1 equiv) was added slowly. After addition,
the mixture was gradually warmed to room tempera-
ture and stirred overnight. The mixture was quenched
with water (30 mL) and extracted with CH2Cl2 (3 x 20
mL). Combined organic phase was dried over MgSO4,
filtered and concentrated under reduced pressure. The
resulting residue was purified by silica gel flash chroma-
tography to give the desired product.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General Procedure for Electrochemical C–H Bro-
mination of 8-Aminoquinoline Amide. The electroca-
talysis was carried out in an undivided cell equipped
with two platinum electrodes (1.0×1.0 cm2). 8-
Aminoquinoline Amide 1a-1aa (0.2 mmol, 1 equiv),
NH4Br (2.4 mmol, 12 equiv), Cu(OAc)2 (10 mol %, 3.62
mg), DMF (3 mL) were added to the electrochemical
cell. Electrocatalysis was preformed at 60 oC in an oil
bath with a constant current of 3 mA. The progress of
the reaction was monitored by TLC. After the comple-
tion of reaction, it was quenched by ice cold water and
extracted with EtOAc. The combined organic extracts
were dried over anhydrous sodium sulphate and fil-
tered. Then, the solvent was evaporated under reduced
pressure to give the crude product which was subjected
to purify by silica gel column chromatography to afford
desired product 2a-2aa.
General Procedure for compounds 1w. A mixture of
8-aminoquinoline (2.08 mmol, 1.0 equiv, 299.8 mg), di-
tert-butyl dicarbonate (4.16 mmol, 2.0 equiv, 907.9 mg)
o
and 1,4-dioxane (10 mL) was stirred at 102 C in an oil
bath for 6 h. The solvent was removed under reduced
pressure. The resulting residue was purified by silica gel
flash chromatography to give the desired product.
General Procedure for compounds 1ab-1ad worked
as General Procedure for compounds 1a-1aa.
N-(5-bromoquinolin-8-yl)benzamide(2a).7k Following
the general procedure, reaction between Substrate 1a
(0.2 mmol, 1 equiv, 49.6 mg) with ammonium bromide
(2.4 mmol, 12 equiv, 232.8 mg) afforded the corre-
sponding Bromination of 8-Aminoquinoline Amide 2a,
which was purified by column chromatography on silica
gel (petroleum ether : ethyl acetate = 10 : 1) to afford
General Procedure for compounds 1ac. To a sus-
pension of sodium hydride (1.24 mmol, 2.05 equiv, 29.8
mg) in dry DMF (3 mL), was added a solution of N-
(quinolin-8-yl)benzamide (0.604 mmol, 1 equiv, 149.8
o
mg) in dry DMF (3 mL) at 0 C. The reaction mixture
1
title compound (61.6 mg, 94%) as a white solid. H
was allowed to warm to room temperature and stirred
for 3 h. Then, methyl iodide (0.785 mmol, 1.3 equiv,
111.4 mg) was added dropwise and the reaction was
stirred at room temperature for 1 h. The reaction was
diluted with DCM (20 mL) and the organic layer was
washed with water (3 x 12 mL), dried over anhydrous
Na2SO4 and concentrated to dryness under reduced
pressure. Pale yellow oil was obtained and purified by
column chromatography on silica gel.
NMR (400 MHz, CDCl3): δ 10.60 (s, 1H), 8.77–8.73 (m,
2H), 8.41(dd, J = 8.8, 1.6 Hz, 1H), 8.03–8.01 (m, 2H),
7.74 (d, J = 8.0 Hz, 1H), 7.57–7.46 (m, 4H);13C{1H}
NMR (100 MHz, CDCl3) δ 165.3, 148.7, 139.3, 135.9,
134.7, 134.4, 132.0, 130.9, 128.8, 127.2, 127.1, 122.7,
116.9, 114.4.
N-(5-bromoquinolin-8-yl)-2-methylbenzamide (2b).7k
Following the general procedure, reaction between Sub-
strate 1b (0.2 mmol, 1 equiv, 52.6 mg) with ammonium
bromide (2.4 mmol, 12 equiv, 232.8 mg) afforded the
corresponding Bromination of 8-Aminoquinoline Am-
ide 3b, which was purified by column chromatography
on silica gel (petroleum ether : ethyl acetate = 10 : 1) to
Compounds 1a-1i , 1k-1z and 1aa-1ad were known
compounds and were prepared according the literature
procedure7e,7i,13
.
N-(quinolin-8-yl)-4-(methylsulfonyl)benzamide (1j)new
.
1
title compound (63.2 mg, 93%) as a white solid. H
Following the general procedure for compounds 1a-1y
to get desired product 1j which was purified by column
chromatography on silica gel (petroleum ether : ethyl
acetate = 1 : 1) to title compound (2.6732g, 82%) as a
NMR (400 MHz, CDCl3) δ 10.18 (s, 1H), 8.83 (d, J =
8.4 Hz, 1H), 8.77 (d, J = 4.0 Hz, 1H), 8.51 (dd, J = 8.6,
1.2 Hz, 1H), 7.83 (d, J = 8.4 Hz,1H), 7.68 (d, J = 7.2 Hz,
1H),7.54 (dd, J = 8.6, 4.4 Hz, 1H), 7.41 (t, J = 7.2 Hz,
1H), 7.32 (t, J = 8.0 Hz, 2H), 2.60 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 168.1, 148.7, 139.2, 136.8,
1
white solid. M.p.: 171.1-171.7 °C. H NMR (400 MHz,
CDCl3) δ 10.76 (s, 1H), 8.86 (dd, J = 5.8, 3.0 Hz, 1H),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 13
Aminoquinoline Amide 2f, which was purified by col-
136.3, 135.9, 134.6, 131.5, 130.9, 130.5, 127.23, 127.19,
126.1, 122.7, 116.9, 114.5, 20.3.
1
2
3
4
5
6
7
8
umn chromatography on silica gel (petroleum ether :
ethyl acetate = 10 : 1) to afford title compound (73.2
mg, 95%) as a white solid. M.p.: 86.0-90.6 °C. 1H NMR
(400 MHz, CDCl3) δ 10.66 (s, 1H), 8.84-8.87 (m, 2H),
8.50 (dd, J = 8.8, 1.6 Hz, 1H), 8.01-7.97 (m, 2H), 7.80
(d, J = 8.4 Hz, 1H), 7.58-7.52 (m, 3H), 1.36 (s , 9H). 13C
{1H}NMR (100 MHz, CDCl3) δ 165.4, 155.6, 148.7,
139.6, 135.9, 134.6, 132.0, 130.9, 127.2, 127.1, 125.8,
122.7, 116.9, 114.2, 35.0, 31.2. IR (neat): 3346, 2959,
1670, 1538, 1510, 1474, 1385, 1363, 1262, 917, 840,
806, 783, 653 cm-1. HRMS (ESI-TOF) Calcd for
C20H19BrN2O, [M+H]+: 383.0754, found 383.0757.
N-(5-bromoquinolin-8-yl)-3-methylbenzamide (2c).7k
Following the general procedure, reaction between Sub-
strate 1c (0.2 mmol, 1 equiv, 52.6 mg), with Ammonium
bromide (2.4 mmol, 12 equiv, 232.8 mg) afforded the
corresponding Bromination of 8-Aminoquinoline Am-
ide 2c, which was purified by column chromatography
on silica gel (petroleum ether : ethyl acetate = 10 : 1) to
afford title compound (63.2 mg, 93%) as a white solid.
1H NMR (400 MHz, CDCl3) δ 10.57 (s, 1H), 8.78 (dd, J
= 4.2, 1.2 Hz, 1H), 8.75 (d, J = 8.4 Hz, 1H), 8.42 (dd, J
=8.6, 1.2 Hz, 1H), 7.84-7.73 (m, 3H), 7.48 (dd, J = 8.2,
4.4 Hz, 1H), 7.42-7.32 (m, 2H), 2.45 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 165.4, 148.7, 139.2, 138.7,
135.8, 134.7, 134.4, 132.7, 130.8, 128.6, 128.0, 127.0,
124.1, 122.6, 116.9, 114.3, 21.5.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-(5-bromoquinolin-8-yl)-4-methoxybenzamide
(2g).7k Following the general procedure, reaction be-
tween Substrate 1g (0.2 mmol, 1 equiv, 55.8 mg) with
ammonium bromide (2.4 mmol, 12 equiv, 232.8 mg)
afforded the corresponding Bromination of 8-
Aminoquinoline Amide 2g, which was purified by col-
umn chromatography on silica gel (petroleum ether :
ethyl acetate = 10 : 1) to afford title compound (66.9
mg, 94%) as a white solid. 1H NMR (400 MHz, CDCl3)
δ 10.63 (s, 1H), 8.85 (d, J = 4.0 Hz, 1H), 8.81 (d, J = 8.4
Hz, 1H), 8.53 (dd, J = 8.4 , 0.8 Hz, 1H), 8.04 (d, J = 8.8
Hz, 2H), 7.83 (d, J = 8.4 Hz, 1H), 7.57 (dd, J = 8.4, 4.4
Hz, 1H), 7.03 (d, J = 8.8 Hz, 2 H), 3.89 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 164.9, 162.6, 148.7, 139.4,
136.0, 134.7, 131.0, 129.2, 127.2, 127.1, 122.7, 116.8,
114.1, 114.0, 55.5.
N-(5-bromoquinolin-8-yl)-4-methylbenzamide (2d).7k
Following the general procedure, reaction between Sub-
strate 1d (0.2 mmol, 1 equiv, 52.6 mg) with Ammonium
bromide (2.4 mmol, 12 equiv, 232.8 mg) afforded the
corresponding Bromination of 8-Aminoquinoline Am-
ide 2d, which was purified by column chromatography
on silica gel (petroleum ether : ethyl acetate = 10 : 1) to
1
title compound (62.5 mg, 92%) as a white solid. H
NMR (400 MHz, CDCl3) δ 10.63 (s, 1H), 8.82 (dd, J =
4.0 , 1.2 Hz, 1H), 8.79 (d, J = 8.4 Hz, 1H), 8.49 (dd, J =
8.6 , 1 Hz, 1H), 7.94 (d, J = 8.2 Hz, 2H), 7.79 (d, J = 8.4
Hz, 1H), 7.54 (dd, J = 8.4, 4.0 Hz, 1H), 7.32 (d, J = 8.0
Hz, 2H), 2.44 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 165.3, 148.7, 142.5, 139.3, 135.9, 134.6,
132.0, 130.9, 129.5, 127.3,127.2, 122.7, 116.9, 114.2,
21.6.
N-(5-bromoquinolin-8-yl)-[1,1'-biphenyl]-4-carbox-
amide (2h).7j Following the general procedure, reaction
between Substrate 1h (0.2 mmol, 1 equiv, 64.8 mg) was
brominated following the general procedure, with am-
monium bromide (2.4 mmol, 12 equiv, 232.8 mg) af-
forded the corresponding Bromination of 8-
Aminoquinoline Amide 2h, which was purified by col-
umn chromatography on silica gel (petroleum ether :
ethyl acetate = 10 : 1) to afford title compound (79.3
mg, 98%) as a white solid. 1H NMR (400 MHz, CDCl3):
δ 10.70 (s, 1H), 8.84 (dd, J = 4.0, 1.2 Hz, 1H), 8.81 (d, J
= 8.4 Hz, 1H), 8.49 (dd, J = 8.4, 1.2 Hz, 1H), 8.12 (d, J
= 8.0 Hz, 2H), 7.81 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.4
Hz, 2H), 7.76 (d, J = 7.2Hz, 2H), 7.54 (dd, J = 8.4, 4.0
Hz, 1H), 7.48 (t, J = 7.2 Hz, 2H), 7.41 (t, J = 7.2 Hz,
1H). 13C{1H} NMR (101 MHz, CDCl3) δ 163.9, 147.7,
143.7, 138.8, 138.3, 134.9, 133.4, 132.3, 129.9, 127.9,
127.1, 126.8, 126.4, 126.2, 126.1, 121.7, 115.9, 113.4.
N-(5-bromoquinolin-8-yl)-4-fluorobenzamide (2e).7k
Following the general procedure, reaction between Sub-
strate 1e (0.2 mmol, 1 equiv, 53.2 mg) with Ammonium
bromide (2.4 mmol, 12 equiv, 232.8 mg) afforded the
corresponding Bromination of 8-Aminoquinoline Am-
ide 2e, which was purified by column chromatography
on silica gel (petroleum ether : ethyl acetate = 10 : 1) to
afford title compound (63.2 mg, 92%) as a white solid.
1H NMR (400 MHz, CDCl3) δ 10.63 (s, 1H), 8.85 (dd, J
= 4 , 1.2 Hz, 1H), 8.79 (d, J = 8.4 Hz , 1H), 8.54 (dd, J =
8.8 , 4 Hz, 1H), 8.06 (dd, J = 8.8, 5.2 Hz, 2H), 7.83 (d, J
= 8.4 Hz, 1H), 7.58 (dd, J = 8.8, 4.0 Hz, 1H), 7.22 (t, J =
8.4 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.1
(d, J = 251.4 Hz), 164.2, 148.8, 139.3, 136.1, 134.3,
131.0 (d, J = 3.1 Hz), 130.9, 129.7 (d, J = 9.0 Hz),
127.2, 122.8, 117.0, 115.9 (d, J = 21.8 Hz), 114.5.
N-(5-bromoquinolin-8-yl)-2-nitrobenzamide
(2i).12k
Following the general procedure, reaction between Sub-
strate 1i (0.2 mmol, 1 equiv, 58.6 mg) was brominated
following the general procedure, with ammonium bro-
mide (2.4 mmol, 12 equiv, 232.8 mg) afforded the corre-
sponding Bromination of 8-Aminoquinoline Amide 2i,
which was purified by column chromatography on silica
N-(5-bromoquinolin-8-yl)-4-tertiary butylbenzamide
(2f).new Following the general procedure, reaction be-
tween Substrate 1f (0.2 mmol, 1 equiv, 60.8 mg) with
ammonium bromide (2.4 mmol, 12 equiv, 232.8 mg)
afforded the corresponding Bromination of 8-
ACS Paragon Plus Environment

Page 7 of 13
1
2
3
4
5
6
7
The Journal of Organic Chemistry
gel (petroleum ether : ethyl acetate = 5 : 1) to afford title
ide 2l, which was purified by column chromatography
on silica gel (petroleum ether : ethyl acetate = 10 : 1) to
afford title compound (60.4 mg, 86%) as a white solid.
1
compound (66.9 mg, 90%) as a yellow solid. H NMR
(600 MHz, CDCl3) δ 10.14 (s, 1H), 8.85-8.75 (m, 2H),
8.56 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.87
(d, J = 8.4 Hz, 1H), 7.80-7.74 (m, 2H), 7.71-7.64 (m,
1H), 7.58 (dd, J = 8.6, 4.2 Hz, 1H). 13C{1H} NMR (100
MHz, CDCl3) δ 164.4, 149.0, 139.9, 139.2, 136.2, 134.2,
133.9, 133.8, 133.0, 131.0, 128.7, 127.4, 124.9, 122.9,
117.7, 115.4.
1
M.p.: 236.0-239.2 °C. H NMR (400 MHz, CDCl3): δ
10.75 (s, 1H), 8.88 (d, J = 4.0 Hz, 1H), 8.79 (d, J = 8.4
Hz, 1H), 8.57 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 8.0 Hz,
2H)), 7.86(m, 3H), 7.62(dd, J = 8.6, 4.2 Hz, 1H).
13C{1H} NMR (100 MHz, CDCl3): δ 163.4, 149.0,
139.3, 138.6, 136.2, 133.8, 132.7, 130.9, 127.9, 127.3,
122.9, 117.9, 117.3, 115.5, 115.3. IR (neat): 3335, 1673,
1521, 1475, 1384, 1321, 1258, 1098, 917, 832, 782, 756,
672, 577 cm-1. HRMS (ESI-TOF) Calcd for
C17H11BrN3O, [M+H]+: 352.0080, found 352.0069.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-(5-bromoquinolin-8-yl)-4-(methylsulfonyl)benz-
amide(2j).new. Following the general procedure, reaction
between Substrate 1j (0.2 mmol, 1 equiv, 65.2 mg) was
brominated following the general procedure, with am-
monium bromide (2.4 mmol, 12 equiv, 232.8 mg) af-
forded the corresponding Bromination of 8-
Aminoquinoline Amide 2j, which was purified by col-
umn chromatography on silica gel (petroleum ether :
ethyl acetate = 1 : 1) to afford title compound (74.3 mg,
Methyl-4-(5-bromoquinolin-8-yicarbamoyl)-benzoate
(2m).7i Following the general procedure, reaction be-
tween Substrate 1m (0.2 mmol, 1 equiv, 61.2mg) with
ammonium bromide (2.4 mmol, 12 equiv, 232.8 mg)
afforded the corresponding Bromination of 8-
Aminoquinoline Amide 2m, which was purified by col-
umn chromatography on silica gel (petroleum ether :
ethyl acetate = 10 : 1) to afford title compound (68.5 mg,
1
92%) as a white solid. M.p.: 186.8-188.3 °C. H NMR
(400 MHz, CDCl3): δ 10.74 (s, 1H), 8.87 (d, J = 4.0 Hz,
1H), 8.78 (d, J = 8.4 Hz, 1H), 8.56 (d, J = 8.8 Hz, 1H),
8.20-8.27 (m, 2H), 8.16-8.09 (m, 2H), 7.85 (d, J = 8.4
Hz, 1H),7.61 (dd, J = 8.4, 4.0 Hz, 1H), 3.12 (s, 3H);
13C{1H} NMR (101 MHz, CDCl3): δ 163.4, 149.0,
143.4 139.6, 139.2, 136.1, 133.8, 130.9, 128.3, 128.0,
127.3, 122.9, 117.2, 115.2, 44.4. IR (neat): 3342,
1671,1535, 1473, 1387, 1368, 1309, 1292, 1146, 968,
918, 782, 662, 569 cm-1. HRMS (ESI-TOF) Calcd for
C17H14BrN2O3S, [M+H]+: 404.9903, found 404.9899
1
89%) as a white solid. H NMR (400 MHz, CDCl3):
10.78 (s,1H), 8.92 (d, J = 4.0 Hz, 1H), 8.86 (d, J = 8.4
Hz, 1H), 8.59 (d, J = 8.4 Hz, 1H), 8.29-8.21 (m, 2H),
8.20-8.13 (m, 2H), 7.89 (d, J = 8.4 Hz, 1H), 7.65 (dd, J =
8.4, 4.0 Hz, 1H), 4.03 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 166.2, 164.3, 148.9, 139.3, 138.5,
136.1, 134.1, 133.1, 130.9, 130.0, 127.3, 127.2, 122.8,
117.1, 114.8, 52.5.
N-(5-bromoquinolin-8-yl)-1-bromobenzamide (2k).new
Following the general procedure, reaction between Sub-
strate 1k (0.2 mmol, 1 equiv, 65.2 mg) with ammonium
bromide (2.4 mmol, 12 equiv, 232.8 mg) afforded the
corresponding Bromination of 8-Aminoquinoline Am-
ide 2k, which was purified by column chromatography
on silica gel (petroleum ether : ethyl acetate = 10 : 1) to
afford title compound (77.5 mg, 95%) as a white solid.
N-(5-bromoquinolin-8-yl)-3-(trifluoromethyl)benz-
amide (2n).7k Following the general procedure, reaction
between Substrate 1n (0.2 mmol, 1 equiv, 63.2 mg) was
brominated following the general procedure, with am-
monium bromide (2.4 mmol, 12 equiv, 232.8 mg) af-
forded the corresponding Bromination of 8-
Aminoquinoline Amide 2n, which was purified by col-
umn chromatography on silica gel (petroleum ether :
ethyl acetate = 10 : 1) to afford title compound (77.9 mg,
1
M.p.: 154.0-156.4 °C. H NMR (400 MHz, CDCl3): δ
1
10.28 (s, 1H), 8.83 (d, J = 8.4 Hz, 1H), 8.79 (d, J = 3.6
Hz, 1H), 8.51 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.4 Hz,
1H)), 7.71 (d, J = 7.2 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H),
7.55 (dd, J = 8.4 , 4 Hz, 1H), 7.44 (t, J = 7.4 Hz, 1H),
7.34 (t, J = 7.4 Hz, 1H). 13C{1H} NMR (100 MHz,
CDCl3): δ 165.8, 148.8, 139.2, 138.0, 135.9, 134.2,
133.7, 131.6, 130.9, 129.6, 127.7, 127.2, 122.8, 119.6,
117.3, 115.0. IR (neat): 3334, 1668, 1519, 1474, 1383,
1361, 1318, 1019, 918, 847, 778, 741, 711, 663 cm-1.
HRMS (ESI-TOF) Calcd for C16H11Br2N2O, [M+H]+:
404.9233, found 404.9240.
98%) as a white solid. H NMR (400 MHz, CDCl3): δ
10.65 (s, 1H), 8.82 (dd, J = 4, 1.6 Hz, 1H), 8.73 (d, J =
8.4 Hz, 1H), 8.48 (dd, J = 8.4, 1.2 Hz, 1H), 8.30 (s, 1H),
8.18 (d, J = 7.6 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.78
(d, J = 8.4 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.55 (dd, J
= 8.8, 4.4 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ
163.7, 148.9, 139.2, 136.0, 135.6, 133.9, 131.4 (q, J =
32.7 Hz), 130.8, 130.2,129.4, 128.5 (q, J = 3.6 Hz),
127.1, 124.5 (q, J = 3.8 Hz), 123.7 (q, J = 271.2 Hz),
122.8, 117.1, 114.9. 19F NMR (376 MHz, CDCl3): δ -
62.7.
N-(5-bromoquinolin-8-yl)-4-cyanobenzamide (2l).new
Following the general procedure, reaction between Sub-
strate 1l (0.2 mmol, 1 equiv, 54.6 mg) with ammonium
bromide (2.4 mmol, 12 equiv, 232.8 mg) afforded the
corresponding Bromination of 8-Aminoquinoline Am-
N-(5-bromoquinolin-8-yl)-2-(4-chlorophenyl)acet-
amide (2o).new Following the general procedure, reaction
between Substrate 1o (0.2 mmol, 1 equiv, 59.2 mg) with
ammonium bromide (2.4 mmol, 12 equiv, 232.8 mg)
afforded the corresponding Bromination of 8-
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 13
Aminoquinoline Amide 2o, which was purified by col- Aminoquinoline Amide 2r, which was purified by col-
1
2
3
4
5
6
7
8
umn chromatography on silica gel (petroleum ether :
ethyl acetate = 10 : 1) to afford title compound (71.9 mg,
96%) as a white solid. M.p.: 127.1-127.9 °C. H NMR
umn chromatography on silica gel (petroleum ether :
ethyl acetate = 10 : 1) to afford title compound (70.1 mg,
95%) as a white solid. H NMR (400 MHz, CDCl3): δ
1
1
(400 MHz, CDCl3): δ 9.83 (s, 1H), 8.69 (dd, J = 4.4, 1.6
Hz, 1H), 8.60 (d, J = 8.4 Hz, 1H), 8.43 (dd, J = 8.4, 1.2
Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.48 (dd, J = 8.4, 4.0
Hz, 1H)), 7.40-7.29 (m, 4H), 3.84 (s, 2H). 13C{1H}
NMR (100 MHz, CDCl3): δ 168.9, 148.7, 138.9, 135.8,
134.0, 133.3, 132.9, 130.9, 130.7, 129.1, 127.0, 122.6,
116.8, 114.4, 44.4. IR (neat): 3361, 1663, 1534, 1501,
9.91 (s, 1H), 8.90 (d, J = 8.4 Hz, 1H), 8.74 (dd, J = 4.2,
1.4 Hz, 1H), 8.52 (dd, J = 8.6, 1.4 Hz, 1H), 7.86 (d, J =
8.4 Hz, 1H), 7.53 (dd, J = 8.4, 4.4 Hz, 1H), 6.93 (s, 2H),
2.40 (s, 6H), 2.34 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 169.1, 148.7, 139.2, 138.9, 135.9, 135.1,
134.5, 134.4, 130.9, 128.5, 127.2, 122.7, 117.2, 114.6,
21.2, 19.4.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1473, 1358, 1026, 952, 921, 853, 808, 778, 747, 638 cm-
1
N-(5-bromoquinolin-8-yl)thiophene-2-carboxamide
(2s).7k Following the general procedure, reaction be-
tween Substrate 1s (0.2 mmol, 1 equiv, 50.8 mg) was
brominated following the general procedure, with am-
monium bromide (2.4 mmol, 12 equiv, 232.8 mg) af-
forded the corresponding Bromination of 8-
Aminoquinoline Amide 2s, which was purified by col-
umn chromatography on silica gel (petroleum ether :
ethyl acetate = 10 : 1) to afford title compound (62.9 mg,
.
HRMS (ESI-TOF) Calcd for C17H13BrN2OCl,
[M+H]+: 374.9894, found 374.9887.
N-(5-bromoquinolin-8-yl)-1-naphthamide (2p).7k Fol-
lowing the general procedure, reaction between Sub-
strate 1p (0.2 mmol, 1 equiv, 59.6 mg) was brominated
following the general procedure, with ammonium bro-
mide (2.4 mmol, 12 equiv, 232.8 mg) afforded the cor-
responding Bromination of 8-Aminoquinoline Amide
2p, which was purified by column chromatography on
silica gel (petroleum ether : ethyl acetate = 10 : 1) to
afford title compound (71.0 mg, 94%) as a white solid.
1H NMR (400 MHz, CDCl3): δ 10.40 (s, 1H), 8.94 (d, J
= 8.4 Hz, 1H), 8.75 (dd, J = 4.4, 1.6 Hz, 1H), 8.56-8.50
(m, 2H), 8.01 (d, J = 8.4 Hz, 1H), 7.95-7.86 (m, 3H),
7.62-7.51 (m, 4H); 13C{1H} NMR (101 MHz, CDCl3): δ
167.7, 148.8, 139.3, 136.0, 134.7, 134.3, 133.9, 131.3,
130.9, 130.3, 128.4, 127.4, 127.3, 126.6, 125.6, 125.5,
124.8, 122.8, 117.2, 114.7.
1
94%) as a yellow solid. H NMR (400 MHz, CDCl3): δ
10.48 (s, 1H), 8.81 (dd, J = 4.2, 0.6 Hz, 1H), 8.68 (d, J =
8.4 Hz, 1H), 8.48 (dd, J = 8.4, 0.8 Hz, 1H), 7.81-7.75
(m, 2H), 7.58 (d, J = 4.8 Hz, 1H), 7.54 (dd, J = 8.6, 4.2
Hz, 1H);7.18-7.15 (m, 1H) . 13C{1H} NMR (100 MHz,
CDCl3): δ 159.9, 148.8, 139.7, 139.0, 135.9, 134.1,
131.2, 130.9, 128.5, 127.9, 127.1, 122.7, 116.9, 114.4.
N-(5-bromoquinolin-8-yl)furan-3-carboxamide
(2t).new Following the general procedure, reaction be-
tween Substrate 1s (0.2 mmol, 1 equiv, 47.6 mg) was
brominated following the general procedure, with am-
monium bromide (2.4 mmol, 12 equiv, 232.8 mg) af-
forded the corresponding Bromination of 8-
Aminoquinoline Amide 2s, which was purified by col-
umn chromatography on silica gel (petroleum ether :
ethyl acetate = 10 : 1) to afford title compound (57.0 mg,
N-(5-bromoquinolin-8-yl)-2,5-dimethylbenzamide
(2q).new Following the general procedure, reaction be-
tween Substrate 1q (0.2 mmol, 1 equiv, 55.2 mg) with
ammonium bromide (2.4 mmol, 12 equiv, 232.8 mg)
afforded the corresponding Bromination of 8-
Aminoquinoline Amide 2q, which was purified by col-
umn chromatography on silica gel (petroleum ether :
ethyl acetate = 10 : 1) to afford title compound (68.2 mg,
1
90%) as a white solid. M.p.: 155.8-156.9 °C. H NMR
(400 MHz, CDCl3): δ 10.20 (s, 1H), 8.80 (dd, J = 4.4,
1.6 Hz, 1H), 8.70 (d, J = 8.4 Hz, 1H), 8.48 (dd, J = 8.6,
1.4 Hz, 1H), 8.16 (d, J = 1.2, 0.8 Hz, 1H)), 7.77 (d, J =
8.4 Hz, 1H), 7.56-7.50 (m, 2H), 6.89 (dd, J = 1.6, 0.8
Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 160.6,
148.7, 145.3, 144.1, 139.0, 135.9, 134.1, 130.9, 127.1,
123.4, 122.7, 116.9, 114.3, 108.5. IR (neat): 3341, 1668,
1570, 1527, 1472, 1385, 1366, 1319, 1161, 1080, 1017,
911, 870, 853, 784, 730, 677, 600 cm-1. HRMS (ESI-
TOF) Calcd for C14H10BrN2O2, [M+H]+: 316.9920,
found 316.9923.
1
96%) as a white solid. M.p.: 141.7-143.5 °C. H NMR
(400 MHz, CDCl3): δ 10.16 (s, 1H), 8.83 (d, J = 8.4 Hz,
1H), 8.78 (dd, J = 4.0, 3.2 Hz, 1H), 8.51 (dd, J = 8.4, 1.2
Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.54 (dd, J = 8.6, 4.2
Hz, 1H)), 7.48 (s, 1H), 7.23-7.16 (m, 2H), 2.55 (s, 3H),
2.40 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
168.3, 148.7, 139.3, 136.2, 135.9, 135.6, 134.7, 133.4,
131.3, 131.2, 130.9, 127.8, 127.2, 122.7, 117.0, 114.4,
21.0, 19.8. IR (neat): 3349, 1680, 1527, 1472, 1375,
1320, 1256, 1153, 935, 832, 806, 784, 699, 673 cm-1.
HRMS (ESI-TOF) Calcd for C18H16BrN2O, [M+H]+:
355.0441, found 355.0454.
N-(5-bromoquinolin-8-yl)propionamide (2u).7g Fol-
lowing the general procedure, reaction between Sub-
strate 1u (0.2 mmol, 1 equiv, 40.0 mg) was brominated
following the general procedure, with ammonium bro-
mide (2.4 mmol, 12 equiv, 232.8 mg) afforded the cor-
responding Bromination of 8-Aminoquinoline Amide
N-(5-bromoquinolin-8-yl)-2,4,6-trimethylbenzamide
(2r).7e Following the general procedure, reaction be-
tween Substrate 1r (0.2 mmol, 1 equiv, 58.0 mg) with
ammonium bromide (2.4 mmol, 12 equiv, 232.8 mg)
afforded the corresponding Bromination of 8-
ACS Paragon Plus Environment

Page 9 of 13
The Journal of Organic Chemistry
1H), 8.66 (d, J = 8.4 Hz, 1H), 8.47 (dd, J = 8.8, 1.6 Hz,
2u, which was purified by column chromatography on
1
2
3
4
5
6
7
8
1H), 7.75 (d, J = 8.4 Hz, 1H), 7.52 (dd, J = 8.6, 4.2 Hz,
1H), 1.40 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ
177.2, 148.6, 139.4, 135.9, 134.6, 130.9, 127.1, 122.5,
116.7, 113.9, 40.4, 27.7.
silica gel (petroleum ether : ethyl acetate = 10 : 1) to
afford title compound (54.5 mg, 97%) as a white solid.
1H NMR (400 MHz, CDCl3): δ 9.75 (s, 1H), 8.77 (d, J =
4.0 Hz, 1H), 8.64 (d, J = 8.4 Hz, 1H), 8.46 (d, J = 8.4
Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.51 (dd, J = 8.6, 4.2
Hz, 1H), 2.58 (q, J = 7.6 Hz, 2H), 1.32 (t, J = 7.6 Hz,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ 172.4, 148.5,
138.9, 135.9, 134.4, 130.9, 127.1, 122.6, 116.8, 113.9,
31.2, 9.6.
N-(5-bromoquinolin-8-yl)methacrylamide (2y).7e Fol-
lowing the general procedure, reaction between Sub-
strate 1y (0.2 mmol, 1 equiv, 42.4 mg) was brominated
following the general procedure, with ammonium bro-
mide (2.4 mmol, 12 equiv, 232.8 mg) afforded the cor-
responding Bromination of 8-Aminoquinoline Amide
2y, which was purified by column chromatography on
silica gel (petroleum ether : ethyl acetate = 10 : 1) to
afford title compound (54.1 mg, 93%) as a yiellow solid.
1H NMR (400 MHz, CDCl3): δ 10.31 (s, 1H), 8.81 (dd, J
= 4.2, 1.0 Hz, 1H), 8.70 (d, J = 8.4 Hz, 1H), 8.50 (dd, J
= 8.4, 1.2 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.54 (dd, J
= 8.4, 4.4 Hz, 1H), 6.04 (s, 1H), 5.57 (s, 1H), 2.18 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ 166.6, 148.7,
140.5, 139.3, 135.9, 134.3, 130.9, 127.1, 122.6, 120.9,
116.9, 114.3, 18.6.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-(5-Bromoquinolin-8-yl)butyramide (2v).7g Follow-
ing the general procedure, reaction between Substrate 1v
(0.2 mmol, 1 equiv, 42.8 mg) was brominated following
the general procedure, with ammonium bromide (2.4
mmol, 12 equiv, 232.8 mg) afforded the corresponding
Bromination of 8-Aminoquinoline Amide 2v, which was
purified by column chromatography on silica gel (petro-
leum ether : ethyl acetate = 10 : 1) to afford title com-
1
pound (53.9 mg, 92%) as a white solid. H NMR (400
MHz, CDCl3): δ = 9.75 (s, 1H), 8.79 (dd, J = 4.2, 1.4
Hz, 1H), 8.66 (d, J = 8.4 Hz, 1H), 8.48 (dd, J = 8.4, 1.2
Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.53 (dd, J = 8.6, 4.2
Hz, 1H), 2.53 (t, J = 7.6 Hz, 2H), 1.90-1.75 (m, 2H),
1.05 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 171.8, 148.5, 139.0, 135.9, 134.4, 130.9,
127.1, 122.6, 116.8, 114.0, 40.1, 19.1, 13.8.
tert-Butyl (5-bromoquinolin-8-yl)carbamate (2z).7m
Following the general procedure, reaction between Sub-
strate 1z (0.2 mmol, 1 equiv, 48.8 mg) was brominated
following the general procedure, with ammonium bro-
mide (2.4 mmol, 12 equiv, 232.8 mg) afforded the cor-
responding Bromination of 8-Aminoquinoline Amide
2a, which was purified by column chromatography on
silica gel (petroleum ether : ethyl acetate = 10 : 1) to
afford title compound (68.3 mg, 97%) as a white solid.
1H NMR (400 MHz, CDCl3): δ 8.99 (s, 1H),8.77 (dd, J =
4.0, 1.2 Hz, 1H), 8.46 (dd, J = 8.4, 1.2 Hz, 1H), 8.29 (d,
J = 8 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.50 (dd, J =
8.6, 4.2 Hz, 1H), 1.58 (s, 9H). 13C{1H} NMR (100
MHz, CDCl3): δ 152.6, 148.4, 138.8, 135.7, 135.1,
130.8, 127.1, 122.5, 114.9, 112.6, 80.7, 28.4.
N-(5-bromoquinolin-8-yl)cyclohexanecarboxamide
(2w).7k Following the general procedure, reaction be-
tween Substrate 1w (0.2 mmol, 1 equiv, 50.8 mg) was
brominated following the general procedure, with am-
monium bromide (2.4 mmol, 12 equiv, 232.8 mg) af-
forded the corresponding Bromination of 8-
Aminoquinoline Amide 2w, which was purified by col-
umn chromatography on silica gel (petroleum ether :
ethyl acetate = 10 : 1) to afford title compound (63.08
mg, 95%) as a white solid. 1H NMR (400 MHz, CDCl3):
δ 9.84 (s, 1H), 8.81 (d, J = 4.4 Hz, 1H),, 8.67 (d, J = 8.4
Hz, 1H), 8.49 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.4 Hz,
1H), 7.53 (dd, J = 8.4, 4.4 Hz, 1H), 2.52-2.43 (m, 1H),
2.07 (d, J = 12.4 Hz, 2H), 1.87 (d, J = 12.8 Hz, 2H),
1.78-1.56 (m, 3H), 1.44-1.22 (m, 3H), 13C{1H} NMR
(100 MHz, CDCl3): δ 174.8, 148.5, 139.1, 135.9, 134.5,
130.9, 127.1, 122.6, 116.9, 113.9, 46.9, 29.7, 25.74,
25.71.
N-(5-bromoquinolin-8-yl)-4-(dimethyl-amino)
3-
bromobenzamide (2aa).new Following the general proce-
dure, reaction between Substrate 1aa (0.2 mmol, 1
equiv, 58.2 mg) with ammonium bromide (2.4 mmol, 12
equiv, 232.8 mg) afforded the corresponding Bromina-
tion of 8-Aminoquinoline Amide 2aa, which was puri-
fied by column chromatography on silica gel (petroleum
ether : ethyl acetate = 30 : 1) to afford title compound
(56.3 mg, 62%) as a white solid. M.p.: 127.5-133.4 °C.
1H NMR (400 MHz, CDCl3): δ 10.55 (s, 1H), 8.84 (dd, J
= 4.0, 1.2 Hz, 1H), 8.76 (d, J = 8.0 Hz, 1H), 8.51 (dd, J
= 8.4, 1.2 Hz, 1H), 8.24 (d, J = 2.0 Hz, 1H)), 7.92 (dd, J
= 8.4, 2.0 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.56 (dd, J
= 8.6 , 4.2 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 2.91 (s,
6H). 13C{1H} NMR (100 MHz, CDCl3): δ 163.7, 155.0,
148.7, 139.3, 136.0, 134.4, 133.5, 130.9, 129.2, 127.2,
127.1, 122.7, 119.7, 117.7, 116.9, 114.3, 43.7. IR (neat):
3362, 1662, 1596, 1535, 1473, 1380, 1359, 1318, 1245,
N-(5-Bromoquinolin-8-yl)pivalamide (2x).7k Follow-
ing the general procedure, reaction between Substrate 1x
(0.2 mmol, 1 equiv, 45.6 mg) was brominated following
the general procedure, with ammonium bromide (2.4
mmol, 12 equiv, 232.8 mg) afforded the corresponding
Bromination of 8-Aminoquinoline Amide 2x, which was
purified by column chromatography on silica gel (petro-
leum ether : ethyl acetate = 10 : 1) to afford title com-
1
pound (57.52 mg, 94%) as a white solid. H NMR (400
MHz, CDCl3): δ 10.20 (s, 1H), 8.70 (dd, J = 4.2, 1.4 Hz,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 13
1317, 939, 910, 811, 780, 645 cm-1. HRMS (ESI-TOF)
Calcd for C17H12BrCl2N2O, [M+H]+: 408.9505, found
408.951.
1227, 1135, 952, 853, 778, 747, 675, 637 cm-1. HRMS
(ESI-TOF) Calcd for C18H16Br2N3O, [M+H]+: 447.9655,
found 447.9647.
1
2
3
4
5
6
7
8
9
[Gram Scale synthesis] The electrocatalysis was car-
ried out in an undivided cell equipped with two plati-
num electrodes (4.0×4.0 cm2). 8-Aminoquinoline Am-
ide 1c (5.34 mmol, 1 equiv, 1.104 g), NH4Br (64.08
mmol, 12 equiv, 6.23 g), Cu(OAc)2 (10 mol %, 96.73 mg),
DMF (80 mL) were added to the electrochemical cell.
Electrocatalysis was preformed at 60 oC in an oil bath
with a constant current of 20 mA, maintaining 84 h.
After the completion of reaction, it was quenched by
ice cold water and extracted with EtOAc. The combined
organic extracts were dried over anhydrous sodium
sulphate, filtered and concentrated. The resulting resi-
due was purified by silica gel column chromatography
to give the product 4c as white solid with 93% yield.
General
Procedure
for
3-methyl-N-(5-
(phenylethynyl)quinolin-8-yl)benzamide (3c).new Sub-
strate 2c (0.25 mmol, 1 equiv, 85.75 mg) added cop-
per(I) iodide (5 mol %), Pd(PPh3)2Cl2 (5 mol %), triethyl-
amine (2.5 mmol), phenylacetylene (0.5 mmol, 2 equiv,
51 mg) and DMF (1.5 mL) under N2 atmosphere. The
reaction mixture was placed in a pre-heated oil bath at
50 oC and vigorously stirred for 6 h. Subsequently it was
cooled down to room temperature, filtered through a
plug of celite and then washed saturated brine and ex-
tracted by with ethyl acetate. The solvents were re-
moved under reduced pressure and the crude reaction
mixture was purified by chromatography on silica gel
using (petroleum ether : ethyl acetate = 50:1) as eluent
to obtain the desired product 3c (72.4 mg, 80%) as yel-
low solid. M.p.: 131.6-132.8 °C. 1H NMR (400 MHz,
CDCl3): δ 10.79 (s, 1H), 8.93 (d, J = 8.4 Hz, 1H), 8.89 (dd,
J = 4.0, 1.6 Hz, 1H), 8.73 (dd, J = 8.4, 1.6 Hz, 1H), 7.92-
7.84 (m, 3H), 7.67-7.62 (m, 2H), 7.58 (dd, J = 8.4, 4.4 Hz,
1H), 7.48–7.36 (m, 5H), 2.50 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ 164.6, 147.6, 137.7, 137.4, 134.11, 134.08,
133.8, 131.8, 130.8, 130.6, 127.7, 127.5, 127.2, 127.1,
123.2, 122.1, 121.2, 115.0, 113.8, 93.1, 85.4, 20.5. IR
(neat): 3354, 1670, 1527, 1486, 1375, 1329, 1267, 1189,
846, 806, 729, 685, 657, 497 cm-1. HRMS (ESI-TOF)
Calcd for C25H19N2O, [M+H]+: 363.1492, found 363.1497.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General
Procedure
for
2,6-Dibromo-N-(5-
(3a).new
bromoquinolin-8-yl)-3-methylbenzamide
Substrate 2c (0.25 mmol, 1 equiv, 85.75 mg) was bro-
minated following the general procedure, with ammo-
nium bromide (5.0 mmol, 20 equiv, 489.7 mg) at 90 °C
in an oil bath for 9 h. Purification by column chroma-
tography on silica gel (petroleum ether : ethyl acetate =
10 : 1) to afford 3a (104.16 mg, 84%) as a white solid.
1
M.p.: 211.5-212.7 °C. H NMR (400 MHz, CDCl3): δ 9.97
(s, 1 H), 8.86 (d, J = 8.4 Hz, 1 H), 8.77 (dd, J = 4.0, 1.6 Hz,
1 H), 8.51 (dd, J = 8.4, 1.6 Hz, 1 H), 7.86 (d, J = 8.4 Hz, 1
H), 7.55 (dd, J = 8.6, 4.2 Hz, 1 H), 7.47 (d, J = 8.4 Hz, 1
H),7.18 (d, J = 8.0 Hz, 1 H), 2.40 (s, 3 H). 13C{1H} NMR
(100 MHz, CDCl3): δ 165.0, 148.9, 140.0, 139.1, 138.4,
136.0, 133.9, 132.3, 131.5, 130.9, 127.3, 122.9, 122.8,
117.6, 117.2, 115.3, 23.1. IR (neat): 3330, 2919, 1676,
1513, 1471, 1436, 1365, 1316, 842, 808, 781, 760, 665 cm-
1. HRMS (ESI-TOF) Calcd for C17H12Br3N2O, [M+H]+:
496.8494, found 496.8502.
General Procedure for 4-bromoquinolin-8-amine
(3d).7k Substrate 2c (0.25 mmol, 1 equiv, 85.75 mg) in
EtOH (2 mL), was added NaOH (1.5 mmol, 6 equiv, 0.06
g). The mixture was heated at 80 °C in an oil bath for 12
h. Then, the mixture was concentrated under reduced
pressure. The residue was purified by chromatography
silica gel (petroleum ether : ethyl acetate = 5: 1) to af-
1
ford the desired product 3d (54.3 mg, 98% ). H NMR
General
Procedure
for
2,6-Dichloro-N-(5-
new-
(400 MHz, CDCl3): δ 8.75 (dd, J = 4.0, 1.2 Hz, 1 H), 8.40
(dd, J = 8.4, 1.6 Hz, 1 H), 7.55 (d, J = 8.4 Hz, 1 H), 7.45
(dd, J = 8.4, 4.0 Hz, 1 H), 6.78 (d, J = 8.0 Hz, 1 H), 5.05 (s,
2H). 13C{1H} NMR (100 MHz, CDCl3): δ 147.8, 144.0,
138.9, 135.4, 130.8, 127.7, 122.4, 110.1, 107.3.
chloroquinolin-8-yl)-3-methylbenzamide (3b).
Substrate 2c (0.25 mmol, 1 equiv, 85.75 mg,) was chlo-
rinated following the general procedure, with ammoni-
um chloride (5.0 mmol, 20 equiv, 267.5 mg) at 90 °C in
an oil bath for 9 h. Purification by column chromatog-
raphy on silica gel (petroleum ether : ethyl acetate =
80 : 1) to afford 3b (74.76 mg, 73%) as a white solid.
M.p.: 206.8-207.6 °C. 1H NMR (400 MHz, CDCl3): δ
10.02 (s, 1 H), 8.89 (d, J = 8.4 Hz, 1 H), 8.79 (dd, J = 4.0,
1.2 Hz, 1 H), 8.55 (dd, J = 8.4, 1.2 Hz, 1 H), 7.89 (d, J = 8.4
Hz, 1 H), 7.57 (dd, J = 8.4, 4.0 Hz, 1 H), 7.29 (d, J = 3.2 Hz,
2 H),2.41 (s, 3 H). 13C{1H} NMR (100 MHz, CDCl3): δ
163.2, 148.8, 139.1, 136.04, 135.99, 135.9, 133.9, 132.2,
132.1, 130.9, 129.4, 127.8, 127.3, 122.8, 117.6, 115.2,
20.0. IR (neat): 3331, 1677, 1514, 1473, 1444, 1383, 1366,
General Procedure for N-(5,7-dideuteroquinolin-8-
yl)benzamide (1a-D2).7c In a 50 mL Schlenk tube with a
magnetic stir bar, 8-aminoquinoline (2.0 mmol, 1 equiv,
288.0 mg) was added, followed by conc. DCl in D2O (1
equiv, 2.0 mL). The tube was capped and sealed and
o
heated for 12 h at 150 C in an oil bath. When it was
completed, the reaction was cooled to room tempera-
ture and diluted with water (25 mL). Extracted with
EtOAc (3 x 15 mL) and the combined organic layer was
washed with 1 M NaHCO3 aqueous solution (3 x 15 mL),
ACS Paragon Plus Environment

Page 11 of 13
The Journal of Organic Chemistry
brine (50 mL), dried with Na2SO4, and filtered through
ACKNOWLEDGMENT
1
2
3
4
5
6
7
8
a pad of Celite. The solvent was removed under re-
duced pressure to afford the deuterated aniline product
Q-D. Then the reaction worked as reported methode
to afford N-(5,7-dideuteroquinolin-8-yl)benzamide (1a-
This work was financially supported by the Strategic Priority
Research Program of the Chinese Academy of Sciences (Grant
XDB20000000), “1000-Youth Talents Plan”, NSF of China
(Grant 21572245, 21772222, 21772220), and S&TCSM of
Shanghai (Grant 17JC1401200, 18JC1415600).
1
D2). H NMR (400 MHz, CDCl3): δ 10.74 (s, 1H), 8.83 (d, J
= 2.0 Hz, 1H), 8.20-8.12 (m, 1H), 8.09 (dd, J = 8.0, 1.6
Hz, 2H), 7.60-7.51 (m, 4H), 7.49-7.21 (m, 1H). 13C{1H}
NMR (100 MHz, CDCl3): δ 164.4, 147.3, 137.7, 135.3,
134.1, 133.5, 130.8, 127.8, 126.9, 126.3, 126.2, 120.7,
120.4, 120.2, 115.5, 115.2, 115.0.
REFERENCES
(1) (a) Butler, A.; Walker, J. V. Marine haloperoxidases.
Chem. Rev. 1993, 93, 1937-1944. (b) Gribble, G. W. Naturally
Occurring Organohalogen Compounds. Acc. Chem. Res. 1998,
31, 141-152. (c) Naumann, K. Influence of chlorine substitu-
ents on biological activity of chemicals: a review. Pest Man-
age. Sci. 2000, 56, 3-21. (d) Sotomayor, N.; Lete, E. Aryl and
heteroaryllithium compounds by metal-halogen exchange.
synthesis of carbocyclic and heterocyclic systems. Curr. Org.
Chem. 2003, 7, 275-300. (e) Jeschke, P. The unique role of
halogen substituents in the design of modern agrochemicals.
Pest Manage. Sci. 2010, 66, 10-27. (f) Tang, M.-L.; Bao, Z.
Halogenated materials as organic semiconductors. Chem. Ma-
ter. 2011, 23, 446-455. (g) Wilcken, R.; Zimmermann, M. O.;
Lange A.; Joerger, A. C.; Boeckler, F. M. Principles and ap-
plications of halogen bonding in medicinal chemistry and
chemical biology. J. Med. Chem. 2013, 56, 1363-1388.
(2) (a) Tong, Y.-C. Chlorination of quinoline. J Heterocycl,
Chem. 1970, 7, 171-175. (b) De La Mare, P. B. D. Electro-
philic halogenation, Cambridge University Press: New York,
1976. (c) Zhou, C-Y.; Li, J.; Peddibhotla, S.; Romo, D. Mild
arming and derivatization of natural products via an In(OTf)3-
catalyzed arene iodination. Org Lett. 2010, 12, 2104-2107.
(3) (a) Snieckus V. Directed ortho metalation. Tertiary amide
and O-carbamate directors in synthetic strategies for polysub-
stituted aromatics. Chem. Rev. 1990, 90, 879-933. (b) Beak, P.;
Snieckus, V. Directed lithiation of aromatic tertiary amides: an
evolving synthetic methodology for polysubstituted aromatics.
Acc. Chem. Res. 1982, 15, 306-312. (c) Gilman, H.; Dietrich,
JJ. Halogen Derivatives of Dibenzo-p-dioxin. J. Am. Chem.
Soc. 1957, 79, 1439-1441.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Parallel experiments.The electrocatalysis was carried
out in an undivided cell equipped with two platinum
electrodes (1.0×1.0 cm2). 8-Aminoquinoline Amide 1a
(0.2 mmol, 1 equiv, 49.6 mg), NH4Br (2.4 mmol, 12
equiv, 232.8 mg), Cu(OAc)2 (10 mol %, 3.62 mg,), DMF
(3 mL) were added to the electrochemical cell. Electro-
o
catalysis was preformed at 60 C in an oil bath with a
constant current of 3 mA, and stopped respectively at
0.5 h, 1 h, 2 h, 3 h and 4 h. In similar, substrate 1a-[D2]
(0.20 mmol, 1 equiv, 50.0 mg) was used instead of 1a
for the reaction .The yield of products was determined
by 1H NMR with CH2Br2 as internal standard and the
reaction rate was obtained by plotting the percentage
yield of the product versus time. The kinetic isotope
effect (kH/kD) was determined to be 1.07.
Electrochemical Procedure for Cyclic Voltammetry.
Cyclic voltammograms were recorded with a CHI660E
potentiostat at room temperature in DMF. n-Bu4NPF6
(0.1 M) was used as the supporting electrolyte, and a Pt
electrode (area = 0.03 cm2) was used as the working
electrode. The auxiliary electrode was a Pt wire. All po-
tentials are referenced against the SCE redox couple.
The scan rate was 100 mV/s.
(4) (a) Hodgson, H. H. The Sandmeyer Reaction. Chem. Rev.
1947, 40, 251-277, (b) Liu, Q.-Y.; Sun, B.-Q.; Zheng, S.; Liu,
Zh.; Kao, Y.; Dong, B.-W.; Jiang, S.-D.; L, F.; Liu, G.-Y.;
Yang, Y.; Mo, F.-Y. A general electrochemical strategy for the
Sandmeyer reaction. Chem. Sci., 2018, 9, 8731-8737.
ASSOCIATED CONTENT
Supporting Information
(5) (a) Borchardt, R. T.; Catechol o-methyltransferase. 2. In
vitro inhibition by substituted 8-hydroxyquinolines. J. Med.
Chem. 1973, 16, 382-387. (b) Fahrni, C. J.; O'Halloran, T. V.
aqueous coordination chemistry of quinoline-based fluores-
cence probes for the biological chemistry of zinc. J. Am. Chem.
Soc. 1999, 121, 11448-11458.(c) Meeusen, J. W.; To-
masiewicz, H.; Nowakowski, A.; Petering, D. H. TSQ (6-
methoxy-8-p-toluenesulfonamido-quinoline), a common fluo-
rescent sensor for cellular zinc, images zinc proteins. Inorg.
Chem. 2011, 50, 7563-7573. (d) Tardito, S.; Barilli, A.; Bas-
sanetti, I.; Tegoni, M.; Bussolati, O.; Franchi-Gazzola, R.;
Mucchino, C.; Marchiò, L. Copper-dependent cytotoxicity of
8-hydroxyquinoline derivatives Correlates with their hydro-
phobicity and does not require caspase activation. J. Med.
Chem. 2012, 55, 10448-10459. (e) Zhu, S.; Lin, W.; Yuan, L.
Development of a ratiometric fluorescent pH probe for cell
imaging based on a coumarin–quinoline platform. Dyes
Pigm.2013, 99, 465-471. (f) Liu, Y.-C.; Wei, J.-H.; Chen, Z.-
F.; Liu, M.; Gu, Y.-Q.; Huang, K.-B.; Li, Z.-Q.; Liang, H. The
reaction optimization, compare the reaction with or
withot copper, mechanistic studies, X-ray crystallog-
1
raphy data, CIF files, H and 13C NMR spectra. This ma-
terial is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: xjuchem_2012@163.com
*E-mail: mei7900@sioc.ac.cn
*E-mail: pfang@sioc.ac.cn
ORCID
Tian-Sheng Mei: 0000-0002-4985-1071
Ping Fang: 0000-0002-3421-2613
Notes
The authors declare no competing financial interests.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 13
antitumor activity of zinc(II) and copper(II) complexes with an enabling and innately sustainable method. ACS Cent. Sci.
1
2
3
4
5
6
7
8
5,7-dihalo-substituted-8-quinolinoline. Eur. J. Med. Chem.
2013, 69, 554-563. (g) Miyaji, R.; Asano, K.; Matsubara, S.
Bifunctional organocatalysts for the enantioselective synthesis
of axially chiral isoquinoline N-Oxides. J. Am. Chem. Soc.
2015, 137, 6766-6769. (h) He, J.; Takise, R.; Fu, H.; Yu, J.-Q.
Ligand-enabled cross-coupling of C(sp3)–H bonds with ar-
ylsilanes. J. Am. Chem. Soc. 2015, 137, 4618-4621.
2016, 2, 302-308. (b) Yan, M.; Kawamata, Y.; Baran, P. S.
Synthetic organic electrochemical methods Since 2000: on the
verge of a renaissance. Chem. Rev. 2017, 117, 13230-13319.
(c) Sauermann, N.; Meyer, T. H.; Qiu, Y.; Ackermann, L.
Electrocatalytic C–H activation. ACS Catal. 2018, 8, 7086-
7103. (d) Liu, K.; Song, C.; Lei, A. Recent advances in iodine
mediated electrochemical oxidative cross-coupling. Org. Bio-
mol. Chem. 2018, 16, 2375-2387. (e) Ma, C.; Fang, P.; Mei,
T.-S. Recent advances in C–H functionalization using electro-
chemical transition metal catalysis. ACS Catal. 2018, 8, 7179-
7189. (f) Yan, M.; Kawamata, Y.; Baran, P. S. Synthetic or-
ganic electrochemistry: calling all engineers. Angew. Chem.
Int.Ed. 2018, 57, 4149-4155. (g) Waldvogel, S. R.; Lips, S.;
Selt, M.; Riehl, B.; Kampf, C. Electrochemical arylation reac-
tion. J. Chem. Rev. 2018, 118, 6706-6765. (h) Yang, Q.-L.;
Fang, P.; Mei, T.-S. Recent advances in organic electrochem-
ical C−H functionalization. Chin. J. Chem. 2018, 36, 338-352.
(i) Nutting, J. E.; Rafiee, M.; Stahl, S. S. Tetramethylpiperi-
dine N-oxyl (TEMPO), phthalimide N-Oxyl (PINO), and re-
lated N-oxyl species: electrochemical properties and their use
in electrocatalytic reactions. Chem. Rev. 2018, 118, 4834-4885.
(j) Yoshida, J.-i.; Shimizu, A.; Hayashi, R. Electrogenerated
cationic reactive intermediates: the pool method and further
advances. use of electrochemistry in the synthesis of heterocy-
clic structures. Chem. Rev. 2018, 118, 4702-473. (k) Jiang, Y.;
Xu, K.; Zeng, C.-C. Use of electrochemistry in the synthesis
of heterocyclic structures. Chem. Rev. 2018, 118, 4485-4540.
(l) Sauer, G. S.; Lin, S. An electrocatalytic approach to the
radical difunctionalization of alkenes. ACS Catal. 2018, 8,
5175-5187.
(6) (a) Michael, J. P. Quinoline, quinazoline and acridone al-
kaloids. Nat. Prod. Rep. 2008, 25, 166-187. (b) Hughes, C.;
MacMillan, J. B.; Gaudêncio, S. P.; Jensen, P. R.; Fenical, W.
The ammosamides: structures of cell cycle modulators from a
marine-derived streptomyces species. Angew. Chem. Int. Ed.
2009, 48, 725-727. (c) Solomon, V.R.; Lee, H. Quinoline as a
privileged scaffold in cancer drug discovery. Curr. Med. Chem.
2011, 18, 1488-1508. (d) Shiraki, H.; Kozar, M.P.; Melendez,
V.; Hudson, T.H.; Ohrt, c.; MagillAi, A. J.; Lin, A. J. Antima-
larial activity of novel 5-aryl-8-aminoquinoline derivatives. J.
Med. Chem. 2011, 54, 131-142. (e) Pandey, R. R.; Srivastava,
A.; Malasoni, R.; Naqvi, A.; Jain, A.; Maikhuri, J. P.; Paliwal,
S.; Gupta G.; Dwivedi, A. K. Synthesis of 3-(1-
alkyl/aminoalkyl-3-vinyl-piperidin-4-yl)-1-(quinolin-4-yl)-
propan-1-ones and their 2-methylene derivatives as potential
spermicidal and microbicidal agents. Bioorg. Med. Chem. Lett.
2012, 22, 5735-5738. (f) Vandekerckhove, S.; Müller, C.;
Vogt, D.; Lategan, C.; Smith, P. J.; Chibale, K.; De Kimpe, N.;
D'hooghe, M. Synthesis and antiplasmodial evaluation of nov-
el (4-aminobutyloxy)quinoline. Bioorg. Med. Chem. Lett.
2013, 23, 318-322. (g) Pan, E.; Oswald, N. W.; Legako, A. G.;
Life, J. M.; Posner, B. A.; MacMillan, J. B. Precursor-directed
generation of amidine containing ammosamide analogs: am-
mosamides E-P. Chem. Sci. 2013, 4, 482-48.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(9) (a) Lyalin, B.-V.; Petrosyan, V. -A. Electrochemical halo-
genation of organic compounds. Russ. J. Electrochem. 2013,
49, 497-529. (b) Sawamura, T.; Takahashi, K.; Inagi, S.; Fuch-
igami, T. Sodium salts dissolution in an aprotic solvent by
coordination of poly(ethylene glycol) for effective anodic re-
actions of organic compounds. Electrochemistry 2013, 81,
365-367. (c) Thasan, R.; Kumarasamy, K.-K. Electrochemical
bromination and oxidation of alkyl aromatic compounds by
two-phase electrolysis. J. Chem. Eng. 2014, 31, 365-373. (d)
Rosen, B. R.; Werner, E. W.; O’Brien, A. G.; Baran, P. S.
Total synthesis of dixiamycin B by electrochemical oxidation.
J. Am. Chem. Soc. 2014, 136, 5571-5574. (e). Tan, Z.; Liu, Y.;
Helmy, R.; Rivera, N. R.; Hesk, D.; Tyagarajan, S.;Yang, L.;
Su, J. Electrochemical bromination of late stage intermediates
and drug molecules. Tetrahedron Lett. 2017, 58, 3014-3018. (f)
Yuan, Y.; Yao, A.; Zheng, Y.; Gao, M.; Zhou, Z.; Qiao, J.; Hu,
J.; Ye, B.; Zhao, J.; Wen, H.; Lei, A.-W. Electrochemical oxi-
dative clean halogenation using HX/NaX with hydrogen evo-
lution. IScience 2019, 12, 293-303. (g)·Xie, W.; Ning, S.; Liu,
N.; Bai, Y.; Wang, S.; Wang, S.; Shi, L.; Che, X.; Xiang, J.
Electrochemical regioselective bromination of electron-rich
(7) (a) Suess, A. M.; Ertem, M. Z.; Cramer, C. J.; Stahl, S. S.
Divergence between Organometallic and Single-Electron-
Transfer Mechanisms in Copper(II)-Mediated Aerobic C–H
Oxidation. J. Am. Chem. Soc. 2013, 135, 9797-9804. (b) Xu, J.;
Zhu, X.; Zhou, G.; Ying, B.; Ye, P.; Su, L.; Shen, C.; Zhang, P.
Copper(II)-catalyzed C5 and C7 halogenation of quinolines
using sodium halides under mild conditions. Org. Biomol.
Chem. 2016, 14, 3016-3021. (c). Ding, J.; Li, W.; Ye, K.; Li, J.
The highly regioselective halogenation of N-(8-
quinolinyl)amides on the C-5 position with cuprous halides
under mild conditions. ChemistrySelect. 2016, 1, 5874-5878.
(d). Liu, X.-X.; Wu, Z.-Y.; Luo, X.-L.; He, Y.-Q.; Zhou, X.-Q.;
Fan, Y.-X.; Huang, G.-S. PhI(OAc)2 oxidative C5 halogena-
tion of quinolines using copper halides under mild conditions.
RSC Adv. 2016, 6, 71485-71488. (e). Wu, C.; Zhou, H.; Wu,
Q.; He, M.; Li, P.; Su, Q.; Mu, Y. Copper-catalyzed regiose-
lective C–H iodination of aromatic carboxamides. Synlett.
2016, 27, 868-875. (f). He, X.; Xu, Y.-Z.; Kong, L.-X.; Wu,
H.-H.; Ji, D.-Z.; Wang, Z.-B.; Xu, Y.-G.; Zhu, Q.-H. Copper(I)
and N-fluorobenzenesulfonimide-mediated direct regioselec-
tive halogenation of 8-amidoquinolines on the C5 position.
Org. Chem. Front. 2017, 4, 1046-1050. (g) Rao, N. S.; Reddy,
G. M.; Sridhar, B.; Sarma, M. H. Copper-mediated remote
highly site-selective C–H bond bromination and chlorination
of quinolines at the C5 position that is geometrically difficult
to access .Eur J. Org. Chem. 2017, 438-442. (h) Long, Y.;
Pan, L.; Zhou, X.-G. Iron(III)-catalyzed highly regioselective
halogenation of 8-amidoquinolines in water. Molecues. 2019,
24, 535.
n
aromatic rings using Bu4NBr. New York –Synlett. 2019, 30,
1313-1316.
(10). (a) Yang, Q.-L.; Wang, X.-Y.; Lu, J.-Y.; Zhang, L.-P.;
Fang, P.; Mei, T.-S. Copper-catalyzed electrochemical C–H
amination of arenes with secondary amines. J. Am. Chem. Soc.
2018, 140, 11487-11494. (b) Tian, C.; Dhawa, U.; Scheremet-
jew A.; and Ackermann, L . Cupraelectro-catalyzed alkyne
annulation: evidence for distinct C−H alkynylation and decar-
boxylative C−H/C−C manifolds. ACS Catal. 2019, 9,
7690−7696
(8) For reviews about recent electrochemistry: (a) Horn, E. J.;
Rosen, B. R.; Baran, P. S. Synthetic organic electrochemistry:
ACS Paragon Plus Environment

Page 13 of 13
The Journal of Organic Chemistry
(11) Yang, Q.-L.; Wang, X.-Y.; Wang, T.-L.; Yang, X.; Liu, 2014, 53, 10209-10212. (d) Rao, W.-H.; Zhan, B.-B.; Chen, K.;
1
2
3
4
5
6
7
8
D.; Tong, X.-F.; Wu, X.-Y.; Mei, T.-S. Palladium-catalyzed
electrochemical C–H bromination using NH4Br as the bromin-
ating reagent. Org.Lett. 2019, 21, 2645-2649.
Ling, P.-X.; Zhang, Zh.-Zh.; Shi B.;-F. Pd(II)-catalyzed direct
sulfonylation of Unactivated C(sp3)–H bonds with sodium
sulfinates. Org. Lett. 2015, 17, 3552−3555. (e) Yi, H.; Chen,
H.; Bian, Ch.-L.; Tang, Z.-L.; Singh, A.-K.; Qi, X.-T.; Yue,
X.-Y.; Lan, Y.; Lee, Fu.-J.; Lei, A.-W. Coordination strategy-
induced selective C–H amination of 8-aminoquinolines. Chem.
Commun., 2017, 53, 6736-6739. (f) Wang, Y.-Z.; Yu, F.-H.;
Han, X.; Li, M.; Tong, Y.; Ding, J.; Hou, H.-W. From surpris-
ing solvothermal reaction to uncommon Zinc(II)-catalyzed
aromatic C–H activation reaction for direct nitroquinoline
synthesis. Inorg. Chem. 2017, 56, 5953-5958. (g) Singh, H.;
Sen, C.; Sahoo, T.; Ghosh, S-C. A visible light-mediated regi-
oselective halogenation of anilides and quinolines by using a
heterogeneous Cu-MnO catalyst. Eur. J. Org. Chem. 2018, 34,
4748 – 4753.
(12) Yu, L.-P.; Jin, X.-B.; Chen, G.-Z. A comparative study of
anodic oxidation of bromide and chloride ions on platinum
electrodes in 1-butyl-3-methylimidazolium hexafluorophos-
phate. J. Electroanal. Chem. 2013, 688, 371−378.
9
(13) (a) Ueda, S.; Nagasawa, H. Copper-catalyzed synthesis
of benzoxazoles via a regioselective C−H functionaliza-
tion/C−O bond formation under an air atmosphere. J. Org.
Chem. 2009, 74, 4272-4277. (b) Tran, L.-D.; Popov, I.; Dau-
gulis O. Copper-promoted sulfenylation of sp2 C–H bonds. J.
Am. Chem. Soc. 2012, 134, 18237-18240 (c) Grigorjeva, L.;
Daugulis, O. Cobalt-catalyzed, aminoquinoline-directed
C(sp2)–H bond alkenylation by alkynes. Angew. Chem. Int. Ed.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment