Transition-Metal-Free Oxidation of Benzylic C-H Bonds of Six-Membered N-Heteroaromatic Compounds

Article abstract of DOI:10.1021/acs.joc.9b00035

A novel oxidation of benzylic C-H bonds for the synthesis of diverse six-membered N-heteroaromatic aldehydes and ketones has been developed. The obvious advantages of this approach are the simple operation, mild reaction conditions, and without use of toxic reagent and transition metal. The present method should provide a useful access for the synthesis and modification of N-heterocycles.

Full text of DOI:10.1021/acs.joc.9b00035

Subscriber access provided by UNIV OF TEXAS DALLAS
Article
Transition-Metal-Free Oxidation of Benzylic C-H Bonds
of Six-Membered N-Heteroaromatic Compounds
Xianying Gao, ShuaiJun Han, Maolin Zheng, Apeng Liang,
Jingya Li, Dapeng Zou, Yusheng Wu, and Yangjie Wu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00035 • Publication Date (Web): 11 Mar 2019
Downloaded from http://pubs.acs.org on March 11, 2019
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 10
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Transition-Metal-Free Oxidation of Benzylic C-H Bonds of Six-
Membered N-Heteroaromatic Compounds
Xianying Gao,† Shuaijun Han,† Maolin Zheng, † Apeng Liang,† Jingya Li, ‡ Dapeng Zou,*,† Yusheng
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
Wu,*, †,‡,§ and Yangjie Wu*,†
†The College of Chemistry and Molecular Engineering, Henan Key Laboratory of Chemical Biology and Organic Chemistry,
Zhengzhou University, Zhengzhou 450052, People’s Republic of China
‡Tetranov Biopharm, LLC. and Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou,
450052, People’s Republic of China
§Tetranov International, Inc. 100 Jersey Avenue, Suite A340, New Brunswick, NJ 08901, USA.
Supporting Information Placeholder
ABSTRACT: A novel oxidation of benzylic C-H bonds for the synthesis of diverse six-membered N-heteroaromatic aldehydes and
ketones has been developed. The obvious advantage of this approach is that simple operation, mild reaction conditions, and without
using toxic reagent and transition metal. The present method should provide a useful access for synthesis and modification of N-
heterocycles.
a methyl group on a heteroaromatic compound using molecu-
lar oxygen as the terminal oxidant.10 Although this was a novel
■ INTRODUCTION
job, the method needs a longer reaction time, and there were
relatively few quinoline and pyridine substrates involved.
Therefore, further research for developing new methods in this
area is still highly required.
The aldehydes and ketones serve as versatile motifs, which
can be widely used in the synthesis of functional chemicals
and pharmaceuticals.1 Due to their importance, extensive re-
search has been devoted to the synthesis of aldehydes and
ketones. The direct oxidation of benzylic methyl and meth-
ylene moieties is an important approach to provide these com-
pounds.2 A variety of methods have been developed for the
direct benzylic oxidation of alkylarenes in the past several
decades.3 The oxygenation of methyl group in N-heterocyclic
compounds easily leads to the formation of carboxylic acids
via over-oxidation, thus, approaches for the synthesis of N-
heterocyclic aldehydes have been studied to a lesser extent.4 In
addition, due to the low reactivity of the heterobenzylic methyl
group, the reported protocols usually use transition metals,
additional oxidants, or even more toxic reagent (Scheme 1, eq
1-3).5 Recently, significant progress has been made in the cop-
per-catalyzed aerobic oxidation of methyl/methylene of N-
heterocyclic compounds (Scheme 1, eq 4).6-9 These works are
very elegant, while they have some limitations like using rela-
tively higher temperatures and transition metal catalysts. In
2016, Nagasawa and co-workers reported a photo-oxidation of
Scheme 1. Methods for the oxidation of benzylic C-H
bonds of six-membered N-heterocyclic compounds
We are always interested in the research on heteroaromatic
or N-substituted heterocyclic cations involved direct C−H
functionalization reaction,11 as well as mild approaches for
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 10
selective C-H oxidation of N-heteroaromatic compounds substrate for the optimization of the reaction parameters and
1
2
3
4
5
6
7
8
without using any transition metal or transition metal-based
reagents and even more toxic reagent. Herein, we report a
transition-metal-free oxidation of benzylic C-H bonds using a
stable and easily available alkyl substitution N-
methoxyquinoline(pyridine)-1-ium tetrafluoroborate as start-
ing material.
the results are summarized in Table 1 (for more details, see
Supporting Information (SI)). When the reaction of 1a in con-
junction with cesium fluoride (CsF) was carried out in di-
chloromethane (CH2Cl2) at room temperature under air for 15
h, the desired product 2a was obtained in 29% yield (Table 1,
entry 1). Next, a survey of different solvents was investigated
(Table 1, entries 2−7) and ethyl acetate (EA) was found to be
the optimal choice (Table 1, entry 2). Subsequently, various
bases were screened (Table 1, entries 8-14), but all of them
were found to be less effective than cesium fluoride for the
reaction. No 2a was obtained when the reaction was per-
formed without base indicated that the base is essential to the
reaction (Table 1, entry 15). The equivalent of cesium fluoride
was then screened and no further improvement was observed
(Table S1; see SI). In addition, the use of additives failed to
give better results (Table S2; see SI). Moreover, the amount of
solvent has a big impact on the reaction efficiency (Table 1,
entries 16-18). The yield of 2a was improved to 80% when the
amount of EA was increased from 2.0 to 5.0 mL (Table 1,
■ RESULTS AND DISCUSSION
Table 1. Optimization of the reaction conditionsa
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
entry
base
solvent (X mL)
temp
(°C )
yield
(%)b
o
CH2Cl2 (2.0)
EA(2.0)
1
2
CsF
CsF
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
10
35
40
29
54
entry 18). Decreasing the reaction temperature from 25 C to
o
o
10 C or increasing the temperature to 50 C, the yields were
all decreased (Table 1, entries 19-22). The reaction time was
also tested and the best yield was obtained under 15 h (Table
S4, See SI). Almost no difference was found when the reaction
was run under an oxygen atmosphere (Table 1, entry 23).
However, when the reaction was protected by argon, only a
trace amount of the desired product 2a was detected (Table 1,
entry 24). Ultimately, the use of 3.0 equiv CsF as the base in
EA (5 mL) at room temperature under air atmosphere for 15 h
were identified as the optimal reaction conditions (Table 1,
entry 18).
CH3CN (2.0)
dioxane(2.0)
DMF (2.0)
ether (2.0)
toluene (2.0)
EA(2.0)
3
CsF
trace
12
CsF
4
CsF
5
trace
28
CsF
6
CsF
7
44
Et3N
Cs2CO3
K2CO3
K3PO4
KF
8
trace
trace
44
EA(2.0)
9
EA(2.0)
10
11
12
13
14
15
16
17
18
19
20
21
22
23c
24d
With the optimized reaction conditions in hand, a variety of
six-membered heteroaromatic derivatives 1a-1z were tested to
examine the scope and generality of this oxygenation system
(Scheme 2). In order to compare the efficiency of this reaction
system with the known direct oxygenation of neutral N-
heterocycles in Scheme 1, the total yield for the synthesis of
N-methoxyquinoline(pyridine)-1-ium tetrafluoroborate salts
(“A”) and the yield for C-H oxygenation (“B”) have been add-
ed one by one separately in Scheme 2. In general, various
functional groups were covered, including methoxy, amino,
methyl, trifluoromethyl, cyano, phenyl and halide. The substi-
tuted 4-methylquinoline substrates can be employed and gave
rise to versatile aldehydes 2a-2e in good yields (54%-78%).
Notably, the mild conditions were also compatible with halo-
genated substrates (51–67%; 2f–2i). In addition, N-methoxy-
2-methylquinolin-1-ium tetrafluoroborate (1j) was similarly
found to be suitable substrate for the transformation. However,
1k was not converted to the corresponding aldehyde under the
current reaction conditions. Furthermore, in the case of 1i,
selective oxygenation took place only at the C4-position to
give 2i in 60% yield. Long-chain aliphatic substrates 1l and
1m performed well, giving the desired products 2l and 2m in
71% and 68% isolated yields, respectively. Substrates with
benzyl substitution were also worked well (2n-2p). After the
successful application of the oxidative reaction of alkyl substi-
tution N-methoxyquinoline-1-ium tetrafluoroborate deriva-
tives, the scope of this method was extended to build up struc-
turally important pyridines (2r-2z). Much to our satisfaction,
pyridine substrates 1r-1y were also well-tolerated under the
standard conditions, thereby offering the respective pyridine
aldehydes and ketones in acceptable yields. This method was
EA(2.0)
47
EA(2.0)
52
t-BuOK
KOAc
-
EA(2.0)
28
EA(2.0)
15
EA(2.0)
0
CsF
EA(1.0)
30
CsF
EA(4.0)
67
CsF
EA(5.0)
80 (78)
48
CsF
EA(5.0)
CsF
EA(5.0)
64
CsF
EA(5.0)
48
CsF
EA(5.0)
50
25
25
40
CsF
EA(5.0)
78
CsF
EA(5.0)
trace
aReaction conditions: 1a (0.25 mmol, 1.0 equiv) and base (0.75
b
mmol, 3.0 equiv) were added in solvent under air for 15 h. The
yield of product 2a is determined by GC analysis using dipentyl
phthalate as an internal standard. The isolated yield of product 2a
c
is given within parentheses. The reaction was performed in oxy-
gen. dThe reaction was performed in nitrogen.
Initially, N-methoxy-4-methylquinolin-1-ium tetrafluoroborate
1a (The compound was prepared by the reaction of heterocy-
clic nitrogen oxidation followed by reaction with trimethylox-
onium tetrafluoroborate, the general procedure for the prepara-
tion of the N-methoxyquinoline-1-ium tetrafluoroborate salts
was given in the experimental section.) was chosen as a test
ACS Paragon Plus Environment

Page 3 of 10
The Journal of Organic Chemistry
diphenylethylene were added to the reaction mixture, the for-
further applied to more complex organic molecules. For ex-
1
2
3
4
5
6
7
8
ample, under the standard conditions, the oxidation of a novel
potent selective TRPC4 (Transient receptor potential channel
4) channel inhibitor derivative 1q and an intermediate of TLR
(Toll-like receptor) inhibitor derivative 1z were investigated.
The target product 2q was obtained in 67% yield. Unfortunate-
ly, only a trace amount of 2z was observed in the reaction.
mation of the corresponding product 2a was almost inhibited
(Scheme 3, eq a, b), indicated that the reaction might involve a
1
radical process. As a result, H NMR and LC-MS analysis
showed that compound 4 was produced (Scheme 3, eq a). At
the same time, benzophenone and the compound 5 were de-
tected by GC-MS (Scheme 3, eq b). The discovery of com-
pound 5 indicated that the alkoxyl radical might exist in the
process. Moreover, entry 23 and entry 24 in Table 1 showed
that oxygen is necessary for the reaction. When the reaction
was carried out in the presence of molecular sieves under the
optimal conditions, the yield of product 2a is 77% (Scheme 3,
eq c). In order to elucidate the real source of oxygen in the
carbonyl group in the desired products, 2.0 equiv of water and
O18-labeled water were added under the optimal conditions,
respectively (Scheme 3, eq d and e). However, O18-labeled 2a
was not detected indicated that the oxygen atom in the carbon-
yl group in the desired products did not come from water.
When 2.0 equiv of water was added to the reaction mixture
under argon, only a trace amount of the desired product 2a
was detected (Scheme 3, eq f). This phenomenon also showed
that oxygen atoms in the carbonyl group did not come from
water.
Comparing with the work in Scheme 1, some of the prod-
ucts have higher yields and some have lower yields than those
shown in Scheme 1. For example, the yield of product 2a in
the process is 69% which is lower than the reported5a 78% in
Scheme 1. Whereas, three-step total yield of product 2w is 40%
which is higher than the reported9b 33% in Scheme 1. Alt-
hough the overall process efficiency of the process is not supe-
rior to the known direct oxygenation of neutral N-heterocycles
(Scheme 1), this process has two obvious advantages. Firstly,
the operation and the post-treatment for the synthesis of quino-
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
line(pyridine)
nitrogen
oxides
and
N-
methoxyquinoline(pyridine)-1-ium tetrafluoroborate salts is
simple. Secondly, the reaction condition of this process is mild
and no transition metal catalysis, additional oxidants, or even
more toxic reagent is needed in the reaction. It is an alternative
method for the synthesis of diverse six-membered N-
heteroaromatic aldehydes and ketones.
Scheme 3. Control experiments
Scheme 2. Scope of the oxidation of benzylic C−H bondsa,b
aStandard reaction conditions: 1 (0.5 mmol, 1.0 equiv), CsF
o
b
(1.5 mmol, 3.0 equiv), EA (10.0 mL), 25 C, under air, 15 h. I-
solated yield. cK2CO3 was used as the base. “A”: The total yield of
1' to 1. “B”: The yield of 1 to 2.
To get an insight into the possible mechanism of the hetero-
benzylic C-H oxidation reaction, several control experiments
were performed under the optimized conditions (Scheme 3, eq
a, b). When the radical scavenger TEMPO and 1,1-
ACS Paragon Plus Environment

The Journal of Organic Chemistry
On the basis of the above results and previous reports6,12, a
Page 4 of 10
All N-methoxyquinoline (pyridine)-1-ium tetrafluoroborate
1
2
3
4
5
6
7
8
plausible mechanism is proposed (Scheme 4). Firstly, the in-
termediate A was formed by deprotonation of the N-
methoxyquinoline (pyridine)-1-ium tetrafluoroborate 1 with
CsF. Then the intermediate A underwent a homolysis of N-O
bond process to get the intermediate radical B and C. Subse-
quently, the intermediate radical C combined with molecular
oxygen to obtain the radical species D. Next, the radical in-
termediate E and a molecule of oxygen were generated from a
pair of radicals D12b,12d. Finally, the desired product 2 was pro-
duced from the species E which accompanies with the genera-
salts were prepared according to the reported proce-
dure.11a,11b,13
N-methoxy-4-methylquinolin-1-ium tetrafluoroborate (1a).
The crude product was purified by recrystallized in EtOAc to
provide the product 1a as a white solid (0.73g, yield 90%); 1H
NMR (400 MHz, DMSO-d6, ppm): δ = 9.87 (d, J = 6.5 Hz, 1
H), 8.59 (d, J = 8.4 Hz, 1 H), 8.55 (d, J = 8.7 Hz, 1 H), 8.36-
8.32 (m, 1 H), 8.16-8.11 (m, 2 H), 4.51 (s, 3 H), 3.03 (s, 3 H).
13C{1H} NMR (100 MHz, DMSO-d6, ppm): δ = 158.0, 143.1,
136.1, 134.9, 130.4, 129.6, 127.0, 122.6, 116.7, 69.5, 19.5.
HRMS (ESI-TOF) m/z: Calcd for C11H12NO+ [M]+: 174.0913,
found: 174.0912.
9
tion of the superoxide radical12e
.
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
Scheme 4. Proposed mechanism
1,7-dimethoxy-4-methylquinolin-1-ium tetrafluoroborate (1b).
The crude product was purified by recrystallized in EtOAc to
provide the product 1b as a white solid (0.68g, yield 89%); 1H
NMR (400 MHz, DMSO-d6, ppm): δ = 9.69 (d, J = 6.6 Hz, 1
H), 8.49-8.47 (m, 1 H), 7.93 (d, J = 6.6 Hz, 1 H), 7.72-7.70 (m,
2 H), 4.47 (s, 3 H), 4.13 (s, 3 H). 13C{1H} NMR (100 MHz,
DMSO-d6, ppm): δ = 165.3, 157.1, 142.2, 137.6, 129.0, 125.0,
122.6, 120.4, 95.5, 68.9, 57.0, 19.3. HRMS (ESI-TOF) m/z:
Calcd for C12H14NO2+ [M]+: 204.1019, found: 204.1020.
1,2-dimethoxy-4-methylquinolin-1-ium tetrafluoroborate (1c).
The crude product was directly used for the next step.
N-methoxy-4-methyl-7-(trifluoromethyl)quinolin-1-ium tetra-
fluoroborate (1d). The crude product was purified by recrys-
tallized in EtOAc to provide the product 1d as a white solid
(0.64g, yield 88%); 1H NMR (400 MHz, DMSO-d6, ppm): δ =
10.06 (d, J = 6.5 Hz, 1 H), 8.88 (s, 1 H), 8.80 (d, J = 8.8 Hz, 1
H), 8.41 (d, J = 8.9 Hz, J = 1.5 Hz, 1 H), 8.33 (d, J = 6.6 Hz, 1
H), 4.56 (s, 3 H), 3.07 (s, 3 H). 13C{1H} NMR (100 MHz,
DMSO-d6, ppm): δ = 158.3, 145.0, 134.8, 134.4 (q, J = 33.3
Hz), 131.3, 129.2, 125.8 (q, J = 3.0 Hz), 124.7, 122.9 (q, J =
272.0 Hz), 115.1 (q, J = 4.5 Hz), 70.0, 19.6. 19F NMR (376
MHz, CDCl3, ppm) : δ = -63.3 (s), -152.1 (s). HRMS (ESI-
TOF) m/z: Calcd for C12H11F3NO+ [M]+: 242.0787, found:
242.0788.
N-methoxy-4-methyl-2-phenylquinolin-1-ium tetrafluoroborate
(1e). The crude product was purified by recrystallized in
EtOAc to provide the product 1e as a white solid (0.64g, yield
90%); 1H NMR (400 MHz, DMSO-d6, ppm): δ = 8.61-8.59 (m,
2 H), 8.36 (t, J = 7.8 Hz, 1 H), 8.29 (s, 1 H), 8.13 (t, J = 7.4 Hz,
1 H), 8.03 (d, J = 6.6 Hz, 2 H), 7.80-7.74 (m, 3 H), 3.92 (s, 3
H), 3.05 (s, 3 H). 13C{1H} NMR (100 MHz, DMSO-d6, ppm):
δ = 157.1, 152.7, 136.2, 135.5, 132.5, 130.4, 130.2, 129.3,
129.1, 129.0, 128.7, 126.9, 125.3, 67.0, 19.4. HRMS (ESI-
TOF) m/z: Calcd for C17H16NO+ [M]+: 250.1226, found:
250.1228.
2-chloro-1-methoxy-4-methylquinolin-1-ium tetrafluoroborate
(1f). The crude product was purified by recrystallized in
EtOAc to provide the product 1f as a off-white solid (0.66g,
yield 87%); 1H NMR (400 MHz, DMSO-d6, ppm): δ = 7.83 (d,
J = 8.0 Hz, 1 H), 7.73-7.69 (m, 1 H), 7.61 (d, J = 7.8 Hz, 1 H),
7.37-7.33 (m, 1 H), 6.60 (d, J = 0.7 Hz, 1 H), 3.96 (s, 3 H),
2.45 (d, J = 0.8Hz, 3 H). 13C{1H} NMR (100 MHz, DMSO-d6,
ppm): δ = 156.2, 146.6, 137.1, 131.2, 125.7, 122.6, 121.0,
119.8, 111.5, 62.6, 18.3. HRMS (ESI-TOF) m/z: Calcd for
C11H11ClNO+ [M]+: 208.0524, found: 208.0520.
■ CONCLUSION
In summary, we have developed a practical and novel meth-
odology of the direct oxidation of benzylic C-H bonds of six-
membered N-heteroaromatic compounds. This method exhib-
its a good functional group tolerance. The present protocol
allows for a mild access to six-membered N-heteroaromatic
aldehydes and ketones without addition of hazardous oxidant,
toxic reagent and transition metal.
■ EXPERIMENTAL SECTION
All reactions were performed in dried glass reaction tube
equipped with a magnetic stir bar under air atmosphere. Un-
less otherwise mentioned, solvents and reagents were pur-
chased from commercial sources and used as received. Flash
column chromatography was performed using silica gel (60-Å
pore size, 32-63 µm, standard grade). Analytical thin-layer
chromatography was performed using silica gel 60 GF254
plates. Thin layer chromatography plates were visualized by
exposure to ultraviolet light. Melting points were recorded by
an XT4A micro melting-point measurement instrument, and
the thermometer was unrevised. Mass spectra and GC yields
were measured on a LC/MSD Trap XCT instrument or GC
(Shimadzu GC-2010 Plus). NMR spectra were obtained on
Bruker AVANCE III systems by using tetramethylsilane
(TMS) as the internal standard, at 400 MHz for 1H NMR, 100
MHz for 13C NMR, and 376 MHz for 19F NMR. The high
resolution mass spectrum was received via Agilent Technolo-
gies 6540 UHD Accurate-mass Q-Tof LC/MS, with ESI as ion
source. Preparative TLC was performed on silica gel plates
and developed with ethyl acetate/hexane. Quinoline (pyridine)
N-oxides were prepared according to the literature.11a
6-bromo-1-methoxy-4-methylquinolin-1-ium tetrafluoroborate
(1g). The crude product was purified by recrystallized in
EtOAc to provide the product 1g as a off-white solid (0.64g,
yield 90%); 1H NMR (400 MHz, DMSO-d6, ppm): δ = 9.89 (d,
J = 6.5 Hz, 1 H), 8.82 (d, J = 1.4 Hz, 1 H), 8.50-8.44 (m, 2 H),
General procedure for the synthesis of substrates (1a-1z).
ACS Paragon Plus Environment

Page 5 of 10
The Journal of Organic Chemistry
provide the product 1m as a white solid (0.68g, yield 88%); 1H
8.18 (d, J = 6.5 Hz, 1 H), 4.50 (s, 3 H), 3.01 (s, 3 H). 13C{1H}
1
2
3
4
5
6
7
8
NMR (100 MHz, DMSO-d6, ppm): δ = 157.4, 143.4, 138.6,
134.0, 130.8, 129.0, 124.1, 123.7, 118.8, 69.7, 19.5. HRMS
(ESI-TOF) m/z: Calcd for C11H11BrNO+ [M]+: 252.0019,
found: 252.0018.
NMR (400 MHz, DMSO-d6, ppm): δ = 9.88 (d, J = 6.6 Hz, 1
H), 8.68 (d, J = 8.4 Hz, 1 H), 8.55 (d, J = 8.7 Hz, 1 H), 8.35-
8.31 (m, 1 H), 8.14-8.09 (m, 2 H), 4.51 (s, 3 H), 3.38 (t, J =
7.8 Hz, 2 H), 1.85-1.76 (m, 2 H), 1.03 (t, J = 6.9 Hz, 3 H).
13C{1H} NMR (100 MHz, DMSO-d6, ppm): δ = 161.4, 143.1,
136.0, 135.3, 130.4, 129.1, 126.6, 122.0, 116.7, 69.5, 33.9,
23.4, 13.7. HRMS (ESI-TOF) m/z: Calcd for C13H16NO+ [M]+:
202.1226, found: 202.1228.
7-chloro-6-fluoro-1-methoxy-4-methylquinolin-1-ium
tetra-
fluoroborate (1h). The crude product was purified by recrys-
tallized in EtOAc to provide the product 1h as a white solid
(0.66g, yield 89%); 1H NMR (400 MHz, DMSO-d6, ppm): δ =
9.90 (d, J = 6.5 Hz, 1 H), 8.98 (d, J = 6.6 Hz, 1 H), 8.68 (d, J =
9.9 Hz, 1 H), 8.20 (d, J = 6.6 Hz, 1 H), 4.50 (s, 3 H), 2.98 (s, 3
H). 13C{1H} NMR (100 MHz, DMSO-d6, ppm): δ = 157.7 (d,
J = 5.2 Hz), 156.9 (d, J = 252.3 Hz), 143.6, 132.5, 130.3 (d, J
= 21.3 Hz), 130.0 (d, J = 9.6 Hz), 123.7, 119.8, 113.0 (d, J =
24.0 Hz), 69.9, 19.6. 19F NMR (376 MHz, CDCl3, ppm) : δ = -
110.3 (s), -148.3 (s). HRMS (ESI-TOF) m/z: Calcd for
C11H10ClFNO+ [M]+: 226.0429, found: 226.0430.
4-benzyl-1-methoxyquinolin-1-ium tetrafluoroborate (1n). The
crude product was purified by recrystallized in EtOAc to pro-
9
1
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
vide the product 1n as a white solid (0.57g, yield 80%); H
NMR (400 MHz, CD3OD, ppm): δ = 9.62 (d, J = 6.6 Hz, 1 H),
8.71 (d, J = 8.5 Hz, 1 H), 8.60 (d, J = 8.8 Hz, 1 H), 8.34-8.30
(m, 1 H), 8.12-8.08 (m, 1 H), 7.86 (d, J = 6.6 Hz, 1 H), 7.39-
7.30 (m, 5 H), 4.85 (s, 2 H), 4.58 (s, 3 H). 13C{1H} NMR (100
MHz, CD3OD, ppm): δ = 164.5, 146.8 146.6, 140.6, 140.0,
139.8, 134.6, 133.0, 132.8, 131.1, 130.6, 126.1, 120.4, 72.9,
42.1. HRMS (ESI-TOF) m/z: Calcd for C17H16NO+ [M]+:
250.1226, found: 250.1228.
N-methoxy-4-(3-methylbenzyl)quinolin-1-ium tetrafluorobo-
rate (1o). The crude product was purified by recrystallized in
EtOAc to provide the product 1o as a white solid (0.65g, yield
92%); 1H NMR (400 MHz, CD3OD, ppm): δ = 9.64 (d, J = 6.6
Hz, 1 H), 9.73 (d, J = 8.5 Hz, 1 H), 8.60 (d, J = 8.8 Hz, 1 H),
8.36-8.31 (m, 1 H), 8.13-8.09 (m, 1 H), 7.86 (d, J = 6.6 Hz, 1
H), 7.29-7.14 (m, 4 H), 4.81 (s, 2 H), 4.58 (s, 3 H), 2034 (s, 3
H). 13C{1H} NMR (100 MHz, CD3OD, ppm): δ = 162.1,
144.2, 140.2, 137.9, 137.5, 137.2, 132.1, 131.1, 131.1, 130.2,
129.2, 128.1, 127.5, 123.5, 117.9, 70.4, 39.6, 21.4 (d, J = 2.8
Hz). HRMS (ESI-TOF) m/z: Calcd for C18H18NO+ [M]+:
264.1383, found:264.1385.
6-fluoro-1-methoxy-4,7-dimethylquinolin-1-ium tetrafluorobo-
rate (1i). The crude product was purified by recrystallized in
EtOAc to provide the product 1i as a white solid (0.70g, yield
1
91%); H NMR (400 MHz, DMSO-d6, ppm): δ = 9.79 (d, J =
6.5 Hz, 1 H), 8.57 (d, J = 6.6 Hz, 1 H), 8.39 (d, J = 10.3 Hz, 1
H), 8.10 (d, J = 6.5 Hz, 1 H), 4.50 (s, 3 H), 2.96 (s, 3 H), 2.65
(s, 3 H). 13C{1H} NMR (100 MHz, DMSO-d6, ppm): δ =
160.8 (d, J = 251.1 Hz), 157.2 (d, J = 5.5 Hz), 142.2, 137.3 (d,
J = 21.9 Hz), 132.1, 129.8 (d, J = 10.4 Hz), 122.6, 119.2 (d, J
= 5.9 Hz), 110.6 (d, J = 25.1 Hz), 69.6, 19.5, 15.5 (d, J = 3.0
Hz). 19F NMR (376 MHz, CDCl3, ppm) : δ = -110.1 (s), -148.3
(s). HRMS (ESI-TOF) m/z: Calcd for C12H13FNO+ [M]+:
206.0976, found: 206.0975
N-methoxy-2-methylquinolin-1-ium tetrafluoroborate (1j). The
crude product was purified by recrystallized in EtOAc to pro-
1
vide the product 1j as a brown solid (0.72g, yield 88%); H
N-methoxy-4-(4-(trifluoromethyl)benzyl)quinolin-1-ium tetra-
fluoroborate (1p). The crude product was purified by recrys-
tallized in EtOAc to provide the product 1p as a white solid
NMR (400 MHz, DMSO-d6, ppm): δ = 9.14 (d, J = 8.6 Hz, 1
H), 8.49 (t, J = 8.6 Hz, 2 H), 8.31 (t, J = 8.0 Hz, 1 H), 8.18 (d,
J = 8.6 Hz, 1 H), 8.06 (d, J = 8.6 Hz, 1 H), 4.43 (s, 3 H), 3.10
(s, 3 H). 13C{1H} NMR (100 MHz, DMSO-d6, ppm): δ =
158.2, 145.3, 136.5, 136.4, 130.6, 130.4, 129.7, 125.3, 116.7,
68.1, 18.8. HRMS (ESI-TOF) m/z: Calcd for C11H12NO+ [M]+:
174.0913, found: 174.0914.
N-methoxy-3-methylquinolin-1-ium tetrafluoroborate (1k).
The crude product was purified by recrystallized in EtOAc to
provide the product 1k as a white solid (0.73g, yield 90%); 1H
NMR (400 MHz, DMSO-d6, ppm): δ = 9.97 (d, J = 1.2 Hz, 1
H), 9.13 (s, 1 H), 8.51 (d, J = 8.8 Hz, 1 H), 8.42 (d, J = 8.2 Hz,
1 H), 8.29-8.25 (m, 1 H), 8.07 (d, J = 7.8 Hz, 1 H), 4.55 (s, 3
H), 2.68 (s, 3 H). 13C{1H} NMR (100 MHz, DMSO-d6, ppm):
δ = 145.2, 145.0, 135.4, 133.9, 133.1, 130.7, 130.1, 129.3,
116.0, 69.6, 18.0 (d, J = 1.4 Hz). HRMS (ESI-TOF) m/z:
Calcd for C11H12NO+ [M]+: 174.0913, found:174.0914.
1
(0.60g, yield 90%); H NMR (400 MHz, CD3OD, ppm): δ =
9.69 (d, J = 6.6 Hz, 1 H), 8.69 (d, J = 8.4 Hz, 1 H), 8.63 (d, J =
8.8 Hz, 1 H), 8.37-8.33 (m, 1 H), 8.14-8.10 (m, 1 H), 7.91 (d,
J = 6.6 Hz, 1 H), 7.70 (d, J = 8.1 Hz, 2 H), 7.57 (d, J = 8.1 Hz,
2 H), 4.97 (s, 2 H), 4.59 (s, 3 H). 13C{1H} NMR (100 MHz,
CD3OD, ppm): δ = 160.7, 144.3, 142.7, 137.6, 137.4, 132.3,
131.2, 130.9, 130.6, 128.0, 127.1 (q, J = 3.85 Hz), 125.6 (q, J
= 269.7 Hz), 123.8, 118.0, 70.4, 39.1. HRMS (ESI-TOF) m/z:
Calcd for C18H15F3NO+ [M]+: 318.1100, found: 318.1099.
N-methoxy-4-methyl-2-(piperidin-1-yl)quinolin-1-ium tetra-
fluoroborate (1q). The crude product was purified by recrys-
tallized in EtOAc to provide the product 1q as a brown solid
(0.67g, yield 95%); 1H NMR (400 MHz, DMSO-d6, ppm): δ =
8.16 (d, J = 8.1 Hz, 1 H), 8.05-8.01 (m, 2 H), 7.74-7.71 (m, 1
H), 7.64 (s, 1 H), 4.01 (s, 3 H), 3.96-3.85 (m, 4 H), 2.73 (s, 3
H), 1.77-1.74 (m, 6 H). 13C{1H} NMR (100 MHz, DMSO-d6,
ppm): δ = 151.5, 151.3, 135.8, 134.2, 127.0, 126.7, 123.8,
116.5, 115.0, 65.2, 52.0, 26.0, 23.4, 19.3. HRMS (ESI-TOF)
m/z: Calcd for C16H21N2O+ [M]+: 257.1648, found: 257.1649.
N-methoxy-4-methylpyridin-1-ium tetrafluoroborate (1r). The
crude product was purified by recrystallized in EtOAc to pro-
4-ethyl-1-methoxyquinolin-1-ium tetrafluoroborate (1l). The
crude product was purified by recrystallized in EtOAc to pro-
1
vide the product 1l as a white solid (0.71g, yield 90%); H
NMR (400 MHz, CD3OD, ppm): δ = 9.64 (d, J = 6.6 Hz, 1 H),
8.67 (d, J = 8.6 Hz, 1 H), 8.60 (d, J = 8.8 Hz, 1 H), 8.36-8.32
(m, 1 H), 8.15-8.10 (m, 1 H), 8.06 (d, J = 6.6 Hz, 1 H), 4.58 (s,
3 H), 3.51 (q, J = 7.5 Hz, 2 H), 1.53 (t, J = 7.5 Hz, 3 H).
13C{1H} NMR (100 MHz, CD3OD, ppm): δ = 165.3, 144.1,
137.4, 137.1, 132.0, 131.0, 127.6, 122.2, 117.9, 70.3, 27.3,
14.2. HRMS (ESI-TOF) m/z: Calcd for C12H14NO+ [M]+:
188.1070, found: 188.1071.
1
vide the product 1r as a white solid (0.88g, yield 91%); H
NMR (400 MHz, DMSO-d6, ppm): δ = 9.30 (s, 2 H), 8.09 (s, 2
H), 4.39 (s, 3 H), 2.63 (s, 3 H). 13C{1H} NMR (100 MHz,
DMSO-d6, ppm): δ = 159.2, 140.2, 129.8, 69.8, 21.6. HRMS
(ESI-TOF) m/z: Calcd for C7H10NO+ [M]+: 124.0757, found:
124.0758.
N-methoxy-4-propylquinolin-1-ium tetrafluoroborate (1m).
The crude product was purified by recrystallized in EtOAc to
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 10
1,2-dimethoxy-4-methylpyridin-1-ium tetrafluoroborate (1s).
35.3. HRMS (ESI-TOF) m/z: Calcd for C13H14NO+ [M]+:
200.1070, found: 200.1072.
1
2
3
4
5
6
7
8
The crude product was purified by recrystallized in EtOAc to
1
provide the product 1s as a white solid (0.79g, yield 91%); H
2-amino-5-bromo-1-methoxy-3,4-dimethylpyridin-1-ium tetra-
fluoroborate (1z). The crude product was purified by recrystal-
lized in EtOAc to provide the product 1z as a brown solid
(0.59g, yield 80%); 1H NMR (400 MHz, DMSO-d6, ppm): δ =
8.98 (s, 1 H), 8.57 (s, 2 H), 4.11 (s, 3 H), 2.40 (s, 3 H), 2.25 (s,
3 H). 13C{1H} NMR (100 MHz, DMSO-d6, ppm): δ = 149.6,
149.5, 133.4, 122.9, 108.3, 67.3, 20.4, 15.2. HRMS (ESI-TOF)
m/z: Calcd for C8H12BrN2O+ [M]+: 231.0128, 233.0107, found:
233.0102.
NMR (400 MHz, CDCl3, ppm): δ = 8.37 (d, J = 7.0 Hz, 1 H),
7.49 (s, 1 H), 7.29 (dd, J = 7.0 Hz, J = 1.7 Hz, 1 H), 4.36 (s, 3
H), 4.27 (s, 3 H), 2.64 (s, 3 H). 13C{1H} NMR (100 MHz,
CDCl3, ppm): δ = 160.9, 157.7, 138.8, 120.5, 113.2, 68.6, 60.2,
+
22.1. HRMS (ESI-TOF) m/z: Calcd for C8H12NO2 [M]+:
154.0863, found: 154.0861.
2-cyano-1-methoxy-4-methylpyridin-1-ium tetrafluoroborate
(1t). The crude product was purified by recrystallized in
EtOAc to provide the product 1t as a white solid (0.79g, yield
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
General procedure for oxidation of benzylic C-H bonds of
six-membered N-heteroaromatic products.
1
90%); H NMR (400 MHz, DMSO-d6, ppm): δ = 9.55 (d, J =
6.8 Hz, 1 H), 8.64 (t, J = 2.2 Hz, 1 H), 8.33-8.31 (m, 1 H),
4.61 (s, 3 H), 2.78 (s, 3 H). 13C{1H} NMR (100 MHz, DMSO-
d6, ppm): δ = 162.7, 143.7, 136.5, 134.0, 125.5, 109.5, 71.4,
22.1(d, J = 1.4 Hz). HRMS (ESI-TOF) m/z: Calcd for
C8H9N2O+ [M]+: 149.0709, found: 149.0708.
A dried glass reaction tube equipped with a magnetic stir bar
was charged with N-methoxyquinoline-1-ium tetrafluorobo-
rate salt (0.5 mmol, 1.0 equiv), cesium fluoride (CsF) (1.5
mmol, 3.0 equiv) and ethyl acetate (EA) (10 mL). The reaction
mixture was then stirred at 25 °C under air atmosphere for 15
h. The reaction progress was monitored by TLC. After com-
pletion of the reaction, the resulting mixture was diluted with
EA and washed with water three times (3×1 0 mL). The organ-
ic layers dried over anhydrous Na2SO4, concentrated in vacuo,
and purified by flash column chromatograph to give the pure
N-methoxy-4-methyl-2-phenylpyridin-1-ium tetrafluoroborate
(1u). The crude product was purified by recrystallized in
EtOAc to provide the product 1u as a white solid (0.71g, yield
1
92%); H NMR (400 MHz, DMSO-d6, ppm): δ = 9.41 (d, J =
6.8 Hz, 1 H), 8.19 (s, 1 H), 8.11-8.09 (m, 1 H), 7.84-7.82 (m, 2
H), 7.71-7.66 (m, 3 H), 4.04 (s, 3 H), 2.67 (s, 3 H). 13C{1H}
NMR (100 MHz, DMSO-d6, ppm): δ = 158.6, 150.0, 140.5,
131.7, 130.9, 129.8, 128.9, 128.4, 128.3, 68.4, 21.2. HRMS
(ESI-TOF) m/z: Calcd for C13H14NO+ [M]+: 200.1070, found:
200.1071.
1
products. The products were characterized by H NMR, 13C
NMR, HRMS, MS, GC-MS and LC-MS.
quinoline-4-carbaldehyde (2a).9a The crude product was puri-
fied by flash chromatography on silica gel (Petroleum
ether/Ethyl acetate = 5:1) to provide the product 2a as a yel-
1
3-bromo-1-methoxy-4-methylpyridin-1-ium tetrafluoroborate
(1v). The crude product was purified by recrystallized in
EtOAc to provide the product 1v as a off-white solid (0.71g,
low solid (61 mg, yield 78%), mp 62-64 °C ; H NMR (400
MHz, CDCl3, ppm): δ = 10.53 (s, 1 H), 9.21 (d, J = 4.2 Hz, 1
H), 9.03 (dd, J = 8.5 Hz, 0.8 Hz, 1 H), 8.23 (d, J = 8.3 Hz, 1
H), 7.85-7.73 (m, 3 H). 13C{1H} NMR (100 MHz, CDCl3,
ppm): δ = 192.8, 150.4, 149.3, 136.7, 130.2, 130.0, 129.4,
125.8, 124.4, 123.8. GC−MS (EI, m/z): [M]+ 157.0. The spec-
tral data are consistent with those previously reported in the
literature.
1
yield 92%); H NMR (400 MHz, CDCl3, ppm): δ = 9.90 (d, J
= 1.8 Hz, 1 H), 9.38 (dd, J = 6.7 Hz, J = 1.8 Hz, 1 H), 8.24 (d,
J = 6.8 Hz, 1 H), 4.41 (s, 3 H), 2.63 (s, 3 H). 13C{1H} NMR
(100 MHz, CDCl3, ppm): δ = 158.6, 142.3, 139.5, 129.7, 125.0,
70.3, 23.0. HRMS (ESI-TOF) m/z: Calcd for C7H9BrNO+ [M]+:
201.9862, found: 201.9860.
7-methoxyquinoline-4-carbaldehyde (2b).14 The crude product
was purified by flash chromatography on silica gel (Petroleum
ether/Ethyl acetate = 5:1) to provide the product 2b as a light
yellow solid (71 mg, yield 76%), mp 90-92 °C ; 1H NMR (400
MHz, CDCl3, ppm): δ =10.47 (s, 1 H), 9.12 (d, J = 4.3 Hz, 1
H), 8.92 (d, J = 9.3 Hz, 1 H), 7.65 (d, J = 4.3 Hz, 1 H), 7.53 (d,
J = 2.6 Hz, 1 H), 7.38 (dd, J = 9.3 Hz, 2.7 Hz, 1 H), 3.99 (s, 3
H). 13C{1H} NMR (100 MHz, CDCl3, ppm): δ = 193.2, 160.9,
151.3, 150.8, 136.6, 125.5, 123.6, 122.4, 119.0, 107.9, 55.5 (d,
J = 4.9 Hz). GC−MS (EI, m/z): [M]+ 187.0. The spectral data
are consistent with those previously reported in the literature.
2-methoxyquinoline-4-carbaldehyde (2c).15 The crude product
was purified by flash chromatography on silica gel (Petroleum
ether/Ethyl acetate = 5:1) to provide the product 2c as a light
yellow solid (64 mg, yield 68%), mp 64-65 °C ; 1H NMR (400
MHz, CDCl3, ppm): δ =10.38 (s, 1 H), 8.87 (dd, J = 8.4 Hz,
1.0 Hz, 1 H), 7.94 (dd, J = 8.4 Hz, 0.6 Hz, 1 H), 7.73-7.69 (m,
1H), 7.55-7.50 (m, 1H), 7.33 (s, 1 H), 4.13 (s, 3 H). 13C{1H}
NMR (100 MHz, CDCl3, ppm): δ = 192.4, 162.2, 147.9, 140.3,
130.3, 127.6, 126.1, 124.6, 120.9, 120.1, 53.9 (d, J = 3.8 Hz).
GC−MS (EI, m/z): [M]+ 187.1. The spectral data are consistent
with those previously reported in the literature.
4-ethyl-1-methoxypyridin-1-ium tetrafluoroborate (1w). The
crude product was purified by recrystallized in EtOAc to pro-
1
vide the product 1w as a viscous solid (0.73g, yield 80%); H
NMR (400 MHz, DMSO-d6, ppm): δ = 9.34 (d, J = 7.0 Hz, 2
H), 8.13 (d, J = 6.8 Hz, 2 H), 4.40 (s, 3 H), 2.94 (q, J = 7.5 Hz,
2 H), 1.27 (t, J = 7.6 Hz, 3 H). 13C{1H} NMR (100 MHz,
DMSO-d6, ppm): δ = 163.5, 140.1, 128.2, 69.4, 27.9, 13.6.
HRMS (ESI-TOF) m/z: Calcd for C8H12NO+ [M]+: 138.0913,
found: 138.0915.
4-benzyl-1-methoxypyridin-1-ium tetrafluoroborate (1x). The
crude product was purified by recrystallized in EtOAc to pro-
1
vide the product 1x as a white solid (0.71g, yield 91%); H
NMR (400 MHz, DMSO-d6, ppm): δ = 9.33 (d, J = 7.0 Hz, 2
H), 8.12 (d, J = 7.0 Hz, 2 H), 7.38-7.26 (m, 5 H), 4.39 (s, 3 H),
4.31 (s, 2 H). 13C{1H} NMR (100 MHz, DMSO-d6, ppm): δ =
161.0, 140.9, 138.0, 129.7, 129.4, 129.2, 127.6, 69.8, 40.5.
HRMS (ESI-TOF) m/z: Calcd for C13H14NO+ [M]+: 200.1070,
found: 200.1072.
2-benzyl-1-methoxypyridin-1-ium tetrafluoroborate (1y). The
crude product was purified by recrystallized in EtOAc to pro-
1
vide the product 1y as a white solid (0.70g, yield 90%); H
NMR (400 MHz, DMSO-d6, ppm): δ = 9.51 (d, J = 6.5 Hz, 1
H), 8.53 (t, J = 7.7 Hz, 1 H), 8.15 (t, J = 6.4 Hz, 1 H), 7.96 (d,
J = 7.4 Hz, 1 H), 7.43-7.33 (m, 5 H), 4.55 (s, 2 H), 4.38 (s, 3
H). 13C{1H} NMR (100 MHz, DMSO-d6, ppm): δ = 154.3,
144.9, 141.1, 134.5, 129.6, 129.4, 129.0, 127.6, 127.5, 69.0,
7-(trifluoromethyl)quinoline-4-carbaldehyde (2d).16 The crude
product was purified by flash chromatography on silica gel
(Petroleum ether/Ethyl acetate = 8:1) to provide the product
1
2d as a yellow solid (67 mg, yield 60%), mp 62-64 °C ; H
NMR (400 MHz, CDCl3, ppm): δ = 10.50 (s, 1 H), 9.32 (d, J =
ACS Paragon Plus Environment

Page 7 of 10
The Journal of Organic Chemistry
4.2 Hz, 1 H), 9.21 (d, J = 8.9 Hz, 1 H), 8.53 (s, 1 H), 7.93-7.90
111.9 (s). GC−MS (EI, m/z): [M]+ 189.01. HRMS (ESI-TOF)
(m, 2 H). 13C{1H} NMR (100 MHz, CDCl3, ppm): δ = 192.3,
151.9, 148.3, 136.7, 132.0 (q, J = 32.9 Hz), 127.7, 127.6 (q, J
= 4.4 Hz), 126.1, 125.3, 124.9 (q, J = 2.9 Hz), 123.6 (q, J =
270.5 Hz). 19F NMR (376 MHz, CDCl3, ppm) : δ = -63.0 (s).
GC−MS (EI, m/z): [M]+ 225.0. The spectral data are consistent
with those previously reported in the literature.
m/z: Calcd for C11H9FNO [M+H]+: 190.0663, found: 190.0662.
quinoline-2-carbaldehyde (2j).9a The crude product was puri-
fied by flash chromatography on silica gel (Petroleum
ether/Ethyl acetate = 5:1) to provide the product 2j as a brown
1
2
3
4
5
6
7
8
1
solid (24 mg, yield 30%), mp 74-76 °C ; H NMR (400 MHz,
CDCl3, ppm): δ = 10.24 (d, J = 0.7 Hz, 1 H), 8.33 (d, J = 8.4
Hz, 1 H), 8.27 (d, J = 8.6 Hz, 1 H), 8.05 (d, J = 8.4 Hz, 1 H),
7.92 (d, J = 8.2 Hz, 1 H), 7.86-7.82 (m, 1H), 7.72-7.68 (m,
1H). 13C{1H} NMR (100 MHz, CDCl3, ppm): δ = 193.8,
152.6, 148.0, 137.4, 130.5, 130.5, 130.1, 129.2, 127.9, 117.4.
GC−MS (EI, m/z): [M]+ 157.0. The spectral data are consistent
with those previously reported in the literature.
2-phenylquinoline-4-carbaldehyde (2e).17 The crude product
was purified by flash chromatography on silica gel (Petroleum
ether/Ethyl acetate = 10:1) to provide the product 2e as a yel-
1
9
low solid (63 mg, yield 54%), mp 64-65 °C ; H NMR (400
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
MHz, CDCl3, ppm): δ = 10.60 (s, 1 H), 9.00 (dd, J = 8.5 Hz,
0.8 Hz, 1 H), 8.28-8.23 (m, 4 H), 7.85-7.81 (m, 1 H), 7.73-
7.69 (m, 1 H), 7.60-7.50 (m, 3 H). 13C{1H} NMR (100 MHz,
CDCl3, ppm): δ = 193.0, 157.4, 149.4, 138.5, 137.7, 130.4,
130.3, 130.0, 129.1, 128.9, 127.4, 124.2, 124.1, 122.9.
GC−MS (EI, m/z): [M]+ 233.0. The spectral data are consistent
with those previously reported in the literature.
1-(quinolin-4-yl)ethan-1-one (2l).20 The crude product was
purified by flash chromatography on silica gel (Petroleum
ether/Ethyl acetate = 5:1) to provide the product 2l as a yellow
oil (60 mg, yield 71%); 1H NMR (400 MHz, CDCl3, ppm): δ =
9.04 (d, J = 4.3 Hz, 1 H), 8.46 (d, J = 8.5 Hz, 1 H), 8.17 (d, J =
8.4 Hz, 1 H), 7.80-7.76 (m, 1 H), 7.67-7.62 (m, 2 H), 2.76 (d,
J = 2.3 Hz, 3 H). 13C{1H} NMR (100 MHz, CDCl3, ppm): δ =
201.3, 149.8, 149.2, 142.6, 130.0, 129.9, 128.4, 125.5, 123.7,
119.8, 30.1. MS (ESI) (m/z): 172.1 [M + H]+. The spectral data
are consistent with those previously reported in the literature.
1-(quinolin-4-yl)propan-1-one (2m).21 The crude product was
purified by flash chromatography on silica gel (Petroleum
ether/Ethyl acetate = 5:1) to provide the product 2m as a yel-
low oil (64 mg, yield 68%); 1H NMR (400 MHz, CDCl3, ppm):
δ = 9.02 (d, J = 4.4 Hz, 1 H), 8.29 (dd, J = 8.6 Hz, 0.8 Hz, 1
H), 8.17 (d, J = 8.5 Hz, 1 H), 7.80-7.75 (m, 1 H), 7.65-7.61 (m,
1 H), 7.55 (d, J = 4.4 Hz, 1 H), 3.07 (q, J = 7.2 Hz, 2 H), 1.30
(t, J = 7.2 Hz, 3 H). 13C{1H} NMR (100 MHz, CDCl3, ppm):
δ = 204.6, 149.8, 149.1, 143.7, 130.0, 129.9, 128.1, 125.3,
123.8, 118.8, 35.8, 8.1. MS (ESI) (m/z): 186.1 [M + H]+. The
spectral data are consistent with those previously reported in
the literature.
2-chloroquinoline-4-carbaldehyde (2f).18 The crude product
was purified by flash chromatography on silica gel (Petroleum
ether/Ethyl acetate = 5:1) to provide the product 2f as a yellow
1
solid (64 mg, yield 67%), mp 96-98 °C ; H NMR (400 MHz,
CDCl3, ppm): δ = 10.47 (s, 1 H), 8.95 (dd, J = 8.5 Hz, 0.9 Hz,
1 H), 8.13 (dd, J = 8.5 Hz, 0.5 Hz, 1 H), 7.87-7.72 (m, 3 H).
13C{1H} NMR (100 MHz, CDCl3, ppm): δ = 191.1, 150.7,
149.2, 139.5, 131.3, 129.5, 129.1, 127.3, 124.5, 122.8.
GC−MS (EI, m/z): [M]+ 191.1. The spectral data are consistent
with those previously reported in the literature.
6-bromoquinoline-4-carbaldehyde (2g).19 The crude product
was purified by flash chromatography on silica gel (Petroleum
ether/Ethyl acetate = 8:1) to provide the product 2g as a light
yellow solid (60 mg, yield 51%), mp 83-85 °C ; 1H NMR (400
MHz, CDCl3, ppm): δ =10.42 (s, 1 H), 9.25 (d, J = 2.2 Hz, 1
H), 9.20 (d, J = 4.2 Hz, 1 H), 8.07 (d, J = 9.0 Hz, 1 H), 7.91-
7.88 (m, 1H), 7.81 (d, J = 4.2 Hz, 1 H). 13C{1H} NMR (100
MHz, CDCl3, ppm): δ = 192.4, 150.7, 147.8, 135.7, 133.9,
131.5, 127.1, 126.9, 124.6, 124.4. GC−MS (EI, m/z): [M]+
237.0. The spectral data are consistent with those previously
reported in the literature.
phenyl(quinolin-4-yl)methanone (2n).22 The crude product was
purified by flash chromatography on silica gel (Petroleum
ether/Ethyl acetate = 8:1) to provide the product 2n as a yel-
low oil (94 mg, yield 81%); 1H NMR (400 MHz, CDCl3, ppm):
δ = 9.02 (d, J = 4.3 Hz, 1 H), 8.20 (d, J = 8.5 Hz, 1 H), 7.87-
7.83 (m, 3 H), 7.78-7.74 (m, 1 H), 7.65-7.61 (m, 1 H), 7.55-
7.45 (m, 3 H), 7.39 (d, J = 4.3 Hz, 1 H). 13C{1H} NMR (100
MHz, CDCl3, ppm): δ = 196.2, 149.6, 148.7, 144.5, 136.7,
134.3, 130.4, 130.1, 128.9, 127.8, 125.5, 125.1, 119.7. MS
(ESI) (m/z): 234.1 [M + H]+. The spectral data are consistent
with those previously reported in the literature.
quinolin-4-yl(m-tolyl)methanone (2o). The crude product was
purified by flash chromatography on silica gel (Petroleum
ether/Ethyl acetate = 8:1) to provide the product 2o as a yel-
low oil (89 mg, yield 72%); 1H NMR (400 MHz, CDCl3, ppm):
δ = 9.03 (d, J = 4.3 Hz, 1 H), 8.21 (d, J = 8.4 Hz, 1 H), 7.87
(dd, J = 8.4 Hz, 0.6 Hz, 1 H), 7.79-7.75 (m, 1 H), 7.70 (s, 1 H),
7.61 (d, J = 7.7 Hz, 1 H), 7.56-7.52 (m, 1 H), 7.46-7.34 (m, 3
H), 2.39 (s, 3 H). 13C{1H} NMR (100 MHz, CDCl3, ppm): δ =
196.3, 149.5, 148.7, 144.6, 138.8, 136.7, 135.1, 130.5, 130.0,
130.0, 128.7, 127.8, 127.6, 125.4, 125.0, 119.5, 21.3 (m). MS
(ESI) (m/z): 248.1 [M + H]+. HRMS (ESI-TOF) m/z: Calcd for
C17H14NO [M+H]+: 248.1070, found: 248.1069.
7-chloro-6-fluoroquinoline-4-carbaldehyde (2h). The crude
product was purified by flash chromatography on silica gel
(Petroleum ether/Ethyl acetate = 5:1) to provide the product
2h as a light yellow solid (65 mg, yield 62%), mp 91-93 °C ;
1H NMR (400 MHz, CDCl3, ppm): δ = 10.38 (s, 1 H), 9.19 (d,
J = 4.2 Hz, 1 H), 8.89 (d, J = 10.6 Hz, 1 H), 8.31 (d, J = 7.4
Hz, 1 H), 7.82 (d, J = 4.2 Hz, 1 H). 13C{1H} NMR (100 MHz,
CDCl3, ppm): δ = 192.5, 158.0 (d, J = 252.4 Hz), 150.8 (d, J =
2.9 Hz), 146.5, 136.2 (d, J = 5.9 Hz), 131.6, 127.4, 126.1 (d, J
= 21.4 Hz), 122.9 (d, J = 10.1 Hz), 110.2 (d, J = 24.8 Hz). 19
F
NMR (376 MHz, CDCl3, ppm) : δ = -110.9 (s). GC−MS (EI,
m/z): [M]+ 209.1. HRMS (ESI-TOF) m/z: Calcd for
C10H6ClFNO [M+H]+: 210.0116, found: 210.0117.
6-fluoro-7-methylquinoline-4-carbaldehyde (2i). The crude
product was purified by flash chromatography on silica gel
(Petroleum ether/Ethyl acetate = 5:1) to provide the product 2i
as a light yellow solid (57 mg, yield 60%), mp 107-109 °C ; 1H
NMR (400 MHz, CDCl3, ppm): δ = 10.40 (s, 1 H), 9.12 (d, J =
4.2 Hz, 1 H), 8.68 (d, J = 11.2 Hz, 1 H), 8.04 (d, J = 7.6 Hz, 1
H), 7.75 (d, J = 4.2 Hz, 1 H). 13C{1H} NMR (100 MHz,
CDCl3, ppm): δ = 192.8, 162.2 (d, J = 250.2 Hz), 149.5 (d, J =
2.8 Hz), 146.7, 136.1 (d, J = 6.1 Hz), 131.9 (d, J = 6.2 Hz),
131.0 (d, J = 21.7 Hz), 126.3, 123.0 (d, J = 11.3 Hz), 108.1 (d,
J = 25.7 Hz), 15.5. 19F NMR (376 MHz, CDCl3, ppm) : δ = -
quinolin-4-yl(4-(trifluoromethyl)phenyl)methanone (2p). The
crude product was purified by flash chromatography on silica
gel (Petroleum ether/Ethyl acetate = 5:1) to provide the prod-
uct 2p as a yellow oil (75 mg, yield 50%); 1H NMR (400 MHz,
CDCl3, ppm): δ = 9.06 (d, J = 4.3 Hz, 1 H), 8.24 (d, J = 8.5 Hz,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 10
2 H), 7.97 (d, J = 8.1 Hz, 1 H), 7.88-7.75 (m, 4 H), 7.60-7.56
H), 8.72 (d, J = 4.8 Hz, 1 H), 7.71 (dd, J = 4.8 Hz, 0.3 Hz, 1
(m, 1 H), 7.40 (d, J = 4.3 Hz, 1 H). 13C{1H} NMR (100 MHz,
CDCl3, ppm): δ = 195.0, 149.5, 148.8, 143.2, 139.4, 135.3 (q,
J = 32.6 Hz), 130.5, 130.3, 130.2, 128.0, 125.9 (q, J = 3.7 Hz),
125.1, 124.7, 123.4 (q, J = 271.3 Hz), 119.8. 19F NMR (376
MHz, CDCl3, ppm) : δ = -63.2 (s). MS (ESI) (m/z): 302.1 [M
+ H]+. HRMS (ESI-TOF) m/z: Calcd for C17H11F3NO [M+H]+:
302.0787, found: 302.0785.
H). 13C{1H} NMR (100 MHz, CDCl3, ppm): δ = 190.6, 153.9,
149.4, 138.6, 122.8, 122.1. GC−MS (EI, m/z): [M]+ 185.02.
The spectral data are consistent with those previously reported
in the literature.
1
2
3
4
5
6
7
8
1-(pyridin-4-yl)ethan-1-one (2w).8b The crude product was
purified by flash chromatography on silica gel (Petroleum
ether/Ethyl acetate = 5:1) to provide the product 2w as a yel-
low oil (30 mg, yield 50%); 1H NMR (400 MHz, CDCl3, ppm):
δ = 8.81 (dd, J = 4.4 Hz, 1.6 Hz, 2 H), 7.74 (dd, J = 4.4 Hz,
1.6 Hz, 2 H), 2.64 (s, 3 H). 13C{1H} NMR (100 MHz, CDCl3,
ppm): δ = 197.3, 150.7 (d, J = 28.6 Hz), 142.6, 121.1 (t, J =
26.2 Hz), 26.6. MS (ESI) (m/z): 122.1 [M + H]+. The spectral
data are consistent with those previously reported in the litera-
ture.
2-(piperidin-1-yl)quinoline-4-carbaldehyde (2q). The crude
product was purified by flash chromatography on silica gel
(Petroleum ether/Ethyl acetate = 5:1) to provide the product
9
1
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
2q as a yellow solid (80 mg, yield 67%), mp 68-70 °C ; H
NMR (400 MHz, CDCl3, ppm): δ = 10.4 (s, 1 H), 8.68 (dd, J =
8.4 Hz, 1.1 Hz, 1 H), 7.76 (m, 1 H), 7.61-7.57 (m, 1 H), 7.40
(s, 1 H), 7.35-7.31 (m, 1 H), 3.79-3.78 (m, 4 H), 1.72-1.69 (m,
6 H). 13C{1H} NMR (100 MHz, CDCl3, ppm): δ = 193.2,
157.0, 149.4, 138.8, 130.1, 126.9, 123.9, 123.9, 118.7, 116.4,
46.2, 25.8, 24.8. HRMS (ESI-TOF) m/z: Calcd for C15H17N2O
[M+H]+: 241.1335, found: 241.1336.
phenyl(pyridin-4-yl)methanone (2x).8b The crude product was
purified by flash chromatography on silica gel (Petroleum
ether/Ethyl acetate = 5:1) to provide the product 2x as a white
1
solid (52 mg, yield 57%), mp 68-69 °C ; H NMR (400 MHz,
isonicotinaldehyde (2r).9a The crude product was purified by
flash chromatography on silica gel (Petroleum ether/Ethyl
acetate = 5:1) to provide the product 2r as a yellow oil (22 mg,
yield 41%); 1H NMR (400 MHz, CDCl3, ppm): δ = 10.08 (s, 1
H), 8.89 (dd, J = 4.4 Hz, 1.6 Hz, 2 H), 7.70 (dd, J = 4.4 Hz,
1.6 Hz, 2 H). 13C{1H} NMR (100 MHz, CDCl3, ppm): δ =
191.5 (d, J = 1.1Hz), 151.1, 141.3, 122.0. GC−MS (EI, m/z):
[M]+ 107.1. The spectral data are consistent with those previ-
ously reported in the literature.
CDCl3, ppm): δ = 8.82-8.80 (m, 2 H), 7.83-7.81 (m, 2 H),
7.67-7.63 (m, 1 H), 7.59-7.57 (m, 2 H), 7.53-7.50 (m, 2 H).
13C{1H} NMR (100 MHz, CDCl3, ppm): δ = 195.1, 150.4,
144.4, 135.9, 133.5, 130.1, 128.6, 122.9. MS (ESI) (m/z):
184.0 [M + H]+. The spectral data are consistent with those
previously reported in the literature.
phenyl(pyridin-2-yl)methanone (2y).8b The crude product was
purified by flash chromatography on silica gel (Petroleum
ether/Ethyl acetate = 5:1) to provide the product 2y as a brown
1
2-methoxyisonicotinaldehyde (2s).23 The crude product was
purified by flash chromatography on silica gel (Petroleum
ether/Ethyl acetate = 5:1) to provide the product 2s as a white
foam (38 mg, yield 42%); H NMR (400 MHz, CDCl3, ppm):
δ = 8.73 (d, J = 4.2 Hz, 1 H), 8.08-8.04 (m, 3 H), 7.93-7.89 (m,
1 H), 7.62-7.58 (m, 1 H), 7.51-7.47 (m, 3 H). 13C{1H} NMR
(100 MHz, CDCl3, ppm): δ = 193.9, 155.1, 148.6, 137.0, 136.3,
132.9, 131.0, 128.2, 126.1, 124.6. MS (ESI) (m/z): 184.0 [M +
H]+. The spectral data are consistent with those previously
reported in the literature.
2-amino-5-bromo-3-methylisonicotinaldehyde (2z). The crude
product was purified by flash chromatography on silica gel
(Petroleum ether/Ethyl acetate = 2:1) to provide the product 2z
as a yellow foam (trace); HRMS (ESI-TOF) m/z: Calcd for
C7H8BrN2O [M+H]+: 214.9815, found: 214.9812.
4-(((2,2,6,6-tetramethylpiperidin-1-yl)oxy)methyl)quinoline
(4). Yellow solid, mp 135-137 °C ; 1H NMR (400 MHz, CDCl3,
ppm): δ = 8.91 (d, J = 4.4 Hz, 1 H), 8.13 (d, J = 8.4 Hz, 1 H),
7.88 (dd, J = 8.4 Hz, 0.7 Hz, 1 H), 7.73-7.69 (m, 1 H), 7.61-
7.52 (m, 2 H), 5.36 (d, J = 0.8 Hz, 2 H), 1.60-1.37 (m, 6 H),
1.28-1.22 (m, 12 H). LC-MS (ESI, m/z): [M+H]+ 299.3.
HRMS (ESI-TOF) m/z: Calcd for C19H27N2O [M+H]+:
299.2118, found: 299.2119.
1
solid (28 mg, yield 42%), mp 32-34 °C ; H NMR (400 MHz,
CDCl3, ppm): δ = 9.92 (s, 1 H), 8.28 (d, J = 5.2 Hz, 1 H), 7.20
(dd, J = 5.1 Hz, 1.2 Hz, 1 H), 7.05 (s, 1 H), 3.91 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3, ppm): δ = 191.2, 165.2,
148.4, 144.5, 114.0, 111.6, 53.9. GC−MS (EI, m/z): [M]+
137.13. The spectral data are consistent with those previously
reported in the literature.
4-formylpicolinonitrile (2t).24 The crude product was purified
by flash chromatography on silica gel (Petroleum ether/Ethyl
acetate = 5:1) to provide the product 2t as a yellow solid (20
1
mg, yield 30%), mp 67-69 °C ; H NMR (400 MHz, CDCl3,
ppm): δ = 10.12 (s, 1 H), 9.02 (d, J = 4.9 Hz, 1 H), 8.12 (s, 1
H), 7.95 (dd, J = 4.9 Hz, 1.4 Hz, 1 H). 13C{1H} NMR (100
MHz, CDCl3, ppm): δ = 189.0, 152.7, 142.3, 135.5, 126.6,
125.5, 116.4. GC−MS (EI, m/z): [M]+ 132.11. The spectral
data are consistent with those previously reported in the litera-
ture.
2-phenylisonicotinaldehyde (2u).25 The crude product was
purified by flash chromatography on silica gel (Petroleum
ether/Ethyl acetate = 5:1) to provide the product 2u as a brown
oil (37 mg, yield 40%); 1H NMR (400 MHz, CDCl3, ppm): δ =
10.15 (s, 1 H), 8.95 (d, J = 4.8 Hz, 1 H), 8.14 (t, J = 1.0 Hz, 1
H), 8.08-8.06 (m, 2 H), 7.64 (dd, J = 4.8 Hz, 1.4 Hz, 1 H),
7.54-7.47 (m, 3 H). 13C{1H} NMR (100 MHz, CDCl3, ppm): δ
= 191.7, 159.2, 151.1, 142.5, 138.2, 129.8, 129.0, 127.0, 120.6,
119.0. GC−MS (EI, m/z): [M]+ 183.1. The spectral data are
consistent with those previously reported in the literature.
3-bromoisonicotinaldehyde (2v).26 The crude product was
purified by flash chromatography on silica gel (Petroleum
ether/Ethyl acetate = 5:1) to provide the product 2v as a light
yellow solid (44 mg, yield 48%), mp 67-68 °C ; 1H NMR (400
MHz, CDCl3, ppm): δ = 10.36 (d, J = 0.6 Hz, 1 H), 8.91 (s, 1
■ ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Optimization of the partial reaction conditions, copies of NMR
spectra analysis for the substrates and the products (PDF).
■ AUTHOR INFORMATION
Author Contributions
*E-mail: zdp@zzu.edu.cn.
*E-mail: wyj@zzu.edu.cn.
*E-mail: yusheng.wu@tetranovglobal.com.
Notes
ACS Paragon Plus Environment

Page 9 of 10
The Journal of Organic Chemistry
16, 635-644. (g) Liu, H. H.; Wang, X. F.; Chen Ma, C. Synthesis of
■ ACKNOWLEDGMENT
Imidazo[1,5-a]quinolines via Metal-Free Oxidative Amination of sp3
C–H Bonds. Synthesis 2018, 50, 2761-2767.
1
We are grateful to the National Natural Science Foundation
of China (21172200, 21702191) for financial support.
2
3
4
5
6
7
8
9
(3) (a) Bonvin, Y.; Callens, E.; Larrosa, I.; Henderson, D. A.; Old-
ham, J.; Burton, A. J.; Barrett, A. G. M. Bismuth-Catalyzed Benzylic
Oxidations with tert-Butyl Hydroperoxide. Org. Lett. 2005, 7, 4549-
4552. (b) Nakanishi, M.; Bolm, C. Iron-Catalyzed Benzylic Oxidation
with Aqueous tert-Butyl Hydroperoxide. Adv. Synth. Catal. 2007, 349,
861-864. (c) Zhang, L.; Ang, G. Y.; Chiba, S. Copper-Catalyzed Ben-
zylic C-H Oxygenation under an Oxygen Atmosphere via N-H Imines
as an Intramolecular Directing Group. Org. Lett. 2011, 13, 1622-1625.
(d) Kumar, R. A.; Maheswari, C. U.; Ghantasala, S.; Jyothi, C.; Red-
dy, K. R. Synthesis of 3H-Quinazolin-4-ones and 4H-3,1-Benzoxazin-
4-ones via Benzylic Oxidation and Oxidative Dehydrogenation using
Potassium Iodide-tert-Butyl Hydroperoxide. Adv. Synth. Catal. 2011,
353, 401-410. (e) Moriyama, K.; Takemura, M.; Togo, H. Direct and
Selective Benzylic Oxidation of Alkylarenes via C-H Abstraction
Using Alkali Metal Bromides. Org. Lett. 2012, 14, 2414-2417. (f)
Allen, S. E.; Walvoord, R. R.; Padilla, S. R.; Kozlowski, M. C. Aero-
bic Copper-Catalyzed Organic Reactions. Chem. Rev. 2013, 113,
6234-6458. (g) Zhang, B.; Zhu, S.-F.; Zhou, Q. L. Copper-Catalyzed
Benzylic Oxidation of C(sp3)-H Bonds. Tetrahedron 2013, 69, 2033-
2037. (h) Mahyari, M.; Laeini, M.; Shaabani, A. Aqueous Aerobic
Oxidation of Alkyl Arenes and Alcohols Catalyzed by Copper(II)
Phthalocyanine Supported on Three-Dimensional Nitrogen-Doped
Graphene at Room Temperature. Chem. Commun. 2014, 50, 7855-
7857. (i) Shen, D.; Miao, C.; Wang, S.; Xia, C.; Sun, W. Efficient
Benzylic and Aliphatic C-H Oxidation with Selectivity for Methyle-
nic Sites Catalyzed by a Bioinspired Manganese Complex. Org. Lett.
2014, 16, 1108-1111. (j) Hossain, M. M.; Shyu, S.-G. Biphasic Cop-
per-Catalyzed C-H Bond Activation of Arylalkanes to Ketones with
Tert-Butyl Hydroperoxide in Water at Room Temperature. Tetrahe-
dron 2016, 72, 4252-4257. (k) Tu, D.-H.; Li, Y.; Li, J. W.; Gu, Y.-J.;
Wang, B.; Liu, Z,-T.; Liu, Z.-W. Lu, J. Selective Oxidation of Arylal-
kanes with N-Graphitic-Modified Cobalt Nanoparticles in Water.
Catal. Commun. 2017, 97, 130-133.
■ REFERENCES
(1) (a) Boger, D. L.; Miyauchi, H.; Hedrick, M. P. α-Keto Hetero-
cycle Inhibitors of Fatty Acid Amide Hydrolase: Carbonyl Group
Modification and α-Substitution. Bioorg. Med. Chem. Lett. 2001, 11,
1517-1520. (b) Shie, J. J.; Fang, J. M. Direct Conversion of Alde-
hydes to Amides, Tetrazoles, and Triazines in Aqueous Media by
One-Pot Tandem Reactions. J. Org. Chem. 2003, 68, 1158-1160. (c)
Hochgürtel, M.; Biesinger, R.; Kroth, H.; Piecha, D.; Hofmann, M.
W.; Krause, S.; Schaaf, O.; Nicolau, C.; Eliseev, A. V. Ketones as
Building Blocks for Dynamic Combinatorial Libraries:ꢀ Highly Active
Neuraminidase Inhibitors Generated via Selection Pressure of the
Biological Target. J. Med. Chem. 2003, 46, 356-358. (d) Reis, D. C.;
Pinto, M. C. X.; Souza-Fagundes, E. M.; Wardell, S. M. S. V.;
Wardell, J. L; Beraldo, H. Antimony(III) Complexes with 2-
Benzoylpyridine-derived Thiosemicarbazones: Cytotoxicity Against
Human Leukemia Cell Lines. Eur. J. Med. Chem. 2010, 45, 3904-
3910. (e) Gopinath, V. S. Design, Synthesis and Biological Evalua-
tion of 2-Substituted Quinolines as Potential Antileishmanial Agents.
Eur. J. Med. Chem. 2013, 69, 527-536. (f) Vitaku, E.; Smith, D.;
Njardarson, J. T. Analysis of the Structural Diversity, Substitution
Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA
Approved Pharmaceuticals. J. Med. Chem. 2014, 57, 10257-10274. (g)
Yadav, A. K.; Srivastava, V. P.; Yadav, L. D. S. Metal-Free, One-Pot
Oxidative Conversion of Aldehydes to Primary Thioamides in Aque-
ous Media. Syn. Commun. 2014, 44, 408-416. (h) Gieseler, M. T.;
Kalesse, M. Synthesis of Angiolam A. Org. Lett. 2014, 16, 548-551.
(i) Mani, G. S.; Shaik, S. P.; Tangella, Y.; Bale, S.; Godugu, C.;
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
Kamal, A.
A Facile I2-Catalyzed Synthesis of Imidazo[1,2-
a]pyridines via sp3 C–H Functionalization of Azaarenes and Evalua-
tion of Anticancer Activity. Org. Biomol. Chem. 2017, 15, 6780-6791.
(j) Yue, P.; Yang, X. L.; Ning, P.; Xi, X. G.; Yu, H. Z.; Feng, Y.;
Shao, R.; Meng, X. M. A Mitochondria-Targeted Ratiometric Two-
Photon Fluorescent Probe for Detecting Intracellular Cysteine and
Homocysteine. Talanta 2018, 178, 24-30. (k) Song, L. J.; Merceron,
R.; Gracia, B.; Quintana, A. L.; Risseeuw, M. D. P.; Hulpia, F.; Cos,
P.; Aínsa, J. A.; Munier-Lehmann, H.; Savvides, S. N.; Calenbergh, S.
V. Structure Guided Lead Generation toward Nonchiral M. tuberculo-
sis Thymidylate Kinase Inhibitors. J. Med. Chem. 2018, 61, 2753-
2775. (l) Tong, M. C.; Wang, S. N.; Zhuang, J. C.; Qin, C.; Li, H.;
Wang, W. Direct Access of the Chiral Quinolinyl Core of Cinchona
Alkaloids via a Brønsted Acid and Chiral Amine Co-catalyzed
Chemo- and Enantioselective α-Alkylation of Quinolinylmethanols
with Enals. Org. Lett. 2018, 20, 1195-1199.
(4) (a) Shibamoto, Y.; Sakaguchi, S.; Ishii, Y. Aerobic Oxidation of
Methylpyridines to Pyridinecarboxylic Acids Catalyzed by N-
Hydroxyphthalimide. Org. Proc. Res. Dev. 2000, 4, 505-508. (b)
Song, Z.; Matsushita, T.; Shishido, T.; Takehira, K. Crystalline
CrV0.95P0.05O4 Catalyst for Vapor-Phase Oxidation of Picolines. Chem.
Commun. 2002, 1306-1307. (c) Vorobyev, P. B.; Saurambaeva, L. I.;
Mikhailovskaya, T. P. Oxidation of 3- and 4-Methylpyridines on
Modified Vanadium Oxide Catalysts. Russ. J. Gen. Chem. 2013, 83,
972-978.
(5) (a) Achremowicz, L. A New Approach to the Oxidation of
Methylquinolines with Selenium Dioxide. Synth. Commun. 1996, 26,
1681-1684. (b) Tagawa, Y.; Yamashita, K.; Higuchi, Y.; Goto, Y.
Improved Oxidation of Active Methyl Group of N-Heteroaromatic
Compounds by Selenium Dioxide in the Presence of tert-Butyl Hy-
droperoxide. Heterocycles 2003, 60, 953-957. (c) Pérez-Melero, C.;
Maya, A. B. S.; del Rey, B.; Peláez, R.; Caballero, E.; Medarde, M. A
New Family of Quinoline and Quinoxaline Analogues of Com-
bretastatins. Bioorg. Med. Chem. Lett. 2004, 14, 3771-3774. (d) New-
some, J. J.; Colucci, M. A.; Hassani, M.; Beall, H. D.; Moody, C. J.
Benzimidazole- and Benzothiazole-quinones: Excellent Substrates for
NAD(P)H: Quinone Oxidoreductase 1. Org. Biomol. Chem. 2007, 5,
3665-3673. (e) Abbott, B. M.; Ferrari, F. D.; Harnor, S. J.; Barnes, J.
C.; Marquez, R. Photochemical Synthesis of Benz[h]isoquinolines.
Tetrahedron 2008, 64, 5072-5078. (f) Mayhoub, A. S.; Marler, L.;
Kondratyuk, T. P.; Park, E.-J.; Pezzuto, J. M.; Cushman, M. Optimi-
zation of the Aromatase Inhibitory Activities of Pyridylthiazole Ana-
logues of Resveratrol. Bioorg. Med. Chem. 2012, 20, 2427-2434. (g)
Ding, D.; Dwoskin, L. P.; Crooks, P. A. Efficient Synthesis of Cis-
2,6-di-(2-quinolylpiperidine). Tetrahedron Lett. 2013, 54, 5211-5213.
(h) Nawratil, S.; Grypioti, M.; Menendez, C.; Mallet-Ladeira, S.;
Lherbet, C.; Baltas, M. Mallet-Ladeira, S.; Lherbet, C.; Baltas, M.
Synthesis of α-Keto-1,2,3-triazoles Through Copper Iodide Catalyzed
Oxygenation. Eur. J. Org. Chem. 2014, 654-659. (i) Hruszkewycz, D.
P.; Miles, K. C.; Thiel, O. R.; Stahl, S. S. Co/NHPI-Mediated Aerobic
Oxygenation of Benzylic C-H Bonds in Pharmaceutically Relevant
(2) (a) Cui, L. Q.; Liu, K.; Zhang, C. Effective Oxidation of Ben-
zylic and Alkane C–H Bonds Catalyzed by Sodium o-
Iodobenzenesulfonate with Oxone as a Terminal Oxidant under
Phase-Transfer Conditions. Org. Biomol. Chem. 2011, 9, 2258-2265.
(b) Gao, X., Zhang, F.; Deng, G. J.; Yang, L. Brønsted Acid Cata-
lyzed Benzylic C–H Bond Functionalization of Azaarenes: Nucleo-
philic Addition to Nitroso Compounds. Org. Lett. 2014, 16, 3664-
3667. (c) Shing, K.-P.; Cao, B.; Liu, Y.; Lee, H. K.; Li, M.-D.; Phil-
lips, D. L.; Chang, X.-Y.; Che, C.-M. Arylruthenium(III) Porphyrin-
Catalyzed C–H Oxidation and Epoxidation at Room Temperature and
[RuV(Por)(O)(Ph)] Intermediate by Spectroscopic Analysis and Den-
sity Functional Theory Calculations. J. Am. Chem. Soc. 2018, 140,
7032-7042. (d) Li, S. L.; Zhu, B.; Lee, R,; Qiao, B. K.; Jiang, Z. Y.
Visible Light-Induced Selective Aerobic Oxidative Transposition of
Vinyl Halides Using a Tetrahalogenoferrate(III) Complex Catalyst.
Org. Chem. Front. 2018, 5, 380-385. (e) Yan, Z. C.; Wan, C. F.;
Yang, Y.; Zha, Z. G.; Wang, Z. Y. The Synthesis of Imidazo[1,5-
a]quinolines via a Decarboxylative Cyclization under Metal-Free
Conditions. RSC Adv. 2018, 8, 23058-23065. (f) Rahim, A.; Shaik, S.
P.; Baig, M. F.; Alarific, A.; Kamal, A. Iodine Mediated Oxidative
Cross-Coupling of Unprotected Anilines and HetEroarylation of
Bbenzothiazoles with 2-Methylquinoline. Org. Biomol. Chem. 2018,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 10
Molecules. Chem. Sci. 2017, 8, 1282-1287. (j) Eberhard, J.; Pe-
Aerobic Oxidation of Benzyl Halides. Org. Lett. 2011, 13, 2168-2171.
untinger, K.; Frohlich, R.; Guldi, D. M.; Mattay, J. Synthesis and
Properties of Acridine and Acridinium Dye Functionalized
Bis(terpyridine) Ruthenium(II) Complexes. Eur. J. Org. Chem. 2018,
2682-2700. (k) Cooper, J. C.; Luo, C. S.; Kameyama, R.; Humbeck, J.
F. V. Combined Iron/Hydroxytriazole Dual Catalytic System for Site
Selective Oxidation Adjacent to Azaheterocycles. J. Am. Chem. Soc.
2018, 140, 1243-1246.
(6) (a) De Houwer, J.; Tehrani, K. A.; Maes, B. U. W. Synthesis of
Aryl(di)azinyl Ketones through Copper- and Iron-catalyzed Oxidation
of the Methylene Group of Aryl(di)azinylmethanes. Angew. Chem.,
Int. Ed. 2012, 51, 2745-2748. (b) Sterckx, H.; Houwer, J. D.; Mensch,
C.; Caretti, I.; Tehrani, K. A.; Herrebout, W. A.; Doorslaer, S. V.;
Maes, B. U. W. Mechanism of the CuII-catalyzed Benzylic Oxygena-
tion of (Aryl)(Heteroaryl)methanes with Oxygen. Chem. Sci. 2016, 7,
346-357.
(7) Wang, Y.; Zhang, F.; Chiba, S. Copper-Catalyzed Aerobic Me-
thyl/Methylene Oxygenation and C-H Formylation with a DABCO-
DMSO System for the Synthesis of Carbonyl Indoles and Pyrroles.
Synthesis 2012, 44, 1526-1534.
(8) (a) Itoh, M.; Hirano, K.; Satoh, T.; Miura, M. Copper-Catalyzed
α-Methylenation of Benzylpyridines Using Dimethylacetamide as
One-Carbon Source. Org. Lett. 2014, 16, 2050-2053. (b)Liu, J.;
Zhang, X.; Yi, H.; Liu, C.; Liu, R.; Zhang, H.; Zhuo, K.; Lei, A.
Chloroacetate-Promoted Selective Oxidation of Heterobenzylic
Methylenes under Copper Catalysis. Angew. Chem., Int. Ed. 2015, 54,
1261-1265.
(9) (a) Zheng, G.; Liu, H.; Wang, M. Copper-Catalyzed Aerobic
Oxidation of Azinylmethanes for Access to Trifluoromethylazinylols.
Chin. J. Chem. 2016, 34, 519-523. (b) Abe, T.; Tanaka, S.; Ogawa, A.;
Tamura, M.; Sato, K.; Itoh, S. Copper-Catalyzed Selective Oxygena-
tion of Methyl and Benzyl Substituents in Pyridine with O2. Chemis-
try Letters 2017, 46, 348-350.
(10) Nagasawa, Y.; Tachikawa, Y.; Yamaguchi, E.; Tada, N.;
Miura, T.; Itoh, A. Catalytic Aerobic Photo-oxidation of a Methyl
Group on a Heterocycle to Produce an Aldehyde via Homolytic C-I
Bond Cleavage Caused by Irradiation with Visible Light. Adv. Synth.
Catal. 2016, 358, 178-182.
(11) (a) Gao, X. Y.; Liang, A. P.; Li, J. Y.; Zou, D. P.; Wu, Y. J.;
Wu, Y. S. A Facile and Environmental Friendly Strategy for the Syn-
thesis of N-methoxyquinolin-2(1H)-ones. Tetrahedron Lett. 2017, 58,
1917-1920. (b) Ren, X. X.; Han, S. J.; Gao, X. Y.; Li, J. Y.; Zou, D.
P.; Wu, Y. J.; Wu, Y. S. Direct Arylation for the Synthesis of 2-
Arylquinolines from N-methoxyquinoline-1-ium Tetrafluoroborate
Salts and Arylboronic Acids. Tetrahedron Lett. 2018, 59, 1065-1068.
(c) Gao, X. Y.; Geng, Y.; Han, S. J.; Liang, A. P.; Li, J. Y.; Zou, D. P.;
Wu, Y. J.; Wu, Y. S. Nickel-Catalyzed C-H Trifluoromethylation of
Pyridine N-oxides with Togni’s Reagent. Tetrahedron Lett. 2018, 59,
1551-1554. (d) Gao, X. Y.; Geng, Y.; Han, S. J.; Liang, A. P.; Li, J.
Y.; Zou, D. P.; Wu, Y. S.; Wu, Y. J. Nickel-Catalyzed Direct C–H
Trifluoromethylation of Free Anilines with Togni’s Reagent. Org.
Lett. 2018, 20, 3732-3735.
(12) (a) Avila, D. V.; Ingold, K. U.; Di Nardo, A. A.; Zerbetto, F.;
Zgierski, M. Z.; Lusztyk, J. Electronic Absorption Spectra of Some
Alkoxyl Radicals. An Experimental and Theoretical Study. J. Am.
Chem. Soc. 1995, 117, 2711-2718. (b) Konya, K. G.; Paul, T.; Lin, S.;
Lusztyk, J.; Ingold, K. U. Laser Flash Photolysis Studies on the First
Superoxide Thermal Source. First Direct Measurements of the Rates
of Solvent-Assisted 1,2-Hydrogen Atom Shifts and a Proposed New
Mechanism for This Unusual Rearrangement. J. Am. Chem. Soc. 2000,
122, 7518-7527. (c) da Silva, G.; Hamdan, M. R.; Bozzelli, J. W. J.
Oxidation of the Benzyl Radical: Mechanism, Thermochemistry, and
Kinetics for the Reactions of Benzyl Hydroperoxide. Chem. Theory
Comput. 2009, 5, 3185-3194. (d) Recupero, F.; Punta, C. Free Radical
Functionalization of Organic Compounds Catalyzed by N-
Hydroxyphthalimide. Chem. Rev. 2007, 107, 3800-3842. (e) Su, Y. J.;
Zhang, L. R.; Jiao, N. Utilization of Natural Sunlight and Air in the
(f) Moriyama, K.; Takemura, M.; Togo, H. Direct and Selective Ben-
zylic Oxidation of Alkylarenes via C-H Abstraction Using Alkali
Metal Bromides. Org. Lett. 2012, 14, 2414-2417. (g) Xie, H.; Liao,
Y.-F.; Chen, S.-Q.; Chen, Y.; Deng, G.-J. Copper-catalyzed Efficient
Direct Amidation of 2-Methylquinolines with Amines. Org. Biomol.
Chem. 2015, 13, 6944-6948. (h) Huang, Y.; Chen, T.-Q.; Li, Q.; Zhou,
Y.-B.; Yin, S.-F. Copper Catalysed Direct Amidation of Methyl
Groups with N–H Bonds. Org. Biomol. Chem. 2015, 13, 7289-7293.
(13) Lorance, E. D.; Kramer, W. H.; Gould, I. R. Kinetics of Re-
ductive N−O Bond Fragmentation: The Role of a Conical Intersection.
J. Am. Chem. Soc. 2002, 124, 15225-15238.
(14) Gemma, S.; Savini, L.; Altarelli, M.; Tripaldi, P.; Chiasserini,
L.; Coccone, S. S.; Kumar, V.; Camodeca, C.; Campiani, G.; Novel-
lino, E.; Clarizio, S.; Delogu, G.; Butini, S. Development of An-
titubercular Compounds Based on a 4-Quinolylhydrazone Scaffold.
Further Structure–Activity Relationship Studies. Bioorg. Med. Chem.
2009, 17, 6063-6072.
(15) Chupak, L. S.; Flanagan, M. E.; Kaneko, T.; Magee, T. V.;
Noe, M. C.; Reilly, U. Preparation of Erythromycin Macrolide Anti-
biotics and Their Use as Antibacterial and Antiprotozoal Agents.
Patent US 20060135447 A1, Jun 22, 2006.
(16) Daluge, S. M.; Skonezny, P. M.; Roth, B.; Rauckman, B. S.
Antibacterial Pyrimidine Compounds. Patent EP 96214 A1, Nov 21,
1983.
(17) Klumpp, D. A.; Jones, A.; Lau, S.; De Leon, S.; Garza, M. The
Superacid Induced Condensation of Quinolinecarboxaldehydes with
Arenes. Synthesis 2000, 8, 1117-1120.
(18) Hasegawa, M. Sur La Reaction Entre La Lepidine, La 2-
Chlorolepidine, Et La N-Bromosuccinimide. Pharm. Bull. 1953, 1, 47.
(19) Lu, B.; Zhang, J.; Jin, F.; He, F.; Tao, W. 1,2,4-Triazine-3-
Amine Derivative, Preparation Method Therefor, and Use Thereof in
Medicine. Patent WO 2018130184 A1, Jul 19, 2018.
(20) Bonnet, M; Flanagan, J. U.; Chan, D. A.; Lai, E. W.; Nguyen,
P.; Giaccia, A. J.; Hay, M. P. SAR Studies of 4-Pyridyl Heterocyclic
Anilines that Selectively Induce Autophagic Cell Death in Von Hip-
pel-Lindau-Deficient Renal Cell Carcinoma Cells. Bioorg. Med.
Chem. 2011, 19, 3347-3356.
(21) McCurdy, A.; Jimenez, L.; Stauffer, D. A.; Dougherty, D. A.
Biomimetic Catalysis of SN2 Reactions through Cation-.pi. Interac-
tions. The Role of Polarizability in Catalysis. J. Am. Chem. Soc. 1992,
114, 10314-10321.
(22) Sterckx, H.; Sambiagio, C.; Medran-Navarrete, V.; Maes, B. U.
W. Copper-Catalyzed Aerobic Oxygenation of Benzylpyridine N-
Oxides and Subsequent Post-Functionalization. Adv. Synth. Catal.
2017, 359, 3226-3236.
(23) Subramanyam, C.; Noguchi, M.; Weinreb, S. M. An Approach
to Amphimedine and Related Marine Alkaloids Utilizing an Intramo-
lecular Kondrat'eva Pyridine Synthesis. J. Org. Chem. 1989, 54,
5580-5585.
(24) Carroll, W. A.; Altenbach, R.J.; Bai, H.; Brioni, J. D.; Brune,
M. E.; Buckner, S. A.; Cassidy, C.; Chen, Y.; Coghlan, M. J.; Daza, A.
V.; et al. Synthesis and Structure−Activity Relationships of a Novel
Series of 2,3,5,6,7,9-Hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-
Dioxide KATP Channel Openers: Discovery of (−)-(9S)-9-(3-Bromo-
4-fluorophenyl)-2,3,5,6,7,9- hexahydrothieno[3,2-b]quinolin-8(4H)-
one 1,1-Dioxide (A-278637), a Potent KATP Opener That Selectively
Inhibits Spontaneous Bladder Contractions. J. Med. Chem. 2004, 47,
3163-3179.
(25) Altınölçek, N.; Aydemir, M.; Tavaslı, M.; Santos, P. L. D.;
Monkman, A. P. Synthesis of Biscyclometalated Iridium(III) Acety-
lacetonate Complexes via a 15 min Bridge-Splitting Reaction, Their
Characterizations and Photophysical Properties. J. Organomet.Chem.
2017, 851, 184-188.
1
2
3
4
5
6
7
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
(26) Miyata, K.; Möller, G.; Schepmann, D.; Wünsch. B. Pyridine
Analogues of Spirocyclic σ1 Receptor Ligands. Bioorg. Med. Chem.
2014, 22, 4277-4284.
ACS Paragon Plus Environment