Deoxygenative Amination of Azine-N-oxides with Acyl Azides via [3 + 2] Cycloaddition

Article abstract of DOI:10.1021/acs.joc.9b03173

A transition-metal-free deoxygenative C-H amination reaction of azine-N-oxides with acyl azides is described. The initial formation of an isocyanate from the starting acyl azide via a Curtius rearrangement can trigger a [3 + 2] dipolar cycloaddition of polar N-oxide fragments to generate the aminated azine derivative. The applicability of this method is highlighted by the late-stage and sequential amination reactions of complex bioactive compounds, including quinidine and fasudil. Moreover, the direct transformation of aminated azines into various bioactive N-heterocycles illustrates the significance of this newly developed protocol.

Full text of DOI:10.1021/acs.joc.9b03173

Subscriber access provided by UNIVERSITY OF CONNECTICUT
Article
Deoxygenative Amination of Azine-N-oxides
with Acyl Azides via [3+2] Cycloaddition
Dongeun Kim, Prithwish Ghosh, Na Yeon Kwon, Sang Hoon Han,
Sangil Han, Neeraj Kumar Mishra, Saegun Kim, and In Su Kim
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03173 • Publication Date (Web): 06 Jan 2020
Downloaded from pubs.acs.org on January 8, 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 11
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
Deoxygenative Amination of Azine-N-oxides with Acyl Azides via
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
[3+2] Cycloaddition
Dongeun Kim, Prithwish Ghosh, Na Yeon Kwon, Sang Hoon Han, Sangil Han, Neeraj Kumar Mishra,
Saegun Kim,* and In Su Kim*
School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
*Corresponding authors. jameskim1991@naver.com (S.K.), insukim@skku.edu (I.S.K.)
KEYWORDS: Amination, Acyl Azides, Azine-N-oxides, C–H functionalization, Curtius rearrangement.
ABSTRACT: Transition-metal-free deoxygenative C–H amination reaction of azine-N-oxides with acyl azides is described. The
initial formation of an isocyanate from the starting acyl azide via a Curtius rearrangement can trigger a [3+2] dipolar cycloaddition
of polar N-oxide fragments to generate the aminated azine derivative. The applicability of this method is highlighted by the late-
stage and sequential amination reactions of complex bioactive compounds, including quinidine and fasudil. Moreover, the direct
transformation of aminated azines into various bioactive N-heterocycles illustrates the significance of this newly developed protocol.
ployed in the C2-amination reaction.4a To overcome the inher-
ent low reactivity of azines, the reaction of azine-N-oxides
Introduction
Azines, which are six-membered aromatic compounds con-
with external stoichiometric reagents were reported.4b-4g In
taining one or more nitrogen atoms, have been recognized as
addition, the transition-metal-catalyzed C–H amination reac-
ubiquitous core structures for a variety of biological applica-
tions. Therefore, the synthesis of substituted azines is
tions of heterocyclic N-oxides have recently been described.5
Scheme 1. C–H Amination of Azine-N-Oxides
important from the perspective of furthering the development
of medicinal, agrochemical, and other chemical entities.1 In
particular, aminated azines are of paramount interest in drug
discovery due to their remarkable therapeutic potential (Figure
1).2
Figure 1. Selected Examples of C2-Aminated Azines
Pioneering work on the C2-amination of pyridines was re-
ported in 1914 by Chichibabin.3 However, due to extremely
low reactivity of azines in the nucleophilic aromatic substitu-
tion (SNAr), ortho-halogenated azines are conventionally em-
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 11
1
2
3
4
5
6
7
8
9
3
5
K2CO3 (2)
NaOMe (2)
NaOH (2)
Et3N (2)
THF
trace
42
Azine-N-oxides possessing a 1,2-dipolar N–O bond can de-
localize the positive charge onto the ortho-position of the ar-
omatic ring, therefore rendering it susceptible to nucleophilic
addition.6 However, C2-functionalization reactions of azine-N-
oxides via a [3+2] dipolar cycloaddition have been rarely re-
ported to date. For example, Ocone and Makosza independent-
ly described the C2-alkylation of pyridine-N-oxides with high-
ly electron-deficient alkenes via a [3+2] cycloaddition reaction
followed by retro-aldol fragmentation (Scheme 1).7 Recently,
Murakami demonstrated the photocatalyzed ortho-alkylation
of pyridine N-oxides via [3+2]-type cycloadduct intermedi-
ates.8 Very recently, our group utilized phosphonium ylides
for the [3+2] dipolar cycloaddition of azine-N-oxides to afford
C2-alkylated azines.9 Acyl azides serve as synthetic precursors
to their corresponding isocyanates via a Curtius rearrangement
under thermal and photochemical conditions.10 Herein, we
describe a transition-metal-free site-selective C2–amination
reaction of various azine-N-oxides using acyl azides via a
[3+2] dipolar cycloaddition reaction followed by aromatiza-
tion. Notably, the late-stage and sequential amination reactions
of complex bioactive compounds leading to the formation of
highly functionalized azines highlight the applicability of this
methodology.
3
6
THF
3
7
THF
trace
trace
trace
5
3
8
THF
3
9
2,6-lutidine (2)
AgBF4 (0.5)
KOtBu (2)
KOtBu (2)
KOtBu (2)
KOtBu (2)
KOtBu (2)
KOtBu (2)
THF
3
10
11
12
13
14
15c
16
THF
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
3
1,4-dioxane
MTBE
MeCN
DMF
trace
95
3
3
17
3
trace
43
3
MTBE
MTBE
p-tolylNCO (3)
82
a
Reaction conditions: 1a (0.2 mmol), reagent (quantity noted), 2a
(quantity noted), solvent (1 mL) at 130 oC for 20 h under N2 atmosphere in
b
pressure tubes (see experimental section for details). Yield after flash
column chromatography. c The reaction was carried out at 80 oC for 40 h.
Scheme 2. Scope of Azine-N-Oxidesa
Y
Y
N
O
X
KOtBu, MTBE
130 oC, 20 h
X
R
R
+
Ar
N3
Ar
N
O
H
N
2a
(Ar = p-tolyl)
H
1a 1t
-
3a-3t, %b
MeO
Cl
F
Result and discussions
Ar
Ar
Ar
Ar
N
N
N
N
H
N
N
N
N
H
H
H
Our initial optimization was carried out by performing the
coupling reaction between quinoline N-oxide (1a) and 4-
methylbenzoyl azide (2a), as shown in Table 1. To our delight,
treatment of 2a (2 equiv.) in the presence of KOtBu (2 equiv.)
in THF afforded C2-aminated quinoline 3a in 36% yield (Ta-
ble 1, entry 1). Increased loading of 2a into 3 equiv. signifi-
cantly increased the formation of 3a in 74% yield (Table 1,
entry 2). However, increasing the amount of KOtBu from 2
equiv. to 3 equiv. was less effective for improving the yield of
3a (Table 1, entry 3). Screening the base revealed that KOtBu
was the most effective in this transformation (Table 1, entries
4–9). Replacement of KOtBu with AgBF4 as a Lewis acid was
unsuccessful, delivering the desired product 3a in 5% yield
(Table 1, entry 10). It was quite surprising that using MTBE
(t-butylmethyl ether) as the reaction solvent resulted in a dra-
matically improved yield (95%) of 3a, as shown in entry 12. A
control experiment indicated that the reaction temperature was
pivotal for the conversion of acyl azide 2a into the desired
isocyanate intermediate, which may react with 1a to give
product 3a (Table 1, entry 15). Finally, p-tolyl isocyanate was
used toward the formation of 3a under the optimal reaction
conditions (Table 1, entry 16).11 This result strongly supports
that isocyanates are potential intermediates in this process.
c
3a
3b
3c
3d
, 51%
, 95% (86%)
, 90%
, 73%
Cl
F
Me
Me
Ar
Ar
Ar
Ar
N
N
N
N
H
N
N
N
N
H
H
H
OMe
3e, 55%
3f
3g, 31%
3h, 28%
,
46%
Cl
Ar
Ar
Ar
N
N
H
Br
N
N
N
N
Ar
Ar
H
H
N
N
Me
Me
Me
H
3i
3j, 73%
3k
3l
, 85%
, 83%
, 78%
Ph
Ar
N
N
H
N
N
H
N
Ar
Ar
N
N
H
N
N
3m
N
H
, 80%
CF3
3o, 38%d
3p, 50%d
3n
, 65%
Me
N
N
N
N
N
Ar
Me
Ar
N
H
N
N
HN
HN
H
Ar
Ar
N
e
e
3q, 45%d
, 43%
3t
f
3r
3s
, 52%
, 22%
Reaction conditions: 1a–1t (0.2 mmol), 2a (0.6 mmol), KOtBu (0.4
a
mmol), MTBE (1 mL) under N2 atmosphere at 130 oC for 20 h in pressure
b
tubes (see experimental section for details). Yield after flash column
chromatography. Gram-scale (1 g, 6 mmol) reaction. KOtBu (0.25
c
d
Table 1. Optimization of Reaction Conditionsa
mmol) and THF (1 mL) were used. e DMF was used as a reaction solvent
f
instead of MTBE. KHMDS (0.2 mmol) and THF were used instead of
KOtBu and MTBE.
With the optimal reaction conditions in hand, the scope of
azine-N-oxides 1a–1t used in the reaction with 2a was exam-
ined (Scheme 2). C6-substituted and C5,C8-disubstituted
quinoline-N-oxides 1b–1e with both electron-rich and elec-
tron-deficient groups were found to be viable substrates in this
coupling reaction, furnishing the desired products 3b–3e. It
should be mentioned that the reaction can be readily scaled up
and performed on a 1 g (6 mmol) scale to provide 3a in 86%
yield. C4-substituted quinoline-N-oxides 1f and 1g were found
entry
reagent (equiv.)
2a (equiv.)
solvent
yield(%)b
2
3
3
3
1
2
3
4
KOtBu (2)
KOtBu (2)
KOtBu (3)
NaOtBu (2)
THF
THF
THF
THF
36
74
73
6
ACS Paragon Plus Environment

Page 3 of 11
The Journal of Organic Chemistry
1
2
3
4
to be relatively less reactive under the current reaction condi-
This method allows the late-stage C–H amination reaction
5
tions. We were pleased to observe that a sterically congested
quinoline-N-oxide 1h was also coupled with 2a to generate 3h,
albeit in 28% yield. Recently, 8-methyl quinolines have been
widely utilized in benzylic C(sp3)–H functionalization reac-
tions under transition-metal catalysis.12 Inspired by the ap-
plicability of 8-methyl quinolines, we performed the reaction
of 8-methyl-quinoline-N-oxides 1i–1k with 2a, which provid-
ed the corresponding C2-aminated 8-methyl-quinolines 3i–3k
in high yields. In addition, π-extended quinoline-N-oxides
derived from benzo[f]quinoline, phenanthridine and 1,10-
phenanthroline were also compatible in this transformation
and gave the desired products 3l–3n in 65–80% yields. The
current method could be applied to the pyridine-N-oxides 1o–
1q under slightly modified reaction conditions, furnishing C2-
aminated pyridines 3o–3q. Particular noteworthy are the syn-
thesized unsymmetrical phenanthroline 3n and bipyridines 3p
and 3q, which can be readily applied as bidentate ligands in
the metal-catalyzed reactions. It should be noted that this
methodology is not only limited to quinoline- and pyridine-N-
oxides. Other azine-N-oxides containing quinoxaline, isoquin-
oline, and phthalazine moieties also participated in this site-
selective C–H amination reaction to give 3r–3t under the
standard or modified reaction conditions.
of commercially available N-heterocyclic drug molecules
(Scheme 4). For example, quinidine-N-oxide 5a containing a
quinoline scaffold was smoothly coupled with 2a to furnish 6a
in 72% yield. In addition, an N-oxide derivative of fasudil, a
RhoA/Rho kinase (ROCK) inhibitor, was selectively aminated
at the C1-position to give 6b in 60% yield.
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
Scheme 4. Late-Stage C–H Amination
N
N
MeO
MeO
standard
conditions
MeO
MeO
Cbz
Me
+
2a
N
O
H
N
N
H
5a from quinidine
6a
, 72%
N
Cbz
N
N
SO2
N
standard
SO2
conditions
2a
+
N
DMF
N
HN
O
H
Me
6b
, 60%
5b from fasudil
8-Aminoquinoline is recognized as a ubiquitous framework
in drug discovery. Moreover, 2,8-diaminoquinoline is also
known as a pivotal core found in biologically relevant mole-
cules such as crenolanib.13 To highlight the utility of our de-
veloped protocol, we performed sequential C–H amination
reactions of quinoline-N-oxide (1a). The iridium(III)-catalyzed
redox-neutral C8-amination14 and subsequent reductive C2-
amination using an acyl azide 2a resulted in the formation of
2,8-diaminoquinoline derivative 7b (Scheme 5).
Scheme 3. Scope of Acyl Azidesa
MeO
MeO
O
KOtBu, MTBE
130 oC, 20 h
+
R
N3
R
N
N
N
O
H
H
2b 2j
-
1b
4b-4j, %b
MeO
MeO
MeO
MeO
N
NH
R
N
NH
N
NH
N
NH
Scheme 5. Sequential C–H Amination
MeO
Me
OMe
4b, 92%
4c, 85% (R = tBu)
4d
4e, 95%
4f, 76%
, 38% (R = CF3)
MeO
NH
MeO
MeO
NH
MeO
N
NH
N
N
NH
N
To illustrate the synthetic utility of C2-aminated quinolines,
intermolecular and intramolecular reactions toward the for-
mation of various N-heterocycles were performed, as shown in
Scheme 6.15 A Pd(II)-catalyzed oxidative coupling reaction
between C2-aminoquinoline 3b and 1,3-diphenylacetylene
afforded 2-(1H-indol-1-yl)quinoline 8a in 79% yield.15a Inter-
estingly, benzimidazo[1,2-a]quinoline 8b, a promising struc-
tural core found in antitumor agents, could be generated by a
CAN-mediated intramolecular cyclization of 3b in 82% yield.
Meanwhile, the Pd(II)-catalyzed cyclizative carbonylation of
3b was used to provide quinolino-quinazolinone derivative 8c
in 45% yield.15b
Br
N
Me
c
c
4g
, 81%
4h
, 80%
4i
4j
, 36%
, 35%
a
Reaction conditions: 1b (0.2 mmol), 2b–2j (0.6 mmol), KOtBu (0.4
mmol), MTBE (1 mL) under N2 atmosphere at 130 oC for 20 h in pressure
b
tubes (see experimental section for details). Yield after flash column
chromatography. c KOtBu (0.25 mmol) was used.
Having a successful scope of azine-N-oxides, we further
evaluated the scope of acyl azides 2b–2j used in the reaction
with 1b, as shown in Scheme 3. Electron-rich acyl azides 2b,
2c, and 2e–2g were readily coupled with 1b giving C2-
aminated quinoline derivatives in high yields. However, elec-
tron-deficient acyl azide 2d was found to be less reactive un-
der the current reaction conditions. This observation may be
rationalized by the partial formation of an isocyanate interme-
diate during the Curtius rearrangement. In addition, 2-
naphthoyl azide (2h) also underwent the C–H amination reac-
tion to afford 4h in 80% yield. Moreover, this reaction was
also suitable for heterocyclic and alkyl acyl azides 2i and 2j,
albeit with decreased reactivity.
Scheme 6. Synthetic Transformations of C2-Aminated
Quinolines
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 11
1
2
3
4
5
6
7
8
9
1q),16d 1r,16e and 5a16f are in agreement with those reported in the
literatures.
5-Fluoro-8-methoxyquinoline 1-oxide (1e): 1.35 g (60%); yel-
low solid; mp = 110.4–110.9 C; H NMR (700 MHz, CDCl3) δ
8.31–8.28 (m, 1H), 7.68–7.63 (m, 1H), 7.15–7.12 (m, 1H), 7.05–
7.01 (m, 1H), 6.85–6.83 (m, 1H), 3.87–3.83 (m, 3H); 13C{1H}
NMR (175 MHz, CDCl3) δ 151.4 (d, JC-F = 245.3 Hz), 149.6 (d,
o
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
JC-F = 4.5 Hz), 138.3, 133.8 (d, JC-F = 8.4 Hz), 123.8 (d, JC-F
20.1 Hz), 121.3, 117.3, 111.7 (d, JC-F = 20.6 Hz), 110.1 (d, JC-F
7.2 Hz); IR (KBr) υ 3086, 3005, 2832, 1980, 1788, 1566, 1455,
1384, 1271, 1182, 1068, 939 cm-1; HRMS (quadrupole, EI) calcd
for C10H8FNO2 [M]+ 193.0534, found 193.0536.
=
=
4-Chloroquinoline 1-oxide (1g): 1.33 g (74%); white solid; mp
= 134.3–135.2 oC; 1H NMR (700 MHz, CDCl3) δ 8.41 (d, J = 9.1
Hz, 1H), 8.34 (d, J = 6.3 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.27
(d, J = 6.3 Hz, 1H); 13C{1H} NMR (175 MHz, CDCl3) δ 141.9,
134.8, 130.8, 129.4, 129.3, 127.7, 124.9, 120.8, 120.1; IR (KBr) υ
3123, 3082, 1643, 1613, 1560, 1502, 1447, 1370, 1303, 1252,
1228, 1059 cm-1; HRMS (quadrupole, EI) calcd for C9H6ClNO
[M]+ 179.0133, found 179.0130.
Conclusion
In conclusion, we have disclosed a transition-metal-free re-
ductive C2-amination reaction of azine-N-oxides with acyl
azides. In view of its mechanistic pathway, isocyanates de-
rived from acyl azides via a Curtius rearrangement undergo a
[3+2] dipolar cycloaddition reaction with polar N-oxides to
afford aminated azines. Notably, the utility of this process has
been demonstrated using late-stage and sequential amination
reactions of complex bioactive compounds such as quinidine
and fasudil. The direct transformation of synthesized products
into bioactive N-heterocycles illustrates the importance of this
newly developed protocol.
7-Bromo-8-methylquinoline 1-oxide (1j): 1.48 g (62%); yellow
o
1
solid; mp = 139.1–140.2 C; H NMR (700 MHz, CDCl3) δ 8.38
(d, J = 6.3 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.4 Hz,
1H), 7.40 (d, J = 8.4 Hz, 1H), 7.16–7.14 (m, 1H), 3.23 (s, 3H);
13C{1H} NMR (175 MHz, CDCl3) δ 141.8, 138.1, 133.0, 132.7,
131.3, 129.2, 126.8, 126.2, 120.9, 23.0; IR (KBr) υ 3064, 2927,
2850, 1692, 1553, 1408, 1330, 1289, 1247, 1167, 1042, 982, 815
cm-1; HRMS (quadrupole, EI) calcd for C10H8BrNO [M]+
236.9784, found 236.9789.
6-Chloro-8-methylquinoline 1-oxide (1k): 0.93 g (48%); yellow
o
1
solid; mp = 116.2–116.8 C; H NMR (700 MHz, CDCl3) δ 8.36
(d, J = 5.6 Hz, 1H), 7.62 (d, J = 2.8 Hz, 1H), 7.53 (d, J = 7.7 Hz,
1H), 7.36–7.35 (m, 1H), 7.20 (dd, J = 8.4, 6.3 Hz, 1H), 3.15 (s,
3H); 13C{1H} NMR (175 MHz, CDCl3) δ 140.1, 137.4, 136.1,
133.8, 133.4, 133.2, 125.2, 125.2, 121.8, 24.7; IR (KBr) υ 3059,
2928, 1670, 1570, 1428, 1373, 1293, 1221, 1131, 1055, 993, 819
cm-1; HRMS (quadrupole, EI) calcd for C10H8ClNO [M]+
193.0289, found 193.0293.
EXPERIMENTAL SECTION
General Information. Commercially available reagents were
used without additional purification, unless otherwise stated.
Sealed tubes (13 × 100 mm2) were purchased from Fischer Scien-
tific and dried in oven for overnight and cooled at room tempera-
ture prior to use. Thin layer chromatography was carried out using
plates coated with Kieselgel 60F254 (Merck). For flash column
chromatography, E. Merck Kieselgel 60 (230–400 mesh) was
used. Nuclear magnetic resonance spectra (1H and 13C NMR)
were recorded on a Bruker Unity 400, 500 and 700 spectrometers
in CDCl3, CD3OD and DMSO-d6 solution and chemical shifts are
reported as parts per million (ppm). Resonance patterns are re-
ported with the notations s (singlet), d (doublet), dd (doublet of
doublets), td (triplet of doublets), t (triplet), q (quartet), and m
(multiplet). In addition, the notation br is used to indicate a broad
signal. Coupling constants (J) are reported in hertz (Hz). IR spec-
tra were recorded on a Varian 2000 Infrared spectrophotometer
and are reported as cm-1. High-resolution mass spectra (HRMS)
were recorded on a JEOL JMS-600 spectrometer.
Benzo[f]quinoline 4-oxide (1l): 1.41 g (72%); white solid; mp
o
1
= 138.0–139.2 C; H NMR (700 MHz, CDCl3) δ 8.63–8.52 (m,
2H), 8.43–8.35 (m, 2H), 7.92–7.84 (m, 2H), 7.61 (s, 2H), 7.35 (s,
1H); 13C{1H} NMR (175 MHz, CDCl3) δ 140.8, 135.9, 131.9,
131.8, 128.8, 128.6, 128.3, 128.2, 127.8, 123.0, 121.1, 120.3,
116.9; IR (KBr) υ 3053, 1587, 1494, 1426, 1321, 1240, 1185,
1064, 912, 802 cm-1; HRMS (quadrupole, EI) calcd for C13H9NO
[M]+ 195.0679, found 195.0682.
9-(Trifluoromethyl)-1,10-phenanthroline 1-oxide (1n): 1.29 g
o
1
(49%); yellow solid; mp = 194.9–195.8 C; H NMR (700 MHz,
CDCl3) δ 8.66 (d, J = 6.3 Hz, 1H), 8.37 (d, J = 8.4 Hz, 1H), 7.92
(d, J = 7.7 Hz, 1H), 7.80 (s, 2H), 7.71 (d, J = 7.7 Hz, 1H), 7.47
(dd, J = 7.7, 6.3 Hz, 1H); 13C{1H} NMR (175 MHz, CDCl3) δ
146.8 (q, JC-F = 35.3 Hz), 141.5, 141.1, 137.8, 137.5, 133.5, 129.6,
128.6, 128.1, 123.9, 123.5, 121.3 (q, JC-F = 273.3 Hz), 119.2 (d,
JC-F = 1.9 Hz); IR (KBr) υ 3068, 2924, 2854, 1627, 1562, 1407,
1336, 1261, 1181, 1120, 1103, 849 cm-1; HRMS (quadrupole, EI)
calcd for C13H7F3N2O [M]+ 264.0505, found 264.0499.
General procedure for the synthesis of azine-N-oxides (1a–1t,
5a and 5b). To an oven-dried round bottom flask charged with
azines (10 mmol, 100 mol %) in CH2Cl2 (0.3 M) was added m-
CPBA (77% w/w, 11 mmol, 110 mol %) portionwise over 15 min
at room temperature. The reaction mixture was allowed to stir for
16 h at room temperature. PPh3 (5 mmol, 50 mol %) was then
added to reduce any unreacted peracid and the mixture was fur-
ther stirred for 2 h at room temperature. The solvent was evapo-
rated under reduced pressure. The residue was purified by flash
column chromatography (CH2Cl2/MeOH = 30:1) to afford the
corresponding azine-N-oxides. The spectral and physical data of
azine-N-oxides (1a–1d, 1f, 1h, 1i),16a (1m, 1t),16b (1o, 1s),16c (1p,
5-((4-((Benzyloxy)carbonyl)-1,4-diazepan-1-
yl)sulfonyl)isoquinoline 2-oxide (5b): 1.81 g (41%); yellow sticky
1
solid; H NMR (700 MHz, CDCl3) δ 9.34 (d, J = 3.5 Hz, 1H),
8.68 (t, J = 6.3 Hz, 1H), 8.39 (t, J = 6.3 Hz, 1H), 8.31 (d, J = 7.0
Hz, 1H), 8.20–8.18 (m, 1H), 7.69–7.67 (m, 1H), 7.34–7.29 (m,
5H), 5.08–5.07 (m, 2H), 3.64–3.60 (m, 2H), 3.59–3.56 (m, 2H),
ACS Paragon Plus Environment

Page 5 of 11
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
3.45–3.41 (m, 2H), 3.38 (t, J = 6.3 Hz, 2H), 2.00–1.92 (m, 2H);
with dichloromethane (10 mL). The filtrate was concentrated
13C{1H} NMR (175 MHz, CDCl3) δ 155.7, 155.4, 153.3, 145.2,
136.5, 136.4, 134.3, 134.2, 133.5, 133.0, 132.9, 131.5, 129.3,
129.2, 128.5, 128.1, 128.1, 127.9, 127.8, 125.9, 125.8, 117.4,
117.3, 67.4, 67.3, 49.8, 49.7, 49.4, 47.5, 47.4, 46.0, 45.7, 28.6,
28.1; IR (KBr) υ 2923, 2140, 1692, 1625, 1477, 1419, 1326, 1224,
1131, 996 cm-1; HRMS (quadrupole, EI) calcd for C22H23N3O5S
[M]+ 441.1353, found 441.1360.
under reduced pressure. The residue was purified by flash column
chromatography (n-hexanes/EtOAc = 3:1) to afford 44.5 mg of 3a
in 95% yield. The residue of 3b–3m, 3s and 4b–4h was purified
by flash column chromatography (n-hexanes/EtOAc = 3:1). The
residue of 3n, 3r, 6a, and 6b were purified by flash column chro-
matography (n-hexanes/EtOAc = 1:1). It should be noted that
compound 6b was synthesized by using DMF (1 mL) solvent
instead of t-butylmethyl ether (MTBE).
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 the synthesis of acyl azides (2a–2j). To
an oven-dried round bottom flask charged with aryl carbamoyl
chlorides (20 mmol, 100 mol %) and sodium azide (30 mmol, 150
mol %) was added acetone/H2O (2:1 v/v, 0.7 M) at room tempera-
ture. The reaction mixture was allowed to stir for 12 h at room
temperature. The reaction mixture was extracted with EtOAc. The
organic layers were washed with brine, dried over MgSO4, filtered
and concentrated under reduced pressure. The residue was puri-
fied by flash column chromatography (n-hexanes/EtOAc = 20:1)
to afford the corresponding acyl azides. The spectral and physical
data of acyl azides (2a–2e and 2i) are in agreement with those
reported in the literature.17
General procedure for the amination of azine-N-oxides using
acyl azides (3o–3q, 3t, 4i, and 4j). To an oven-dried sealed tube
charged with acyl azide (0.6 mmol, 300 mol %) and THF (1 mL)
under air at room temperature and allowed to stir at 110 oC for 2 h,
and cooled to room temperature. Then azine N-oxide (0.2 mmol,
100 mol %) was added in the reaction mixture and allowed to stir
o
on oil bath at 130 C for 12 h, and cooled to room temperature.
Next, a solution of KOtBu (0.25 mmol, 125 mol %) in THF (0.25
mL) was added dropwise to the reaction mixture at 0 oC. The
reaction mixture was allowed to stir at room temperature for 2 h.
The reaction mixture was filtered through celite and washed with
dichloromethane (10 mL). The filtrate was concentrated under
reduced pressure. The residue of 3o–3q, 3t and 4i was purified by
flash column chromatography (n-hexanes/EtOAc = 1:1). The
residue of 4j was purified by flash column chromatography (n-
hexanes/EtOAc = 3:1).
3,4-Dimethoxybenzoyl azide (2f): 3.15 g (76%); white solid;
mp = 75.6–76.5 oC; 1H NMR (700 MHz, CDCl3) δ 7.63–7.62 (m,
1H), 7.47 (s, 1H), 6.85–6.83 (m, 1H), 3.90–3.89 (m, 6H); 13C{1H}
NMR (175 MHz, CDCl3) δ 171.5, 154.2, 148.8, 123.9, 123.1,
111.3, 110.2, 56.0, 55.9; IR (KBr) υ 3297, 3092, 2939, 2843,
2704, 2622, 2258, 2133, 1671, 1590, 1509, 1415, 1241, 1142,
1014 cm-1; HRMS (quadrupole, EI) calcd for C9H9N3O3 [M]+
207.0639, found 207.0635.
N-(p-Tolyl)quinolin-2-amine (3a): 44.5 mg (95%); yellow sol-
id; mp = 102.5–103.2 oC; 1H NMR (400 MHz, CDCl3) δ 7.89 (d,
J = 8.8 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.64–7.56 (m, 2H), 7.39
(d, J = 8.0 Hz, 2H), 7.29 (t, J = 7.6 Hz, 1H), 7.17 (d, J = 8.0 Hz,
2H), 6.96 (d, J = 9.2 Hz, 1H), 2.35 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 154.6, 146.7, 138.1, 137.0, 133.4, 130.0, 129.8,
127.4, 125.8, 123.8, 123.1, 121.5, 111.2, 20.8; IR (KBr) υ 3359,
2925, 2835, 1606, 1512, 1321, 1248, 1154, 956, 788, 757 cm-1;
HRMS (orbitrap, ESI) calcd for C16H15N2 [M+H]+ 235.1235,
found 235.1232.
3-Bromo-4-methylbenzoyl azide (2g): 3.41 g (71%); colorless
oil; 1H NMR (700 MHz, CDCl3) δ 8.18 (d, J = 2.1 Hz, 1H), 7.85
(d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 2.46 (s, 3H);
13C{1H} NMR (175 MHz, CDCl3) δ 171.1, 145.0, 133.2, 130.9,
130.0, 128.1, 125.1, 23.3; IR (KBr) υ 2348, 2265, 2193, 2132,
1671, 1599, 1558, 1448, 1380, 1276, 1227, 1205, 1176, 1139,
1010, 804 cm-1; HRMS (quadrupole, EI) calcd for C8H6BrN3O
[M]+ 238.9689, found 238.9690.
6-Methoxy-N-(p-tolyl)quinolin-2-amine (3b): 447.5 mg (90%);
o
1
yellow solid; mp = 111.2–113.8 C; H NMR (400 MHz, CDCl3)
δ 7.83 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.37 (d, J =
8.0 Hz, 2H), 7.27–7.26 (m, 1H), 7.16 (d, J = 8.0 Hz, 2H), 6.99–
6.95 (m, 2H), 6.83 (s, 1H), 3.89 (s, 3H), 2.34 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 155.5, 153.3, 142.6, 137.5, 137.0,
132.9, 129.8, 127.5, 124.4, 121.5, 121.0, 111.5, 106.3, 55.5, 20.8;
IR (KBr) υ 3401, 3196, 2998, 2918, 2850, 2731, 1601, 1572, 1509,
1459, 1394, 1348, 1317, 1262, 1226, 1159, 1112, 1030, 826, 807
cm-1; HRMS (orbitrap, ESI) calcd for C17H17N2O [M+H]+
265.1341, found 265.13382.
2-Naphthoyl azide (2h): 1.85 g (47%); white solid; mp = 78.6–
o
1
79.9 C; H NMR (700 MHz, CDCl3) δ 8.58 (d, J = 0.7 Hz, 1H),
8.02 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.87 (d, J = 8.4
Hz, 2H), 7.61 (t, J = 8.4 Hz, 1H), 7.55 (t, J = 8.4 Hz, 1H);
13C{1H} NMR (175 MHz, CDCl3) δ 172.4, 136.1, 132.3, 131.4,
129.5, 128.9, 128.4, 127.8, 127.7, 126.9, 124.4; IR (KBr) υ 3058,
2261, 2131, 1682, 1626, 1598, 1466, 1353, 1273, 1262, 1182,
1124, 1029, 996, 939 cm-1; HRMS (quadrupole, EI) calcd for
C11H7N3O [M]+ 197.0584, found 197.0588.
(3r,5r,7r)-Adamantane-1-carbonyl azide (2j): 1.68 g (41%);
o
1
6-Chloro-N-(p-tolyl)quinolin-2-amine (3c): 39.2 mg (73%);
brown solid; mp = 108.1–110.2 oC; 1H NMR (400 MHz, CDCl3) δ
7.78 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.59 (s, 1H),
7.49 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0
Hz, 2H), 6.94 (d, J = 9.2 Hz, 1H), 2.35 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 154.9, 146.0, 137.0, 136.7, 133.4, 130.3,
129.8, 128.0, 127.9, 126.1, 124.5, 121.4, 112.2, 20.8; IR (KBr) υ
3241, 3026, 2919, 2855, 1671, 1617, 1509, 1489, 1369, 1348,
1243, 1191, 1076, 932, 878, 826, 807 cm-1; HRMS (orbitrap, ESI)
calcd for C16H14ClN2 [M+H]+ 269.0845, found 269.0841.
white solid; mp = 59.4–60.1 C; H NMR (700 MHz, CDCl3) δ
2.01 (s, 3H), 1.83 (s, 6H), 1.72–1.65 (m, 6H); 13C{1H} NMR (175
MHz, CDCl3) δ 185.3, 45.2, 42.7, 38.5, 36.2, 35.7, 27.8; IR (KBr)
υ 2906, 2852, 2244, 2129, 1708, 1503, 1453, 1354, 1179, 1057,
1006, 971, 877 cm-1; HRMS (quadrupole, EI) calcd for
C11H15N3O [M]+ 205.1210, found 205.1210.
General procedure for the amination of azine-N-oxides using
acyl azides (3a–3n, 3r, 3s, 4b–4h, 6a and 6b). To an oven-dried
sealed tube charged with 4-methylbenzoyl azide (2a) (96.7 mg,
0.6 mmol, 300 mol %) and t-butyl methyl ether (1 mL) under air
at room temperature. The reaction mixture was allowed to stir at
6-Fluoro-N-(p-tolyl)quinolin-2-amine (3d): 25.7 mg (51%);
o
1
o
yellow solid; mp = 105.5–107.1 C; H NMR (400 MHz, CDCl3)
δ 7.83 (d, J = 8.8 Hz, 1H), 7.74–7.71 (m, 1H), 7.40 (d, J = 8.0 Hz,
2H), 7.34 (t, J = 9.2 Hz, 1H), 7.28–7.26 (m, 1H), 7.17 (d, J = 8.0
Hz, 2H), 6.97 (d, J = 8.8 Hz, 1H), 2.35 (s, 3H); 13C{1H} NMR
110 C for 2 h, and cooled to room temperature. Then quinoline
N-oxide (1a) (29.0 mg, 0.2 mmol, 100 mol %) and KOtBu (44.9
mg, 0.4 mmol, 200 mol %) was added in the reaction mixture
under air at room temperature. The reaction mixture was allowed
to stir on oil bath at 130 oC for 18 h, and cooled to room tempera-
ture. The reaction mixture was filtered through celite and washed
(100 MHz, CDCl3) δ 158.4 (d, JC-F = 241.2 Hz), 154.3 (d, JC-F
=
1.3 Hz), 144.3, 137.2, 137.0 (d, JC-F = 4.5 Hz), 133.2, 129.8, 128.2
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 11
1
2
3
4
5
6
7
8
9
(d, JC-F = 8.4 Hz), 124.0 (d, JC-F = 9.4 Hz), 121.2, 119.2 (d, JC-F
=
24.8 Hz), 112.3, 110.8 (d, JC-F = 21.7 Hz), 20.8; IR (KBr) υ 3367,
2926, 1665, 1622, 1608, 1571, 1512, 1401, 1356, 1319, 1245,
1137, 1107, 812 cm-1; HRMS (orbitrap, ESI) calcd for C16H14FN2
[M+H]+ 253.1141, found 253.1135.
2.35 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 153.4, 145.3,
137.5, 136.9, 136.7, 132.7, 132.4, 129.6, 127.1, 124.8, 120.1,
115.5, 112.4, 20.8, 17.9; IR (KBr) υ 3346, 3027, 2857, 2853,
1652, 1606, 1538, 1483, 1344, 1318, 1248, 1071, 862, 808, 784
cm-1; HRMS (orbitrap, ESI) calcd for C17H16BrN2 [M+H]+
327.0496, found 327.0493.
5-Fluoro-8-methoxy-N-(p-tolyl)quinolin-2-amine (3e): 31.0 mg
o
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
(55%); yellow solid; mp = 122.5–123.7 C; H NMR (400 MHz,
CDCl3) δ 8.11 (d, J = 9.2 Hz, 1H), 7.25 (d, J = 7.6 Hz, 2H), 7.18
(d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 6.8 Hz,
2H), 4.02 (s, 3H), 2.35 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 155.2, 152.5 (d, JC-F = 244.3 Hz), 149.7 (d, JC-F = 2.9 Hz), 139.5,
136.8, 134.0, 131.2 (d, JC-F = 4.0 Hz), 130.0, 122.2, 114.8 (d, JC-F
= 17.7 Hz), 110.5 (d, JC-F = 2.2 Hz), 107.4 (d, JC-F = 9.0 Hz),
105.5 (d, JC-F = 21.1 Hz), 56.1, 20.8; IR (KBr) υ 3351, 2920, 2855,
1681, 1604, 1535, 1509, 1483, 1415, 1312, 1248, 1154, 1091,
1041, 996, 945, 806 cm-1; HRMS (orbitrap, ESI) calcd for
C17H16FN2O [M+H]+ 283.1246, found 283.1245.
6-Chloro-8-methyl-N-(p-tolyl)quinolin-2-amine (3k): 47.0 mg
o
1
(83%); orange solid; mp = 137.5–139.1 C; H NMR (700 MHz,
CDCl3) δ 7.76 (d, J = 9.1 Hz, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.45
(d, J = 2.1 Hz, 1H), 7.41–7.40 (m, 1H), 7.18 (d, J = 8.4 Hz, 2H),
6.87 (d, J = 9.1 Hz, 1H), 6.68 (brs, 1H), 2.68 (s, 3H), 2.35 (s, 3H);
13C{1H} NMR (175 MHz, CDCl3) δ 153.4, 145.1, 137.6, 136.8,
136.7, 132.4, 130.2, 129.6, 127.6, 124.2, 123.8, 120.1, 112.4, 20.8,
17.9; IR (KBr) υ 3410, 3027, 2920, 2854, 1703, 1661, 1654, 1533,
1342, 1317, 1148, 1071, 894, 861, 806, 783 cm-1; HRMS (orbitrap,
ESI) calcd for C17H16ClN2 [M+H]+ 283.1002, found 283.1000.
N-(p-Tolyl)benzo[f]quinolin-3-amine (3l): 44.4 mg (78%);
brown solid; mp = 205.1–206.2 oC; 1H NMR (700 MHz, CDCl3) δ
8.68 (d, J = 9.1 Hz, 1H), 8.42 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 9.1
Hz, 1H), 7.88 (d, J = 7.7 Hz, 1H), 7.76 (d, J = 9.1 Hz, 1H), 7.63–
7.61 (m, 1H), 7.52 (td, J = 7.7, 0.7 Hz, 1H), 7.41 (d, J = 8.4 Hz,
2H), 7.19 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 9.1 Hz, 1H), 6.93 (brs,
1H), 2.37 (s, 3H); 13C{1H} NMR (175 MHz, CDCl3) δ 155.2,
147.6, 137.5, 133.0, 132.6, 130.8, 130.2, 130.1, 129.8, 128.6,
126.9, 126.8, 125.3, 121.5, 121.2, 119.3, 109.5, 20.8; IR (KBr) υ
3411, 3053, 2907, 2838, 1617, 1606, 1573, 1509, 1467, 1402,
1321, 1240, 1180, 811 cm-1; HRMS (orbitrap, ESI) calcd for
C20H17N2 [M+H]+ 285.1391, found 285.1388.
4-Methyl-N-(p-tolyl)quinolin-2-amine (3f): 22.8 mg (46%);
brown solid; mp = 117.5–119.2 oC; 1H NMR (700 MHz, CDCl3) δ
7.80 (dd, J = 8.4, 1.4 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.57 (t, J
= 7.0 Hz, 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.30 (t, J = 7.0 Hz, 1H),
7.18 (d, J = 7.7 Hz, 2H), 6.82 (s, 1H), 2.57 (s, 3H), 2.35 (s, 3H);
13C{1H} NMR (175 MHz, CDCl3) δ 154.5, 147.0, 146.1, 137.2,
133.2, 129.8, 129.7, 126.5, 124.2, 123.6, 122.8, 121.6, 111.2, 20.8,
18.9; IR (KBr) υ 3405, 3059, 2919, 2853, 1605, 1511, 1474, 1447,
1394, 1327, 1246, 1193, 1130, 1034, 850, 814 cm-1; HRMS (or-
bitrap, ESI) calcd for C17H17N2 [M+H]+ 249.1391, found
249.1386.
4-Chloro-N-(p-tolyl)quinolin-2-amine (3g): 16.7 mg (31%);
N-(p-Tolyl)phenanthridin-6-amine (3m): 45.5 mg (80%);
brown solid; mp = 201.1–202.9 oC; 1H NMR (400 MHz, CDCl3) δ
8.57 (d, J = 8.4 Hz, 1H), 8.38 (d, J = 8.0 Hz, 1H), 8.03 (d, J = 8.0
Hz, 1H), 7.83–7.78 (m, 2H), 7.72 (d, J = 8.0 Hz, 2H), 7.64 (t, J =
7.6 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H),
7.21 (d, J = 8.0 Hz, 2H), 2.37 (s, 3H); 13C{1H} NMR (125 MHz,
DMSO-d6) δ 151.0, 138.3, 133.5, 130.8, 128.9, 128.8, 127.4,
126.6, 125.6, 124.0, 123.2, 122.8, 122.4, 121.3, 121.2, 120.7,
119.2, 20.5; IR (KBr) υ 3446, 3302, 3060, 2921, 2854, 1616,
1584, 1509, 1465, 1423, 1405, 1350, 1317, 1232, 1157, 1037, 815
cm-1; HRMS (orbitrap, ESI) calcd for C20H17N2 [M+H]+ 285.1391,
found 285.1389.
o
yellow solid; mp = 109.5–110.1 C; 1H NMR (500 MHz, CDCl3)
δ 8.03 (d, J = 8.5 Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.62 (t, J =
8.0 Hz, 1H), 7.37–7.34 (m, 3H), 7.20 (d, J = 8.0 Hz, 2H), 7.07 (s,
1H), 6.88 (brs, 1H), 2.36 (s, 3H); 13C{1H} NMR (175 MHz,
CDCl3) δ 154.6, 148.4, 143.5, 136.7, 133.9, 130.8, 130.0, 126.7,
124.0, 123.6, 122.3, 121.9, 110.7, 20.9; IR (KBr) υ 3398, 3060,
3026, 2923, 2851, 1604, 1563, 1533, 1420, 1343, 1248, 1181,
1148, 1029, 956, 869, 813, 796 cm-1; HRMS (orbitrap, ESI) calcd
for C16H14ClN2 [M+H]+ 269.0845, found 269.0841.
3-Methyl-N-(p-tolyl)quinolin-2-amine (3h): 13.9 mg (28%);
o
yellow solid; mp = 118.9–119.8 C; 1H NMR (400 MHz, CDCl3)
δ 7.81 (d, J = 8.0 Hz, 1H), 7.74–7.72 (m, 3H), 7.59 (d, J = 8.0 Hz,
1H), 7.52 (t, J = 7.6 Hz, 1H), 7.29–7.27 (m, 1H), 7.18 (d, J = 8.0
Hz, 2H), 6.50 (brs, 1H), 2.39 (s, 3H), 2.35 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 152.8, 146.2, 137.7, 136.4, 131.9, 129.3,
128.5, 126.6, 126.4, 124.3, 122.9, 119.9, 119.8, 20.8, 17.7; IR
(KBr) υ 3449, 3303, 3026, 2921, 2853, 1735, 1660, 1629, 1570,
1547, 1473, 1433, 1351, 1309, 1251, 1111, 1007, 900, 810 cm-1;
HRMS (orbitrap, ESI) calcd for C17H17N2 [M+H]+ 249.1391,
found 249.1390.
N-(p-Tolyl)-9-(trifluoromethyl)-1,10-phenanthrolin-2-amine
(3n): 46.0 mg (65%); yellow solid; mp = 212.5–213.2 oC; 1H
NMR (700 MHz, CDCl3) δ 8.37 (d, J = 8.4 Hz, 1H), 7.99 (d, J =
9.1 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H),
7.58 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.21 (t, J = 8.4
Hz, 3H), 2.37 (s, 3H); 13C{1H} NMR (175 MHz, CDCl3) δ 156.3,
146.8 (q, JC-F = 33.9 Hz), 144.2, 137.9, 137.7, 137.0, 133.8, 130.3,
130.0, 128.6, 125.8, 123.6, 122.0, 121.9 (q, JC-F = 272.8 Hz),
121.2, 118.5 (q, JC-F = 2.3 Hz), 111.3, 20.9; IR (KBr) υ 3336,
2991, 2853, 1705, 1607, 15914, 1514, 1466, 1369, 1333, 1243,
1159, 1112, 1064, 851, 815 cm-1; HRMS (orbitrap, ESI) calcd for
C20H15F3N3 [M+H]+ 354.1219, found 354.1218.
8-Methyl-N-(p-tolyl)quinolin-2-amine (3i): 42.2 mg (85%);
brown solid; mp = 127.5–129.0 oC; 1H NMR (700 MHz, CDCl3) δ
7.87 (d, J = 9.1 Hz, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 7.7
Hz, 1H), 7.46 (d, J = 7.0 Hz, 1H), 7.20–7.18 (m, 3H), 6.87 (d, J =
8.4 Hz, 1H), 6.68 (brs, 1H), 2.72 (s, 3H), 2.36 (s, 3H); 13C{1H}
NMR (175 MHz, CDCl3) δ 153.3, 146.5, 137.9, 137.8, 134.5,
132.0, 129.9, 129.5, 125.2, 123.7, 122.6, 119.9, 111.5, 20.8, 18.1;
IR (KBr) υ 3401, 3044, 3019, 2920, 2863, 1649, 1536, 1427, 1343,
1318, 1244, 1159, 1143, 1060, 814 cm-1; HRMS (orbitrap, ESI)
calcd for C17H17N2 [M+H]+ 249.1391, found 249.1389.
4-Phenyl-N-(p-tolyl)pyridin-2-amine (3o): 18.1 mg (35%);
o
1
white solid; mp = 84.1–86.2 C; H NMR (400 MHz, CDCl3) δ
8.19 (s, 1H), 7.56–7.55 (m, 2H), 7.46–7.41 (m, 2H), 7.26–7.23 (m,
4H), 7.17 (d, J = 8.4 Hz, 2H), 7.05 (s, 1H), 6.96 (s, 1H), 2.34 (s,
3H); 13C{1H} NMR (125 MHz, CDCl3) δ 156.9, 150.5, 148.3,
138.8, 137.6, 133.1, 129.9, 128.9, 128.8, 126.9, 121.5, 113.3,
105.5, 20.8; IR (KBr) υ 3392, 2855, 2803, 1655, 1558, 1522,
1451, 1333, 1322, 1188, 1111, 1025, 851 cm-1; HRMS (orbitrap,
ESI) calcd for C18H17N2 [M+H]+ 261.1391, found 261.1390.
7-Bromo-8-methyl-N-(p-tolyl)quinolin-2-amine (3j): 47.8 mg
o
1
(73%); yellow solid; mp = 106.5–109.0 C; H NMR (700 MHz,
CDCl3) δ 7.76 (d, J = 9.1 Hz, 1H), 7.61 (d, J = 2.1 Hz, 1H), 7.57–
7.53 (m, 3H), 7.18 (d, J = 7.0 Hz, 1H), 6.71 (brs, 1H), 2.67 (s, 3H),
N-(p-Tolyl)-[2,2'-bipyridin]-6-amine (3p): 26.2 mg (50%); yel-
low solid; mp = 85.0–86.8 oC; 1H NMR (400 MHz, CDCl3) δ 8.67
ACS Paragon Plus Environment

Page 7 of 11
The Journal of Organic Chemistry
1
2
3
4
(d, J = 8.4 Hz, 1H), 8.32 (d, J = 8.0 Hz, 1H), 7.82–7.79 (m, 2H),
MHz, CDCl3) δ 7.84 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.8, Hz, 1H),
5
7.61 (t, J = 8.0 Hz, 1H), 7.31–7.27 (m, 3H), 7.17 (d, J = 8.0 Hz,
2H), 6.83 (d, J = 8.4 Hz, 1H), 6.59 (brs, 1H), 2.34 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 156.3, 155.8, 154.6, 149.1,
138.6, 137.8, 136.8, 132.5, 129.8, 123.4, 121.0, 120.8, 112.1,
108.3, 20.8; IR (KBr) υ 33947, 3310, 3054, 29250, 2852, 1596,
1581, 1564, 1511, 1454, 1428, 1342, 1296, 1247, 1156, 1100, 985,
812, 775 cm-1; HRMS (orbitrap, ESI) calcd for C17H16N3 [M+H]+
262.1339, found 262.1338.
7.42–7.36 (m, 4H), 7.28–7.26 (m, 1H), 7.00–6.98 (m, 1H), 3.88 (s,
3H), 1.33 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 155.6,
153.0, 146.4, 161.8, 137.4, 137.1, 127.0, 126.1, 124.2, 121.6,
120.7, 111.6, 106.4, 55.5, 34.3, 31.4; IR (KBr) υ 3392, 2958,
2903, 2865, 1655, 1589, 1521, 1461, 1397, 1361, 1322, 1265,
1230, 1193, 1111, 1033, 831, 738 cm-1; HRMS (orbitrap, ESI)
calcd for C20H23N2O [M+H]+ 307.1805, found 307.1803.
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
6-Methoxy-N-(4-(trifluoromethyl)phenyl)quinolin-2-amine
(4d): 24.2 mg (38%); yellow solid; mp = 142.9–145.1 oC 1H
NMR (700 MHz, CDCl3) δ 7.91 (d, J = 8.4 Hz, 1H), 7.76 (d, J =
9.1, Hz, 1H), 7.73 (d, J = 8.4, Hz, 2H), 7.58 (d, J = 8.4, Hz, 2H),
7.30 (dd, J = 9.1, 2.8 Hz, 1H), 7.02 (d, J = 2.8 Hz, 1H), 6.97 (d, J
= 8.4, Hz, 1H), 3.90 (s, 3H); 13C{1H} NMR (175 MHz, CDCl3) δ
156.1, 151.6, 143.8, 142.6, 137.1, 128.3, 126.4 (q, JC-F = 3.3 Hz),
124.9, 124.4 (q, JC-F = 268.9 Hz), 123.5 (q, JC-F = 31.6 Hz), 121.8,
118.1, 112.7, 106.1, 55.5; IR (KBr) υ 3299, 3193, 3127, 3060,
2921, 2854, 1688, 1613, 1582, 1537, 1510, 1414, 1321, 1242,
1019, 813, 756 cm-1; HRMS (orbitrap, ESI) calcd for
C17H14F3N2O [M+H]+ 319.1058, found 319.1053.
4,4'-Dimethyl-N-(p-tolyl)-[2,2'-bipyridin]-6-amine (3q): 33.1
mg (57%); yellow solid; mp = 102.0–103.2 oC; 1H NMR (700
MHz, CDCl3) δ 8.61 (d, J = 4.9 Hz, 1H), 8.25 (t, J = 0.7 Hz, 1H),
7.75 (s, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.37–7.35 (m, 2H), 7.25 (d,
J = 7.7 Hz, 2H), 7.19–7.18 (m, 1H), 6.51 (s, 1H), 6.65 (brs, 1H),
2.51 (s, 3H), 2.43 (s, 3H), 2.40 (s, 3H); 13C{1H} NMR (175 MHz,
CDCl3) δ 156.1, 154.5, 149.7, 148.9, 147.8, 138.1, 132.5, 129.8,
124.3, 121.9, 121.1, 113.8, 108.4, 21.4, 21.3, 20.8; IR (KBr) υ
2923, 2854, 1597, 1563, 1513, 1453, 1404, 1291, 1186, 822 cm-1;
HRMS (orbitrap, ESI) calcd for C19H20N3 [M+H]+ 290.1657,
found 290.1654.
N-(p-Tolyl)quinoxalin-2-amine (3r): 20.3 mg (43%); brown sol-
6-Methoxy-N-(m-tolyl)quinolin-2-amine (4e): 50.3 mg (95%);
o
1
o
1
id; mp = 167.5–170.2 C; H NMR (700 MHz, CDCl3) δ 8.42 (s,
1H), 7.91 (dd, J = 8.4, 1.4 Hz, 1H), 7.77 (dd, J = 8.4, 1.4 Hz, 1H),
7.62–7.60 (m, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.46–7.44 (m, 1H),
7.20 (d, J = 8.4 Hz, 2H), 6.90 (brs, 1H), 2.36 (s, 3H); 13C{1H}
NMR (175 MHz, CDCl3) δ 149.6, 141.3, 138.2, 137.8, 136.4,
133.5, 130.2, 129.8, 128.8, 126.7, 125.3, 120.4, 20.8; IR (KBr) υ
3376, 1211, 3061, 2922, 2850, 1601, 1527, 1398, 1316, 1229,
1159, 1108, 1064, 1031, 831 cm-1; HRMS (orbitrap, ESI) calcd
for C15H14N3 [M+H]+ 236.1187, found 236.1185.
yellow solid; mp = 109.9–110.2 C; H NMR (700 MHz, CDCl3)
δ 7.83 (d, J = 8.4, Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.32 (d, J =
8.4 Hz, 1H), 7.29 (brs, 1H), 7.27 (d, J = 2.8 Hz, 1H), 7.26 (d, J =
2.8 Hz, 1H), 7.23 (t, J = 7.7 Hz, 1H), 7.00–6.99 (m, 2H), 6.89 (d,
J = 7.7 Hz, 1H), 6.81 (brs, 1H), 3.89 (s, 3H), 2.36 (s, 3H);
13C{1H} NMR (175 MHz, CDCl3) δ 155.5, 153.0, 143.1, 140.4,
139.0, 136.7, 129.0, 128.0, 124.5, 123.6, 121.4, 120.8, 117.2,
111.9, 106.2, 55.5, 21.5; IR (KBr) υ 3394, 3046, 2995, 2922,
2853, 1697, 1571, 1538, 1331, 1263, 1113, 1031, 848, 827, 773,
687 cm-1; HRMS (orbitrap, ESI) calcd for C17H17N2O [M+H]+
265.1341, found 265.1341.
N-(p-Tolyl)isoquinolin-1-amine (3s): 24.4 mg (52%); brown
solid; mp = 94.3–95.8 oC; 1H NMR (700 MHz, CDCl3) δ 8.07 (d,
J = 6.3 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H),
7.63 (t, J = 8.4 Hz, 1H), 7.54–7.51 (m, 3H), 7.17 (d, J = 8.4 Hz,
2H), 7.10 (d, J = 6.3 Hz, 2H), 7.06 (brs, 1H), 2.34 (s, 3H);
13C{1H} NMR (175 MHz, CDCl3) δ 152.6, 141.0, 137.7, 137.4,
132.4, 129.8, 129.5, 127.4, 126.3, 121.4, 120.8, 118.7, 113.0,
20.8; IR (KBr) υ 3297, 3049, 2917, 2851, 1709, 1624, 1595, 1509,
1393, 1321, 1230, 1143, 1057, 906, 862, 796 cm-1; HRMS (or-
bitrap, ESI) calcd for C16H15N2 [M+H]+ 235.1235, found
235.1231.
N-(3,4-Dimethoxyphenyl)-6-methoxyquinolin-2-amine
(4f):
47.2 mg (76%); yellow solid; mp = 159.7–161.2 oC; 1H NMR
(500 MHz, CDCl3) δ 7.81 (d, J = 9.0 Hz, 1H), 7.66 (d, J = 9.0 Hz,
1H), 7.26–7.24 (m, 2H), 6.98 (d, J = 2.5 Hz, 1H), 6.94 (dd, J = 8.5,
2.5 Hz, 1H), 6.89–6.82 (m, 3H), 3.90–3.88 (m, 9H); 13C{1H}
NMR (125 MHz, CDCl3) δ 155.4, 153.7, 149.3, 145.4, 142.8,
136.8, 133.8, 127.6, 124.3, 121.4, 113.4, 111.8, 111.5, 106.5,
106.3, 56.2, 55.9, 55.5; IR (KBr) υ 3372, 2996, 2928, 2853, 1641,
1462, 1401, 1362, 1227, 1161, 1132, 1113, 1027, 831, 743 cm-1;
HRMS (orbitrap, ESI) calcd for C18H19N2O3 [M+H]+ 311.1390,
found 311.1389.
N-(p-Tolyl)phthalazin-1-amine (3t): 10.4 mg (22%); yellow sol-
id; mp = 102.9–105.2 oC; 1H NMR (400 MHz, CD3OD) δ 8.94 (s,
1H), 8.41 (d, J = 8.0 Hz, 1H), 7.99–7.90 (m, 3H), 7.56 (d, J = 8.4
Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 2.33 (s, 3H); 13C{1H} NMR
(125 MHz, CDCl3:CD3OD, 5:1 v/v) δ 156.3, 148.3, 137.0, 136.0,
135.9, 133.4, 131.7, 130.6, 125.9, 125.4, 124.0, 24.5; IR (KBr) υ
3077, 3059, 2915, 1854, 1622, 1602, 1514, 1455, 1408, 1271,
1155, 817 cm-1; HRMS (orbitrap, ESI) calcd for C15H14N3
[M+H]+ 236.1183, found 236.1185.
N-(3-Bromo-4-methylphenyl)-6-methoxyquinolin-2-amine (4g):
55.6 mg (81%); yellow solid; mp = 129.1–130.1 oC; 1H NMR
(400 MHz, CDCl3) δ 7.85–7.83 (m, 2H), 7.72 (d, J = 9.2 Hz, 1H),
7.36 (d, J = 7.6 Hz, 1H), 7.28–7.26 (m, 1H), 7.17 (d, J = 8.0 Hz,
1H), 6.99 (s, 1H), 6.90 (d, J = 8.8 Hz, 1H), 6.69 (brs, 1H), 3.89 (s,
3H), 2.36 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 155.6,
152.4, 142.9, 139.4, 136.8, 131.6, 130.8, 128.2, 124.9, 124.6,
123.3, 121.5, 118.8, 112.0, 106.1, 55.5, 22.1; IR (KBr) υ 3406,
2923, 2853, 1617, 1566, 1539, 1422, 1393, 1229, 1161, 1113,
1032, 995, 829, 807 cm-1; HRMS (orbitrap, ESI) calcd for
C17H16BrN2O [M+H]+ 343.0441, found 343.0441.
6-Methoxy-N-phenylquinolin-2-amine (4b): 46.1 mg (92%);
o
brown solid; mp = 97.5–100.2 C; 1H NMR (700 MHz, CDCl3) δ
7.83 (d, J = 9.1 Hz, 1H), 7.72 (d, J = 9.1, Hz, 1H), 7.53 (dd, J =
8.4, 1.4 Hz, 2H), 7.35 (dd, J = 8.4, 7.0 Hz, 2H), 7.27 (dd, J = 9.1,
2.8 Hz, 1H), 7.06 (t, J = 7.0, Hz, 1H), 6.99–6.97 (m, 2H), 6.87
(brs, 1H), 3.88 (s, 3H); 13C{1H} NMR (175 MHz, CDCl3) δ 155.5,
152.9, 143.1, 140.5, 136.6, 129.1, 128.0, 124.6, 122.6, 121.3,
119.9, 111.9, 106.2, 55.4; IR (KBr) υ 3041, 3053, 3004, 2961,
1595, 1525, 1486, 1360, 1320, 1229, 1161, 1111, 1027, 996, 853,
829 cm-1; HRMS (orbitrap, ESI) calcd for C16H15N2O [M+H]+
251.1184, found 251.1186.
6-Methoxy-N-(naphthalen-2-yl)quinolin-2-amine (4h): 48.1 mg
o
1
(80%); brown solid; mp = 190.1–192.2 C; H NMR (500 MHz,
CDCl3) δ 8.14 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.82–7.76 (m,
4H), 7.52–7.44 (m, 2H), 7.39–7.35 (m, 1H), 7.30 (d, J = 8.4 Hz,
1H), 7.08 (d, J = 8.4 Hz, 1H), 7.02 (s, 1H), 3.90 (s, 3H); 13C{1H}
NMR (175 MHz, CDCl3) δ 155.8, 152.7, 142.4, 137.8, 137.1,
134.3, 130.1, 129.0, 127.7, 127.6, 127.1, 126.4, 124.6, 124.3,
121.6, 121.1, 115.6, 112.1, 106.3, 55.5; IR (KBr) υ 3398, 3055,
2948, 1678, 1586, 1531, 1361, 1240, 1229, 1162, 1113, 1032, 952,
N-(4-(tert-Butyl)phenyl)-6-methoxyquinolin-2-amine (4c): 52.1
mg (85%); brown solid; mp = 187.2–190.1 oC; 1H NMR (400
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 11
1
2
3
4
5
6
7
8
9
848, 831, 813 cm-1; HRMS (orbitrap, ESI) calcd for C20H17N2O
The filtrate was concentrated under reduced pressure. The residue
was purified by flash column chromatography (n-hexanes/EtOAc
= 3:1) to afford 1.21 g of 3a in 86% yield.
[M+H]+ 301.1341, found 301.1338.
6-Methoxy-N-(pyridin-3-yl)quinolin-2-amine (4i): 17.6 mg
o
1
(35%); brown solid; mp = 167.5–170.2 C; H NMR (400 MHz,
CD3OD + CDCl3) δ 8.95 (s, 1H), 8.48 (d, J = 8.4 Hz, 1H), 8.07 (s,
1H), 7.93 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.34 (dd, J
= 8.0, 4.8 Hz, 1H), 7.23 (dd, J = 8.8, 2.8 Hz, 1H), 7.08 (d, J = 2.4
Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 3.88 (s, 3H); 13C{1H} NMR
(100 MHz, CD3OD+CDCl3) δ 156.9, 153.5, 143.3, 141.5, 140.2,
137.7, 128.7, 126.6, 125.7, 124.9, 124.8, 121.9, 114.6, 107.1,
55.8; IR (KBr) υ 3295, 3193, 2949, 2924, 2852, 1616, 1543, 1471,
1409, 1363, 1292, 1235, 1162, 1116, 1030, 830, 802 cm-1; HRMS
(orbitrap, ESI) calcd for C15H14N3O [M+H]+ 252.1136, found
252.1135.
Experimental procedure for the synthesis of (7a). To an oven-
dried sealed tube charged with quinoline N-oxide (1a) (29.0 mg,
0.2 mmol, 100 mol %), [IrCp*Cl2]2 (3.2 mg, 0.004 mmol, 2.0
mol %), AcOH (3.6 mg, 0.06 mmol, 30 mol %) and 4-
methylbenzenesulfonyl azide (59.2 mg, 0.3 mmol, 150 mol %)
was added AgNTf2 (7.8 mg, 0.02 mmol, 10 mol %) and DCE (0.5
mL) under air at room temperature. The reaction mixture was
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
o
allowed to stir on oil bath at 50 C for 12 h, and cooled to room
temperature. The reaction mixture was diluted with EtOAc (3 mL)
and concentrated in vacuo. The residue was purified by flash col-
umn chromatography (n-hexanes/EtOAc = 8:1) to afford 55.4 mg
of 7a in 88% yield.
N-((3S,5S,7S)-Adamantan-1-yl)-6-methoxyquinolin-2-amine
(4j): 22.3 mg (36%); yellow solid; mp = 102.6–103.2 oC; 1H
NMR (400 MHz, CDCl3) δ 11.4 (s, 1H), 8.67 (d, J = 8.8 Hz, 1H),
8.35 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 9.2
Hz, 1H), 7.11 (s, 1H), 3.96 (s, 3H), 2.21 (s, 6H), 2.13 (s, 3H),
1.78–1.70 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.2,
158.8, 137.1, 132.3, 125.6, 123.4, 123.1, 121.7, 105.8, 55.8, 52.2,
41.4, 36.4, 29.4; IR (KBr) υ 2899, 2842, 2107, 1665, 1618, 1545,
1457, 1376, 1244, 1185, 1026, 852 cm-1; HRMS (orbitrap, ESI)
calcd for C20H25N2O [M+H]+ 309.1962, found 309.1962.
8-((4-Methylphenyl)sulfonamido)quinoline N-oxide (7a): 55.4
mg (88%); brown solid; mp = 177.3–180.2 oC; 1H NMR (400
MHz, CDCl3) δ 14.41 (s, 1H), 8.31 (d, J = 6.0 Hz, 1H), 7.87–7.83
(m, 3H), 7.45 (d, J = 8.4 Hz, 1H), 7.49–7.41 (m, 2H), 7.29–7.23
(m, 1H), 7.21 (d, J = 8.0 Hz, 2H), 2.34 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 143.6, 136.9, 136.6, 133.7, 132.3, 131.0,
129.5, 129.1, 128.9, 127.3, 122.2, 120.8, 117.8, 21.4; IR (KBr) υ
3065, 2924, 1659, 1580, 1521, 1458, 1392, 1317, 1277, 1190,
1155, 1087, 889, 814, 746 cm-1; HRMS (orbitrap, ESI) calcd for
C16H15N2O3S [M+H]+ 315.0803, found 315.0802.
6-Methoxy-4-((1S)-methoxy((1S,4S,5R)-5-vinylquinuclidin-2-
yl)methyl)-N-(p-tolyl)quinolin-2-amine (6a): 63.9 mg (72%);
brown solid; mp = 267.5–270.2 oC; 1H NMR (500 MHz, CDCl3) δ
7.74 (d, J = 9.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.26–7.24 (m,
1H), 7.18–7.14 (m, 3H), 7.04 (s, 1H), 6.66 (brs, 1H), 6.09–6.02
(m, 1H), 5.09–4.98 (m, 3H), 3.89 (s, 3H), 3.33 (s, 3H), 3.30–3.28
(m, 1H), 3.02–2.88 (m, 3H), 2.81–2.75 (m, 3H), 2.34 (s, 3H),
2.26–2.21 (m, 1H), 2.04–2.00 (m, 1H), 1.74 (s, 1H), 1.52–1.46 (m,
1H), 1.16 (brs, 1H); 13C{1H} NMR (175 MHz, CDCl3) δ 155.4,
152.8, 146.0, 143.8, 140.8, 138.1, 131.9, 129.6, 129.0, 122.8,
120.7, 119.7, 114.3, 109.3, 102.4, 83.5, 59.4, 57.2, 55.6, 50.2,
49.6, 40.2, 28.3, 26.5, 21.2, 20.8; IR (KBr) υ 2923, 2867, 1714,
1641, 1577, 1528, 1404, 1348, 1263, 1236, 1171, 1120, 1035, 916,
815 cm-1; HRMS (orbitrap, ESI) calcd for C28H34N3O2 [M+H]+
444.2646, found 444.2646.
Experimental procedure for the synthesis of (7b). To an oven-
dried sealed tube charged with 4-methylbenzoyl azide (2a) (96.7
mg, 0.6 mmol, 300 mol %) and t-butyl methyl ether (1 mL) under
air at room temperature. The reaction mixture was allowed to stir
o
at 110 C for 2 h, and cooled to room temperature. Then, in the
reaction mixture 8-((4-methylphenyl)sulfonamido)quinoline N-
oxide (7a) (62.9 mg, 0.2 mmol, 100 mol %) and KOtBu (44.9 mg,
0.4 mmol, 200 mol %) was added under air at room temperature.
o
The reaction mixture was allowed to stir on oil bath at 130 C for
18 h, and cooled to room temperature. The reaction mixture was
filtered through celite and washed with dichloromethane (10 mL).
The filtrate was concentrated under reduced pressure. The residue
was purified by flash column chromatography (n-hexanes/EtOAc
= 1:1) to afford 46.0 mg of 7b in 57% yield.
Benzyl
4-((1-(p-tolylamino)isoquinolin-5-yl)sulfonyl)-1,4-
4-Methyl-N-(2-(p-tolylamino)quinolin-8-yl)benzenesulfonamide
(7b): 46.0 mg (57%); brown solid; mp = 136.5–139.0 oC; 1H
NMR (700 MHz, CDCl3) δ 8.75 (brs, 1H), 7.77 (d, J = 8.4 Hz,
1H), 7.74–7.71 (m, 3H), 7.33 (d, J = 7.7 Hz, 2H), 7.27–7.26 (m,
1H), 7.22 (d, J = 7.7 Hz, 2H), 7.14 (t, J = 7.7 Hz, 1H), 7.10 (d, J =
7.7 Hz, 2H), 6.85 (d, J = 9.1 Hz, 1H), 6.73 (brs, 1H), 2.37 (s, 3H),
2.26 (s, 3H); 13C{1H} NMR (175 MHz, CDCl3) δ 153.5, 143.5,
137.8, 137.7, 136.7, 136.5, 133.6, 131.3, 129.7, 129.4, 127.1,
123.5, 122.7, 122.1, 121.3, 116.4, 112.3, 21.4, 20.8; IR (KBr) υ
3373, 3256, 3055, 2921, 2854, 1603, 1530, 1429, 1323, 1284,
1249, 1158, 1069, 1057, 916, 811, 754 cm-1; HRMS (orbitrap,
ESI) calcd for C23H22N3O2S [M+H]+ 404.1433, found 404.1433.
diazepane-1-carboxylate (6b): 63.9 mg (60%); brown solid; mp =
o
1
187.1–190.6 C; H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H),
8.81 (d, J = 8.4 Hz, 1H), 8.24–8.21 (m, 1H), 8.09 (t, J = 5.2 Hz,
1H), 7.73–7.60 (m, 4H), 7.37–7.29 (m, 5H), 7.14 (d, J = 8.0 Hz,
2H), 5.02 (s, 2H), 3.53–3.37 (m, 8H), 2.28 (s, 3H), 1.72 (brs, 2H);
13C{1H} NMR (125 MHz, DMSO-d6) δ 154.8, 154.7, 153.6, 143.1,
138.0, 136.9, 133.7, 133.6, 132.9, 131.8, 131.4, 131.3, 129.1,
128.7, 128.4, 127.8, 127.7, 127.4, 127.3, 124.8, 124.7, 121.3,
119.3, 119.2, 108.1, 108.0, 79.2, 66.2, 47.9, 47.7, 47.2, 46.9, 46.7,
45.5, 45.2, 28.9, 28.5, 20.5; IR (KBr) υ 3030, 2933, 2854, 1689,
1614, 1527, 1455, 1419, 1372, 1227, 1153, 1121, 1041, 980, 905,
810 cm-1; HRMS (orbitrap, ESI) calcd for C29H31N4O4S [M+H]+
531.2061, found 531.2061.
Experimental procedure for the synthesis of (8a). To an oven-
dried sealed tube charged with Pd(MeCN)2Cl2 (4.2 mg, 0.016
mmol, 4 mol %), CuCl2 (113.0 mg, 0.84 mmol, 210 mol %), 6-
methoxy-N-(p-tolyl)quinolin-2-amine (3b) (105.7 mg, 0.4 mmol,
100 mol %) and diphenylacetylene (106.9 mg, 0.6 mmol, 150
mol %) was added DMF (2 mL) under N2 atmosphere at room
temperature. The reaction mixture was allowed to stir on oil bath
Gram scale experiment. To an oven-dried sealed tube charged
with 4-methylbenzoyl azide (2a) (2.9 g, 18 mmol, 300 mol %)
and t-butyl methyl ether (5 mL) under air at room temperature.
o
The reaction mixture was allowed to stir at 110 C for 2 h, and
cooled to room temperature. Then, in the reaction mixture quino-
line N-oxide (1a) (1.0 g, 6 mmol, 100 mol %) and KOtBu (1.35 g,
12 mmol, 200 mol %) was added under air at room temperature.
o
at 110 C for 12 h, and cooled to room temperature. The reaction
mixture was extracted with EtOAc (15 mL x 3). The combined
organic layers were washed with brine (10 mL x 2), dried over
MgSO4, filtered and concentrated under reduced pressure. The
o
The reaction mixture was allowed to stir on oil bath at 130 C for
18 h, and cooled to room temperature. The reaction mixture was
filtered through celite and washed with dichloromethane (80 mL).
ACS Paragon Plus Environment

Page 9 of 11
The Journal of Organic Chemistry
1
2
3
4
5
6
residue was purified by flash column chromatography (n-
hexanes/EtOAc = 1:1) to afford 69.7 mg of 8a in 79% yield.
1135, 1040, 862, 806 cm-1; HRMS (orbitrap, ESI) calcd for
C18H15N2O2 [M+H]+ 291.1128, found 291.1125.
6-Methoxy-2-(5-methyl-2,3-diphenyl-1H-indol-1-yl)quinoline
(8a): 69.7 mg (79%); yellow solid; mp = 146.5–148.8 oC; 1H
NMR (700 MHz, CDCl3) δ 8.08 (d, J = 9.1 Hz, 1H), 7.84 (d, J =
8.4 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.58 (s, 1H), 7.46 (d, J =
9.1 Hz, 1H), 7.42 (d, J = 7.7 Hz, 2H), 7.38 (t, J = 7.7 Hz, 2H),
7.29 (t, J = 7.0 Hz, 1H), 7.22 (d, J = 7.7 Hz, 2H), 7.19 (d, J = 6.3
Hz, 1H), 7.17–7.15 (m, 3H), 7.06 (d, J = 2.8 Hz, 1H), 6.82 (d, J =
8.4 Hz, 1H), 3.93 (s, 3H), 2.50 (s, 3H); 13C{1H} NMR (175 MHz,
CDCl3) δ 157.9, 149.2 (one carbon overlap), 143.0, 136.1, 135.9,
135.6, 134.8, 131.9, 130.9, 130.8, 130.3 (one carbon overlap),
128.6, 128.2, 128.0, 127.3, 126.0, 124.9, 122.5, 120.7, 119.1,
118.0, 111.6, 105.1, 55.5, 21.5; IR (KBr) υ 3055, 2922, 2853,
1621, 1601, 1571, 1420, 1373, 1229, 1162, 1112, 1030, 921, 832,
733 cm-1; HRMS (orbitrap, ESI) calcd for C31H25N2O [M+H]+
441.1967, found 441.1964.
7
8
9
ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra for all
compounds. This material is available free of charge via the Inter-
net at http://pubs.acs.org.
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
AUTHOR INFORMATION
Corresponding Authors
* E-mail for S.K.: jameskim1991@naver.com
* E-mail for I.S.K.: insukim@skku.edu
ORCID
Saegun Kim: 0000-0002-9998-9853
In Su Kim: 0000-0002-2665-9431
Experimental procedure for the synthesis of (8b). To an oven-
dried sealed tube charged with ammonium cerium(IV) nitrate
(219.3 mg, 0.4 mmol, 200 mol %) and 6-methoxy-N-(p-
tolyl)quinolin-2-amine (3b) (52.9 mg, 0.2 mmol, 100 mol %) was
Notes
The authors declare no competing financial interest.
o
added H2O:MeCN (5:1, 1.2 mL) under air at 0 C. The reaction
mixture was allowed to stir for 1.5 h at room temperature. The
reaction mixture was extracted with EtOAc (15 mL x 3). The
combined organic layers were washed with brine (10 mL x 2),
dried over MgSO4, filtered and concentrated under reduced pres-
sure. The residue was purified by flash column chromatography
(n-hexanes/EtOAc = 1:1) to afford 43.1 mg of 8b in 82% yield.
ACKNOWLEDGMENTS
This work was supported by the National Research Foundation of
Korea (NRF) grant funded by the Korea government (MSIP) (Nos.
2017R1A2B2004786 and 2019R1A4A2001451).
REFERENCES
3-Methoxy-10-methylbenzo[4,5]imidazo[1,2-a]quinoline (8b):
43.1 mg (82%); brown solid; mp = 167.1–170.2 oC; 1H NMR (400
MHz, CDCl3) δ 8.45 (d, J = 9.2 Hz, 1H), 8.09 (s, 1H), 7.87 (d, J =
8.4 Hz, 1H), 7.61–7.55 (m, 2H), 7.35–7.29 (m, 2H), 7.21 (d, J =
2.4 Hz, 1H), 3.92 (s, 3H), 2.64 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 155.8, 147.4, 142.4, 132.5, 130.8, 130.4, 130.1, 125.9,
124.6, 119.7, 118.1, 117.7, 116.4, 113.6, 111.2, 55.6, 22.3; IR
(KBr) υ 2938, 1688, 1660, 1595, 1563, 1535, 1479, 1422, 1254,
1168, 807, 750 cm-1; HRMS (orbitrap, ESI) calcd for C17H15N2O
[M+H]+ 263.1179, found 263.1179.
(1) For selected reviews, see: (a) Joule, J. A.; Mills, K. In Hetero-
cyclic Chemistry, 5th edition; Wiley-Blackwell: New York, 2010; pp
249–288. (b) Asif, M. Recent Efforts for the Development of An-
titubercular Drug Containing Diazine Ring. Med. Chem. 2012, 2,
151–167. (c) Nikishkin, N. I.; Huskens, J.; Verboom, W. Transition
Metal-Catalyzed Functionalization of Pyrazines. Org. Biomol. Chem.
2013, 11, 3583–3602. (d) Baumann, M.; Baxendale, I. R. An Over-
view of the Synthetic Routes to the Best Selling Drugs Containing 6-
Membered Heterocycles. Beilstein J. Org. Chem. 2013, 9, 2265-2319.
(e) Dolezal, M.; Zitko, J. Pyrazine Derivatives: A Patent Review
(June 2012–present). Expert Opin. Ther. Patents 2015, 25, 33–47.
(2) (a) Fourie, T.; Cromarty, D.; Duncan, N.; Wolter, K.; Naidoo,
V. The Safety and Pharmacokinetics of Carprofen, Flunixin and Phe-
nylbutazone in the Cape Vulture (Gyps coprotheres) Following Oral
Exposure. PLoS One 2015, 10, e0141419. (b) Gao, Z.-G.; Verzijl, D.;
Zweemer, A.; Ye, K.; Göblyös, A.; Ijzerman, A. P.; Jacobson, K. A.
Functionally Biased Modulation of A3 Adenosine Receptor Agonist
Efficacy and Potency by Imidazoquinolinamine Allosteric Enhancers.
Biochem. Pharmacol. 2011, 82, 658–668. (c) Contreras, J.-M.; Rival,
Y. M.; Chayer, S.; Bourguignon, J.-J.; Wermuth, C. G. Amino-
pyridazines as Acetylcholinesterase Inhibitors. J. Med. Chem. 1999,
42, 730–741. (d) Manley, P. W.; Cowan-Jacob, S. W.; Buchdunger,
E.; Fabbro, D.; Fendrich, G.; Furet, P.; Meyer, T.; Zimmermann, J.
Imatinib: A Selective Tyrosine Kinase Inhibitor. Eur. J. Cancer 2002,
38, S19–S27. (e) Giatromanolaki, A.; Koukourakis, M. I.; Sivridis, E.;
Gatter, K. C.; Trarbach, T.; Folprecht, G.; Shi, M. M.; Lebwohl, D.;
Jalava, T.; Laurent, D.; Meinhardt, G.; Harris, A. L. Vascular Density
Analysis in Colorectal Cancer Patients Treated with Vatalanib
(PTK787/ZK222584) in the Randomised CONFIRM Trials. Brit. J.
Cancer 2012, 107, 1044–1050.
Experimental procedure for the synthesis of (8c). To an oven-
dried sealed tube charged with Pd(OAc)2 (5.0 mg, 0.02 mmol, 10
mol %), Cu(TFA)2·xH2O (114.7 mg, 0.24 mmol, 120 mol %), 6-
methoxy-N-(p-tolyl)quinolin-2-amine (3b) (52.9 mg, 0.2 mmol,
100 mol %) was added toluene (2 mL) under air atmosphere. The
reaction mixture was allowed to stir at room temperature and
subsequently formic acid (60.4 µL, 1.6 mmol, 800 mol %) and
acetic anhydride (151.2 µL, 1.6 mmol, 800 mol %) were added
dropwise. The reaction mixture was allowed to stir on oil bath at
o
110 C for 12 h, and cooled to room temperature. The reaction
mixture was extracted with EtOAc. The combined organic layers
were washed with brine and saturated NH4OH solution, dried over
MgSO4, filtered and concentrated under reduced pressure. The
residue was purified by flash column chromatography (n-
hexanes/EtOAc = 2:1) to afford 26.2 mg of 8c in 45% yield.
3-Methoxy-10-methyl-12H-quinolino[2,1-b]quinazolin-12-one
(8c): 26.2 mg (45%); yellow solid; mp = 148.0–149.2 oC; 1H
NMR (400 MHz, CDCl3) δ 9.58 (d, J = 9.6 Hz, 1H), 8.22 (s, 1H),
7.66–7.61 (m, 2H), 7.51 (d, J = 9.2 Hz, 1H), 7.22 (d, J = 9.2 Hz,
1H), 7.15 (dd, J = 9.6, 2.8 Hz, 1H), 7.01 (d, J = 2.8 Hz, 1H), 3.90
(s, 3H), 2.53 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.8,
157.1, 147.0, 144.3, 136.3, 136.1, 134.6, 129.5, 126.6, 126.1,
125.9, 125.5, 123.4, 119.6, 116.1, 110.7, 55.5, 21.5; IR (KBr) υ
3057, 2923, 2853, 1673, 1610, 1569, 1478, 1455, 1266, 1238,
(3) Chichibabin, A. E.; Zeide, O. A. New Reaction for Compounds
Containing the Pyridine Nucleus. J. Russ. Phys. Chem. Soc. 1914, 46,
1216–1236.
(4) (a) Murakami, K.; Yamada, S.; Kaneda, T.; Itami, K. C–H
Functionalization of Azines. Chem. Rev. 2017, 117, 9302–9332. (b)
Londregan, A. T.; Jennings, S.; Wei, L. General and Mild Preparation
of 2-Aminopyridines. Org. Lett. 2010, 12, 5254–5257. (c) Yin, J.;
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 11
1
2
3
4
5
6
7
8
9
Xiang, B.; Huffman, M. A.; Raab, C. E.; Davies, I. W. A General and
(11) Hisano, T.; Yoshikawa, S.; Muraoka, K. Reaction of Aromatic
Efficient 2-Amination of Pyridines and Quinolines. J. Org. Chem.
2007, 72, 4544–4557. (d) Medley, J. W.; Movassaghi, M. Direct De-
hydrative N-Pyridinylation of Amides. J. Org. Chem. 2009, 74, 1341–
1344. (e) Bi, W.-Z.; Sun, K.; Qu, C.; Chen, X.-L.; Qu, L.-B.; Zhu, S.-
H.; Li, X.; Wu, H.-T.; Duan, L.-K.; Zhao, Y.-F. A Direct Metal-free
C2–H Functionalization of Quinoline N-Oxides: A Highly Selective
Amination and Alkylation Strategy Towards 2-Substituted Quinolines.
Org. Chem. Front. 2017, 4, 1595–1600. (f) Behera, A.; Sau, P.; Sahoo,
A. K.; Patel, B. K. Cyano-Sacrificial (Arylthio)arylamination of
N-Oxides with Dipolarophiles. I. Reaction Products of 3-Picoline 1-
Oxide with Phenyl Isocyanate. Chem. Pharm. Bull. 1974, 22, 1611–
1617.
(12) (a) Liu, B.; Zhou, T.; Li, B.; Xu, S.; Song, H.; Wang, B. Rho-
dium(III)‐Catalyzed Alkenylation Reactions of 8-Methylquinolines
with Alkynes by C(sp3)–H Activation. Angew. Chem., Int. Ed. 2014,
53, 4191–4195. (b) Kang, T.; Kim, Y.; Lee, D.; Wang, Z.; Chang,
S. Iridium-Catalyzed Intermolecular Amidation of sp3 C–H Bonds:
Late-Stage Functionalization of an Unactivated Methyl Group. J. Am.
Chem. Soc. 2014, 136, 4141–4144. (c) Han, S.; Park, J.; Kim, S.; Lee,
S. H.; Sharma, S.; Mishra, N. K.; Jung, Y. H.; Kim, I. S. Rhodi-
um(III)-Catalyzed C(sp3)–H Alkylation of 8-Methylquinolines with
Maleimides. Org. Lett. 2016, 18, 4666–4669.
(13) Galanis, A.; Ma, H.; Rajkhowa, T.; Ramachandran, A.; Small,
D.; Cortes, J.; Levis, M. Crenolanib is a Potent Inhibitor of FLT3 with
Activity Against Resistance-Conferring Point Mutants. Blood 2014,
123, 94–100.
(14) Hwang, H.; Kim, J.; Jeong, J.; Chang, S. Regioselective Intro-
duction of Heteroatoms at the C-8 Position of Quinoline N-Oxides:
Remote C–H Activation Using N-Oxide as a Stepping Stone. J. Am.
Chem. Soc. 2014, 136, 10770–10776.
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
Quinoline
and
Isoquinoline
N-Oxides
Using
N-(2-
(Arylthio)aryl)cyanamides. J. Org. Chem. 2018, 83, 11218–11231.
(g) Xie, L.-Y.; Peng, S.; Jiang, L.-L.; Peng, X.; Xia, W.; Yu, X.;
Wang, X.-X.; Cao, Z.; He, W.-M. AgBF4-Catalyzed Deoxygenative
C2-Amination of Quinoline N-Oxides with Isothiocyanates. Org.
Chem. Front. 2019, 6, 167–171.
(5) (a) Nakao, Y. Transition-Metal-Catalyzed C–H Functionaliza-
tion for the Synthesis of Substituted Pyridines. Synthesis 2011, 2011,
3209–3219. (b) Iwai, T.; Sawamura, M. Transition-Metal-Catalyzed
Site-Selective C–H Functionalization of Quinolines beyond C2 Selec-
tivity. ACS Catal. 2015, 5, 5031–5040. (c) Stephens, D.; Larionov, O.
Recent Advances in the C–H Functionalization of the Distal Positions
in Pyridines and Quinolines. Tetrahedron 2015, 71, 8683–8716. For
Cu(II)-mediated C2-amination of quinoline N-oxides, see: (d) Li, G.;
Jia, C.; Sun, K. Dehydrogenative Amidation/Amination of Quinoline
N-Oxides with Lactams/Cyclamines. Org. Lett. 2013, 15, 5198–5201.
(e) Zhu, C.; Yi, M.; Wei, D.; Chen, X.; Wu, Y.; Cui, X. Copper-
Catalyzed Direct Amination of Quinoline N-Oxides via C–H Bond
Activation under Mild Conditions. Org. Lett. 2014, 16, 1840–1843.
(f) Wang, Z.; Han, M.-Y.; Li, P.; Wang, L. Copper-Catalyzed Deoxy-
genative C-2 Amination of Quinoline N-Oxides. Eur. J. Org. Chem.
2018, 2018, 5954–5960. (g) Biswas, A.; Karmakar, U.; Nandi, S.;
Samanta, R. Copper-Catalyzed Direct, Regioselective Arylamination
of N-Oxides: Studies To Access Conjugated π-Systems. J. Org. Chem.
2017, 82, 8933–8942.
(6) For the chemistry of heteroaromatic N-oxides, see: (a) Wang,
Y.; Zhang, L. Recent Developments in the Chemistry of Heteroaro-
matic N-Oxides. Synthesis 2015, 47, 289–305. For C2-amination
using external activating reagents, see: (b) Manley, P. J.; Bilodeau, M.
T. A Mild Method for the Formation and in Situ Reaction of Imidoyl
Chlorides:ꢀ Conversion of Pyridine-1-oxides to 2-Aminopyridine
Amides. Org. Lett. 2002, 4, 3127–3129. (c) Medley, J. W.; Movas-
saghi, M. Direct Dehydrative N-Pyridinylation of Amides. J. Org.
Chem. 2009, 74, 1341–1344. (d) Yin, J.; Xiang, B.; Huffman, M. A.;
Raab, C. E.; Davies, I. W. A General and Efficient 2-Amination of
Pyridines and Quinolines. J. Org. Chem. 2007, 72, 4544–4557.
(7) (a) Mailey, E. A.; Ocone, L. R. Fluoroalkylpyridines. A Novel
Rearrangement. J. Org. Chem. 1968, 33, 3343–3344. (b) Loska, R.;
Makosza, M. New Synthesis of 2-Heteroarylperfluoropropionic Acids
Derivatives by Reaction of Azine N-Oxides with Hexafluoropropene
Chem. Eur. J. 2008, 14, 2577–2589.
(15) (a) Chen, J.; Pang, Q.; Sun, Y.; Li, X. Synthesis of N-(2-
Pyridyl)indoles via Pd(II)-Catalyzed Oxidative Coupling. J. Org.
Chem. 2011, 76, 3523–3526. (b) Yang, R.; Yu, J.-T.; Sun, S.; Cheng,
J. Palladium-catalyzed CO-free Cyclizative Carbonylation of 2-
Benzylpyridines Leading to Pyridoisoquinolinones. Org. Chem. Front.
2018, 5, 962–966.
(16) (a) Zhang, Y.; Zhang, S.; Xu, G.; Li, M.; Tang, C.; Fan, W.
Cu-Catalyzed Carbamoylation versus Amination of Quinoline N-
Oxide with Formamides. Org. Biomol. Chem. 2019, 17, 309–314. (b)
Bertuzzi, G.; Pecorari, D.; Bernardi, L.; Fochi, M. An Organocatalytic
Enantioselective Direct α-Heteroarylation of Aldehydes with Isoquin-
oline N-Oxides. Chem. Commun. 2018, 54, 3977–3980. (c) Roudesly,
F.; Veiros, L. F.; Oble, J.; Poli, G. Pd-Catalyzed Direct C–H Alkenyl-
ation and Allylation of Azine N-Oxides. Org. Lett. 2018, 20, 2346–
2350. (d) Wang, H.; Pei, Y.; Bai, J.; Zhang, J.; Wu, Y.; Cui, X. Di-
merization of Heteroaromatic N-Oxides under Metal-free Conditions
RSC Adv. 2014, 4, 26244–26246. (e) Ma, X.; Dang, H.; Rose, J. A.;
Rablen, P.; Herzon, S. B. Hydroheteroarylation of Unactivated Al-
kenes Using N-Methoxyheteroarenium Salts. J. Am. Chem. Soc. 2017,
139, 5998–6007. (f) Jo, W.; Kim, J.; Choi, S.; Cho, S. H. Transition-
Metal-Free Regioselective Alkylation of Pyridine N-Oxides Using
1,1-Diborylalkanes as Alkylating Reagents. Angew. Chem., Int. Ed.
2016, 55, 9690–9694.
(17) Miloserdov, F. M.; Grushin, V. V. Palladium-Catalyzed Aro-
matic Azidocarbonylation. Angew. Chem., Int. Ed. 2012, 51, 3668–
3672.
(8) (a) Zhou, W.; Miura, T.; Murakami, M. Photocatalyzed ortho-
Alkylation of Pyridine N-Oxides through Alkene Cleavage. Angew.
Chem., Int. Ed. 2018, 57, 5139–5142. (b) Xu, J.-h.; Wu, W.-b.; Wu, J.
Photoinduced Divergent Alkylation/Acylation of Pyridine N-Oxides
with Alkynes under Anaerobic and Aerobic Conditions. Org. Lett.
2019, 21, 5321–5325.
(9) (a) Ghosh, P.; Kwon, N. Y.; Han, S.; Kim, S.; Han, S. H.;
Mishra, N. K.; Jung, Y. H.; Chung, S. J.; Kim, I. S. Site-Selective C–
H Alkylation of Diazine-N-Oxides Enabled by Phosphonium Ylides.
Org. Lett. 2019, 21, 6488–6493. (b) Han, S.; Chakrasali, P.; Park, J.;
Oh, H.; Kim, S.; Kim, K.; Pandey, A. K.; Han, S. H.; Han, S. B.; Kim,
I. S. Reductive C2-Alkylation of Pyridine- and Quinoline-N-Oxides
Using Wittig Reagents. Angew. Chem., Int. Ed. 2018, 57, 12737–
12740.
(10) Bräse, S.; Gil, C.; Knepper, K.; Zimmermann, V. Organic Az-
ides: An Exploding Diversity of a Unique Class of Compounds. An-
gew. Chem., Int. Ed. 2005, 44, 5188–5240.
ACS Paragon Plus Environment

Page 11 of 11
The Journal of Organic Chemistry
1
2
3
4
5
6
Table of Contents (TOC)
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
ACS Paragon Plus Environment