Co(III)-Catalyzed C-H Amidation of Nitrogen-Containing Heterocycles with Dioxazolones under Mild Conditions

Article abstract of DOI:10.1021/acs.joc.0c01237

A cobalt(III)-catalyzed C-8 selective C-H amidation of quinoline N-oxide using dioxazolone as an amidating reagent under mild conditions is disclosed. The reaction proceeds efficiently with excellent functional group compatibility. The utility of the current method is demonstrated by gram scale synthesis of C-8 amide quinoline N-oxide and by converting this amidated product into functionalized quinolines. Furthermore, the developed catalytic method is also applicable for C-7 amidation of N-pyrimidylindolines and ortho-amidation of benzamides.

Full text of DOI:10.1021/acs.joc.0c01237

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Article
Co(III)-Catalyzed C-H Amidation of Nitrogen Containing
Heterocycles with Dioxazolones under Mild Condition
Ankit Kumar Dhiman, ANKITA THAKUR, INDER KUMAR, Rakesh Kumar, and Upendra Sharma
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01237 • Publication Date (Web): 19 Jun 2020
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The Journal of Organic Chemistry
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Co(III)-Catalyzed C-H Amidation of Nitrogen Containing Heter-
ocycles with Dioxazolones under Mild Condition
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Ankit Kumar Dhiman, Ankita Thakur, Inder Kumar, Rakesh Kumar and Upendra Sharma*
Natural Product Chemistry and Process Development Division and AcSIR, CSIR-IHBT, Palampur-176061, India
Supporting Information
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ABSTRACT: A cobalt(III)-catalyzed C8 selective C-H amidation of quinoline N-oxide using dioxazolone as amidating reagent
under mild condition is disclosed. The reaction proceeds efficiently with ex-
cellent functional group compatibility. The utility of current method is
demonstrated by gram scale synthesis of C-8 amide quinoline N-oxide and by
converting this amidated product into functionalized quinolines. Further, de-
veloped catalytic method is also applicable for C-7 amidation of N-pyrim-
idylindolines and ortho-amidation of benzamides.
KEYWORDS: Cp*Co(III), C-H activation, amidation, quinoline N-oxide,
indoline
INTRODUCTION
2
report the foremost CoCp*(CO)I -catalyzed C-8 amidation of
quinoline N-oxide and C-7 amidation of indoline with
Quinoline is one of the important structural motifs encountered
dioxazolones under mild reaction condition.
1
2
3
in medicinal, synthetic and material chemistry, and exhibits
numerous biological activities. Therefore, researchers have con-
tinuously developed new synthetic methods to access novel
quinoline derivatives, and during past few years transition
metal-catalyzed C-H functionalization is turn out to be an effec-
4
tive approach for quinoline modification by C-H alkylation,
alkenylation, arylation,
5
4d, 6
7
7, 8
halogenation and amidation us-
ing N-oxide as a directing group. Among the various function-
alization of quinoline, the C(8)-H amidation attracted great at-
tention due to the abundance of 8-aminoquinoline derivatives in
9
pharmaceutical drugs (Fig. 1). Amidation at the C8 position of
quinoline is always a challenge and very few methods have
been reported till date. Recent methods for C-8 amidation of
7
a
quinoline N-oxide involved the use of Ir(III)/tosyl azide, and
8
a
8b
Scheme 1. C-8 Amidation of Quinoline N-oxides
RESULTS AND DISCUSSION
use
of
dioxazolones,
amidobenziodoxolones,
8
c
trifluoromethylacetamide as an amidating reagent with Rh(III)
catalyst. In 2019, our group also reported the C-8 amidation of
quinoline N-oxide with Rh(III) catalyst where NFSI was
7b
Initially quinoline N-oxide (1a) was reacted with 3-phenyl-
1,4,2-dioxazol-5-one (2a) in the presence of CoCp*(CO)I
explored as a new amidating reagent (Scheme 1a).
2
(10
mol%)/AgSbF (20 mol%) in HFIP at 50 ˚C for 12 h to afford
6
the desired C8 amidated product (3a) in 10% isolated yield (Ta-
ble 1, entry 2). Isolated product was characterized on the basis
of 1D NMR and ESI-MS spectroscopy, and finally with single-
1
4
crystal X-ray diffraction (See the supporting information).
Figure 1. Structure of 8-Aminoquinoline Based Drug Mole-
cules
Further, to surge the desired product yield, different bases and
acids as an additive in catalytic as well as in stoichiometric
14
amount were screened. Among various additives, acetic acid
Despite the high regioselectivity, broad substrate scope and
excellent yield of products, all of these methods require
expensive noble metal catalysts and their replacement with
relatively cheap earth abundant metal is still a big challenge.
(20 mol%) displayed significant improvement in yield along
with the formation of di-amidated product in traces (Table 1,
entry 1). Di-amidated product was observed in LC–MS analysis
of crude reaction mixture and isolated by further scaling up the
Although, CoCp*(CO)I
2
/dioxazolones combination had been
nd
reaction but the position of 2 C-H amidation other than the C8
explored for the amidation of various heterocyclic compounds
position on the quinoline moiety could not be confirmed. Low-
ering of temperature curtailed product yield even after increased
reaction time (Table 1, entry 7). Also, change of the solvent to
TFE resulted in 66% yield of 3a (Table 1, entry 6). Other sil-
2 4
ver salts such as AgNTf and AgBF were found to be inferior
10
10
11
12
such as pyridones, isoquinolones, indole, thiophene,
benzo[h]quinoline,
12a,
12b
13
and 8-methylquinoline,
C-8
amidation of quinoline N-oxide and C-7 amidation of indoline
with this combination is not disclosed till date. Incentivized
from these developments and our previous work, herein, we
14
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(Table 1, entry 8–9). The control experiment indi-
Page 2 of 11
to AgSbF
1
2
3
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8
9
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1
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cated the indispensable role of cobalt catalyst for the amidation
reaction (Table 1, entry 10). It was further noted that
[IrCp*Cl ] and [Ru(p-cymene)Cl ] were unproductive under
2 2 2 2
current reaction conditions (Table 1, entry 11-12).
Table 1. Optimization Studya
0
1
2
3
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0
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3
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0
3
a
yield 4a yield
entry variation from standard condition
b
b
(%)
(%)
c
1
2
3
4
5
6
7
8
9
1
1
none
88 (84)
15 (10)
n.r.
<5
c
without AcOH
without AgSbF
n.d.
n.r.
6
and AcOH
NaOAc in place of AcOH
AcOH (1.0 equiv.)
TFE in place of HFIP
rt for 24 h
10
n.d.
traces
n.d.
n.d.
traces
n.d.
n.r.
80
66
60
AgNTf
AgBF
without Cp*Co(CO)I
[IrCp*Cl in place of CoCp*(CO)I
Ru(p-cymene)Cl in place of
2
in place of AgSbF
6
76
4
in place of AgSbF
6
<10
n.r.
0
1
2
2
]
2
2
n.r.
n.r.
[
2 2
]
12
n.r.
n.r.
CoCp*(CO)I
2
a
a
reaction conditions: 1a (0.2 mmol), 2a (1.1 equiv.), CoCp*(CO)I
mol%), AgSbF (20 mol%), AcOH (20 mol%), HFIP (0.5 mL), 50 ˚C, 12 h.
NMR yield by using TCE (1,1,2,2-tetrachloroethane) as an internal stand-
2
(10
reaction conditions: 1a (0.2 mmol), 2a (1.1 equiv.), CoCp*(CO)I
mol%), AgSbF (20 mol%), AcOH (20 mol%), HFIP (0.5 mL), 50 ˚C, 12 h.
ratio is calculated on the basis of isolated yield.
2
(10
6
6
b
b
c
ard). isolated yield in parenthesis. n.r.: no reaction, n.d.: not detected.
Next, the substrate scope with 3-substituted dioxazolones was
examined (Table 3).
With best optimized conditions, substrate scope was studied
with a series of quinoline N-oxides (Table 2). Methyl group on
different positions of quinoline N-oxide (1b-e) provided the
corresponding amidated products in 67-89% yields (3b-e).
Quinoline N-oxide bearing -OMe, - Bu and -Cl at C6-position
were fully compatible and produced the desired product in 70-
Table 3. Substrate Scope with 3-Substituted-1,4,2-dioxazol-5-
one
a
t
7
9% yields (3f–h). Although, poor conversion was observed
with methylester at C6 position (3i) quinoline N-oxide with ni-
tro group at C6 position failed to provide even the traces of the
amidated product (3j). Halogen substituted quinoline N-oxide
provided corresponding desired product in 51-64% yield (3k-l).
Similar reactivity was observed with 2-phenylquinoline N-ox-
ide (3m, 67%). Amidation of 2,6-di-substituted quinoline N-ox-
ide proceeded well to afford the final product in good to excel-
lent yields (3n–q). Alike 6-nitroquinoline N-oxide, 6-nitroqui-
naldine N-oxide also failed to provide the desired product (3r).
Polyheteroarenes (1s–v) also afforded amidated products in
good to excellent yields (51-87%, 3s-v). In the case of 4,7-di-
chloroquinoline N-oxide, the corresponding product 3w was ob-
tained in 60% yield. Isoquinoline N-oxide was found unsuitable
under the developed reaction condition (3x). Moreover, -
NH(Boc) protected 6-aminoquinoline N-oxide delivered 6-
amino-8-benzamidoquinoline N-oxide (3y) in 20% yield.
Along with required amidated product, the diaminated product
was also obtained in case of 2-Me, 3-Me, 3-Br and 2-phe-
nylquinoline N-oxides (4a-c, l-m).
a
reaction conditions: 1a (0.2 mmol), 2a (1.1 equiv.), CoCp*(CO)I (10
2
6
mol%), AgSbF (20 mol%), AcOH (20 mol%), HFIP (0.5 mL), 50 ˚C, 12 h.
3-Methyl dioxazolone gave 92% yield of the corresponding
amidated product (3z). Various meta- and para-substituted phe-
nyl dioxazolones were well tolerated and provided excellent
yield (86–99%) of the desired products (3za-e). The amidation
Table 2. Substrate Scope with Quinoline N-oxidesa
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was further extended with cyclopentane and cyclohexane diox-
2a (Scheme 3b). The competitive as well as parallel experiment
gave P /P ratio 4.26 suggesting that the C-H bond cleavage
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
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2
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5
5
6
azolone and products were isolated in good yields (3zf–g). Ad-
ditionally, 9-carbazole dioxazolone afforded 3zh in 65% yield.
Notably, the product 3a was isolated in 61% yield in a gram-
scale synthesis (10 mmol) which shows the synthetic applica-
bility of current work (Scheme 2).
H
D
might be the rate determining step. Competition experiments
were conducted with electron-rich as well as electron-deficient
3-phenyl-1,4,2-dioxazol-ones and quinoline N-oxides. These
experiments revealed that electron-rich quinoline N-oxides and
electron-deficient dioxazolone are more-favored under current
reaction condition (Scheme 4).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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9
0
1
2
3
4
5
6
7
8
9
0
Scheme 2. Gram Scale Synthesis
We also scrutinized one more important heterocyclic compound
i.e. indoline under developed reaction conditions (Table 4).
Here C-7 amidation was found to be favored regardless of the
position of the substituent on N-(2-pyrimidyl) indoline afford-
ing the corresponding product (6a-d) in high yields (Table 4).
This is first report Co(III)-catalyzed C-7 amidation of in-
1
5-16
Scheme 4. Competition Experiment
dolines.
The structure of amidated indoline was confirmed
1
5
by comparing the spectral data with literature. Encouraged by
these initial findings, other directing group N Bu amide, pyri-
t
On the basis of preliminary experiments and literature reports a
4b, 6, 12c, 16
probable mechanism was proposed (Scheme 5).
The
dine and quinoline were also tested under current developed re-
action condition for C–H amidation (Table 4) and decent yields
were observed in these cases (6e-g).
reaction may proceed through reversible C8-H activation of 1a
with Co(III)-catalyst producing an intermediate B. The subse-
quent coordination of 2a with B resulted in the formation of in-
termediate C. Than 2a might undergo nitrene insertion through
Table 4. Other Directing Groups Compatibilitya
2
CO extrusion in intermediate C to form intermediate D. There-
after, migration insertion delivers the amido-inserted species E
which on protodemetallation of E may give product 3a along
with the regeneration of the active cobalt species (A).
a
reaction condition: 1a (0.2 mmol), 2a (1.1 equiv.), CoCp*(CO)I
2
(10
mol%), AgSbF (20 mol%), AcOH (20 mol%), HFIP (0.5 mL), 50 ˚C, 12 h.
6
For the mechanism understanding, deuterium labeling experi-
ments were conducted (Scheme 3).
Scheme 5. Proposed Mechanism
Scheme 3. Deuterium Labeling Experiments
Final product 3a could be easily converted to N-(quinolin-8-
yl)benzamide (3aa), 8-aminoquinoline N-oxide (3ab), N-(2-
chloroquinolin-8-yl)benzamide (3ac) and 2-aryl-8-amidoquin-
oline N-oxide (3ad) in moderate to good yield by following the
In deuterium labeling experiments, 40% deuteration was de-
tected on the C8 position in the presence of Co(III)-catalyst
without 2a, suggesting that the C–H activation step could be
reversible in nature (Scheme 3a). Competitive and parallel ex-
22-25
reported procedures.
periments were also carried out by reacting 1a and 1a–D with
7
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1
7e
1r)17a (1s)17f (1u, 1v)17c (1x, 1t, 1w)17b. Other quinoline N-ox-
(
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
ides were used from commercially available sources and 1y was
synthesized from above procedure and characterization data is
given below.
Characterization Data. 6-methoxy-2-methylquinoline N-oxide
(
1y). Off white solid, Yield = 364.0 mg (70%). Isolated from flash
1
chromatography (100% EtOAc). H NMR (600 MHz, CDCl
8
1
Hz, 1H), 7.23 (dd, J = 8.4, 6.0 Hz, 1H), 1.47 (s, 9H). C{ H}NMR
(150 MHz, CDCl , δ): 153.0, 139.4, 137.7, 134.3, 131.7, 126.6,
1
2
6
2
3
, δ):
.64 (d, J = 9.0 Hz, 1H), 8.44 (dd, J = 6.0, 0.6 Hz, 1H), 8.30 (s,
H), 8.25 (br, s, 1H, NH), 7.68 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 9.0
13
1
3
–
1
23.7, 121.4, 120.6, 113.6, 81.2, 28.4. IR (ZnSe): νmax (cm ) 3120,
976, 1718, 1595, 1465, 1365, 1244, 1157, 1095, 970, 871, 788,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
17 2 3
38. HRMS (ESI–TOF) (m/z): [M+H] calcd for C14H N O ,
61.1234; found, 261.1230.
General procedure for the synthesis of 3-substituted-1,4,2-dioxa-
8
a, 16d, 18
zol-5-ones from acid chloride.
A flask was charged with
hydroxylamine hydrochloride (1 equiv.), potassium carbonate (1
equiv.) and solvent (diethyl ether/water; 7.5:1). The reaction was
Scheme 6. Synthetic Transformation of 3a
o
cooled to 0 C with vigorous stirring before addition of acid chlo-
CONCLUSIONS
ride (1 equivalent) dropwise. The reaction was stirred overnight,
diluted with water and extracted with ethyl acetate. The combined
organic layers were washed with brine, dried over anhydrous so-
dium sulfate and concentrated in vacuo. The crude hydroxamic acid
product was purified by washing with pentane/diethyl ether if nec-
essary. To the above hydroxamic acid in freshly distilled dichloro-
methane (50 mL) was added carbonyldiimidazole (0.50 g, 5 mmol).
The reaction mixture was stirred at room temperature (10-30 min)
until a high conversion was reached (as indicated by TLC). Then,
a cold 1 N aqueous solution of HCl (25 mL) was added, and the
mixture was extracted with dichloromethane, dried over magne-
sium sulfate and concentrated under reduced pressure to give the 3-
substituted-1,4,2-dioxazol-5-one. Almost all synthesized dioxa-
In summary, we have developed an efficient Co(III)-catalyzed
coupling of quinoline N-oxide and indoline with diaoxazolones
under mild reaction condition. The method tolerated a variety
of functional groups with good to excellent yields.
EXPERIMENTAL SECTION
General Information. All reactions were carried out under air at-
mosphere in screw cap reaction vials, unless otherwise stated. All
solvents were bought from Sigma Aldrich and TCI in sure–seal bot-
tle and used as such. All chemicals were bought from Sigma Al-
drich, Alfa–aesar and TCI. For column chromatography, silica gel
18b
12i
8a
zolones were known compounds. (2a, 2b,) (2d ) (2c, 2f)
(230-400 mesh) from Merck was used. A gradient elution using n–
18c
(2i) . Compound 2g, 2h and 2j were synthesized from above pro-
cedure and characterization data is given below.
hexane and ethyl acetate was performed based on Merck alumin-
ium TLC sheets (silica gel 60F254).
Analytical information. The melting points were recorded on a
Bronsted Electro thermal 9100 and Labindia visual melting range.
Characterization Data. 3-(3,5-dimethylphenyl)-1,4,2-dioxazol-
5
-one (2g). White solid, Yield = 624.0 mg (65%). Mp 72-75 °C.
1
Isolated from flash chromatography (10% EtOAc). H NMR (600
MHz, CDCl , δ): 7.45 (d, J = 0.6 Hz, 2H), 7.26 (s, 1H), 2.39 (s,
H). C{ H} NMR (150 MHz, CDCl , δ): 163.9, 154.1, 139.4,
135.7, 124.3, 119.9, 21.3. IR (ZnSe): νmax (cm ) 3153, 2906, 1793,
1
13
All isolated compounds were characterized by H NMR, C NMR,
LC-MS and IR. In addition, all the compounds were further char-
acterized by HRMS. Mass spectra were recorded on Water Q-ToF-
Micro Micromass, maXis Impact mass spectrometers and high-res-
olution 6560 Ion Mobility Q-TOF LC/MS (Agilent, Santa Clara,
USA). IR was analyzed by Shimadzu IR Prestige-21with ZnSe Sin-
gle reflection ATR accessory. Nuclear magnetic resonance spectra
were recorded either on a Bruker-Avance 600 or 300 MHz instru-
3
13
1
6
3
–1
1
502, 1438, 1382, 1232, 1192, 1083, 929, 862, 798.
-cyclopentyl-1,4,2-dioxazol-5-one (2h). viscous liquid, Yield =
32.5 mg (30%). Isolated from flash chromatography (10%
3
2
1
EtOAc). H NMR (600 MHz, CDCl
3
, δ): 3.03–3.08 (m, 1H), 2.01–
2
2
.06 (m, 2H), 1.81-1.87 (m, 2H), 1.75–1.79 (m, 2H), 1.66–1.72 (m,
1
ment. All H NMR experiments were reported in units, parts per
13
1
3
H). C{ H}NMR (150 MHz, CDCl , δ): 169.6, 154.5, 35.2, 29.4,
million (ppm) and were measured relative to the signals for residual
–1
25.5. IR (ZnSe): νmax (cm ) 3153, 2956, 2872, 1793, 1670, 1440,
chloroform (7.26) and DMSO-d
6
(2.50) in the deuterated solvents.
All C{1H} NMR spectra were reported in ppm relative to deuter-
ated chloroform (77.16) and DMSO-d (39.52), all were obtained
1247, 1192, 1093, 987, 775, 694.
1
3
3
-(9H-carbazol-9-yl)-1,4,2-dioxazol-5-one (2j). White Solid,
6
Yield = 453.6 mg (36%). Isolated from flash chromatography (10%
1
with H decoupling. Optimization studies were done by NMR and
NMR yield were calculated by using TCE (tetrachloroethane) as an
internal standard.
1
3
EtOAc). H NMR (600 MHz, CDCl , δ): 8.04 (t, J = 8.4 Hz, 4H),
13
1
7
.53-7.56 (m, 2H), 7.44-7.47 (m, 2H). C{ H} NMR (150 MHz,
3
CDCl , δ): 157.4, 151.7, 136.5, 128.0, 126.2, 124.6, 120.6, 114.8.
7
b, 17
General procedure for the synthesis of quinoline N-oxides.
solid reactants, m-CPBA (4.0 mmol) and quinoline (2.0 mmol)
were added in schlenk tube and put under vacuum for 2 h, then
All
–1
IR (ZnSe): νmax (cm ) 3219, 2916, 1761, 1666, 1442, 1327, 1213,
1182, 1024, 985, 850, 744, 617.
General procedure for the synthesis of 1-(pyrimidin-2-yl) indo-
CH
2
Cl
2
(4 mL) was added at 0 °C. The reaction was allowed to stir
19
line derivatives (5a-5d). The indoline (2.0 mmol) and 2-chloro-
at room temperature for 12 h. On completion, the reaction mixture
was extracted with ethyl acetate and organic extract was dried over
pyrimidine (2.4 mmol, 1.2 equiv.) were dissolved in a mixture of
EtOH and water (2 mL) in 4:1 ratio. Concentrated hydrochloric
acid (0.2 mL or 200 µL) was added to the mixture. Then, the re-
sulting solution was refluxed overnight. EtOH was then removed
under reduced pressure, and the aqueous phase was extracted twice
with ethyl acetate. The combined organic layers were dried over
Na
crude product was purified by flash chromatography on silica gel
230-400 mesh size) with n-hexane/EtOAc to afford desired N-ox-
ide. Almost all synthesized N-oxides are known compounds. [ (1a,
2 4
SO , filtered and concentrated under reduced pressure. The
(
1
7g
17d
7b
1
b, 1c, 1d, 1e, 1f, 1h, 1i, 1j, 1l, 1v) , (1n) (1o, 1p) (1k, 1q),
ACS Paragon Plus Environment

Page 5 of 11
The Journal of Organic Chemistry
Na
rification was performed by flash column chromatography on silica
gel with n-hexane/EtOAc eluent.
-(pyrimidin-2-yl)indoline (5a). Viscous brown, Yield = 334.9
2
SO
4
, filtered, and evaporated under reduced pressure. The pu-
Characterization Data. 8-benzamidoquinoline N-oxide (Table
2, entry 3a). Brown solid, Yield = 44.5 mg (84%). Mp 137–140
°C. Isolated from flash chromatography (60% EtOAc/n-hexane).
3
H NMR (600 MHz, CDCl , δ): 15.19 (br, s, 1H, NH), 9.27 (d, J =
1
6
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
1
1
mg (85%). Isolated from flash chromatography (5% EtOAc). H
NMR (600 MHz, CDCl , δ): 8.49 (d, J = 4.2 Hz, 2H), 8.41 (d, J =
.4 Hz, 1H), 7.20-7.25 (m, 2H), 6.93-6.96 (m, 1H), 6.67–6.69 (m,
7.8 Hz, 1H), 8.40 (d, J = 6.0 Hz, 1H), 8.08 (d, J = 7.2 Hz, 2H), 7.79
(d, J = 8.4 Hz, 1H), 7.60–7.63 (m, 1H), 7.50–7.55 (m, 4H), 7.40
3
13
1
8
1
(dd, J = 7.8, 6.6 Hz, 1H). C{ H} NMR (150 MHz, CDCl
3
, δ):
13
1
H), 4.22-4.25 (m, 2H), 3.18-3.21 (m, 2H). C{ H} NMR (150
, δ): 159.3, 157.5, 143.7, 132.3, 127.3, 124.7, 121.6,
165.7, 137.6, 135.2, 134.8, 132.4, 131.9, 131.2, 129.9, 129.7,
–
1
MHz, CDCl
115.4, 111.5, 48.8, 27.3. IR (ZnSe): νmax (cm ) 3037, 2897, 1577,
446, 1386, 1282, 1182, 991, 860. HRMS (ESI–TOF) (m/z):
3
128.9, 127.5, 122.3, 120.8, 119.7. IR (ZnSe): νmax (cm ) 3076,
–
1
2852, 2326, 1654, 1537, 1489, 1344, 1257, 1159, 1033, 883, 746,
+
1
646. HRMS (ESI-TOF) (m/z): [M+H] calcd for C16
265.0974; found, 265.0974.
13 2 2
H N O ,
+
[
M+H] calcd for C12
-methyl-1-(pyrimidin-2-yl)indoline (5b). Viscous brown, Yield
295.4 mg (70%). Isolated from flash chromatography (2%
12 3
H N , 198.1026; found, 198.1022.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
8-benzamido-2-methylquinoline N-oxide (Table 2, entry 3b).20
Brown solid, Yield = 37.3 mg (67%). Mp 142–145 °C. Isolated
from flash chromatography (40% EtOAc/n-hexane). H NMR (600
MHz, CDCl , δ): 15.41 (br, s, 1H, NH), 9.26 (d, J = 8.4 Hz, 1H),
=
1
1
EtOAc). H NMR (600 MHz, CDCl
3
, δ): 8.48 (d, J = 4.2 Hz, 2H),
8.40–8.42 (m, 1H), 7.26–7.29 (m, 1H), 7.24 (d, J = 7.8 Hz, 1H),
6.98–7.00 (m, 1H), 6.65 (t, J = 4.8 Hz, 1H), 4.99–5.04 (m, 1H),
3
8.10–8.12 (m, 2H), 7.68 (d, J = 8.4 Hz, 1H), 7.56–7.58 (m, 1H),
7.51–7.55 (m, 3H), 7.47 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 8.4 Hz,
3
3
1
.43–3.47 (m, 1H), 2.73 (d, J = 15.6 Hz, 1H), 1.39 (d, J = 6.6 Hz,
1
3
1
13
1
H). C{ H} NMR (150 MHz, CDCl
3
, δ): 158.9, 157.5, 142.5,
3
1H), 2.69 (s, 3H). C{ H} NMR (150 MHz, CDCl , δ): 165.7,
31.1, 127.2, 124.9, 121.7, 116.2, 111.3, 55.8, 35.7, 20.0. IR
147.6, 135.5, 134.5, 131.8, 131.4, 131.2, 128.9, 128.8, 128.2,
–1
–1
(ZnSe): νmax (cm ) 3037, 1581, 1487, 1346, 1280, 1118, 1078, 975,
127.5, 122.9, 122.4, 119.7, 19.3. IR (ZnSe): νmax (cm ) 3053, 2848,
+
8
C
54, 756, 640. HRMS (ESI–TOF) (m/z): [M+H] calcd for
, 212.1182; found, 212.1180.
5-methyl-1-(pyrimidin-2-yl)indoline (5c). Light brown solid,
Yield = 337.6 mg (80%). Mp 50–52 °C. Isolated from flash chro-
2328, 1653, 1537, 1435, 1355, 1257, 1170, 1074, 877, 750, 651.
+
13
H
14
N
3
HRMS (ESI-TOF) (m/z): [M+H] calcd for C17
found, 279.1129.
15 2 2
H N O , 279.1128;
8-benzamido-3-methylquinoline N-oxide (Table 2, entry 3c).
Brown solid, Yield = 40.6 mg (73%). Mp 212–214 °C. Isolated
1
matography (5% EtOAc). H NMR (600 MHz, CDCl
J = 4.8 Hz, 2H), 8.27–8.29 (m, 1H), 7.02–7.04 (m, 2H), 6.64–6.65
m, 1H), 4.20–4.23 (m, 2H), 3.15–3.18 (m, 2H), 2.33 (s, 3H).
3
, δ): 8.47 (d,
1
from flash chromatography (35% EtOAc/n-hexane). H NMR (600
(
3
MHz, CDCl , δ): 15.14 (br, s, 1H, NH), 9.18 (d, J = 7.8 Hz, 1H),
13
1
C{ H} NMR (150 MHz, CDCl
3
, δ): 159.3, 157.5, 141.4, 132.4,
8.28 (s, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.54–7.58 (m, 2H), 7.53 (d,
J = 6.6 Hz, 1H), 7.49–7.52 (m, 2H), 7.41 (d, J = 7.8 Hz, 1H), 2.43
1
31.0, 127.7, 125.5, 115.2, 111.1, 48.9, 27.3, 20.9. IR (ZnSe): νmax
–
1
13
1
(cm ) 2922, 1579, 1492, 1444, 1388, 1280, 1188, 1078, 970, 815,
7
2
(s, 3H). C{ H} NMR (150 MHz, CDCl
3
, δ): 165.6, 138.8, 135.3,
+
14 3
90, 636. HRMS (ESI–TOF) (m/z): [M+H] calcd for C13H N ,
134.6, 132.2, 131.9, 131.2, 129.8, 129.4, 129.1, 128.9, 127.5,
–
1
12.1182; found, 212.1179.
121.7, 118.7, 18.5. IR (ZnSe): νmax (cm ) 3061, 2920, 2326, 1662,
5
-bromo-1-(pyrimidin-2-yl)indoline (5d). Brown solid, Yield =
1535, 1450, 1384, 1261, 1190, 1056, 993, 873, 788, 690. HRMS
+
4
12.5 mg (76%). Mp 92-95 °C. Isolated from flash chromatog-
(ESI-TOF) (m/z): [M+H] calcd for C17
279.1130.
15 2 2
H N O , 279.1128; found,
1
raphy (5% EtOAc). H NMR (600 MHz, CDCl
3
, δ): 8.48 (d, J = 4.8
Hz, 2H), 8.27 (d, J = 9.0 Hz, 1H), 7.29–7.30 (m, 2H), 6.71 (t, J =
8-benzamido-4-methylquinoline N-oxide (Table 2, entry 3d).
1
3
1
4.8 Hz, 1H), 4.22–4.24 (m, 2H), 3.16–3.19 (m, 2H). C{ H} NMR
(150 MHz, CDCl , δ): 159.2, 157.6, 142.9, 134.7, 130.1, 127.7,
Brown solid, Yield = 49.5 mg (89%). Mp 183-185 °C. Isolated
1
3
from flash chromatography (35% EtOAc/n-hexane). H NMR (600
–
1
1
1
16.8, 113.8, 111.9, 48.9, 27.1. IR (ZnSe): νmax (cm ) 2922, 1577,
494, 1342, 1278, 1172, 1078, 948, 823, 786. HRMS (ESI–TOF)
3
MHz, CDCl , δ): 15.53 (br, s, 1H, NH), 9.30 (d, J = 7.8 Hz, 1H),
8.30–8.32 (m, 1H), 8.09 (d, J = 5.4 Hz, 2H), 7.65 (d, J = 7.8 Hz,
1H), 7.60 (d, J = 7.8 Hz, 1H), 7.51–7.52 (m, 3H), 7.13–7.15 (m,
+
(m/z): [M+H] calcd for C12
3
H11BrN , 276.0131; found, 276.0129.
13
1
General procedure for the synthesis of 8–amidoquinoline N–ox-
1H), 2.63 (s, 3H). C{ H} NMR (150 MHz, CDCl
3
, δ): 165.7,
ides. To a solution of various substituted quinoline N–oxide (1a-y)
(0.2 mmol) in HFIP (0.5 mL per mmol) in a reaction vial equipped
with magnetic stir bar, 3-substituted-1,4,2-dioxazol-5-one (2a-j)
137.9, 136.7, 135.4, 131.9, 131.6, 129.7, 128.9, 127.5, 121.6,
–
1
119.7, 118.6, 19.5. IR (ZnSe): νmax (cm ) 3047, 2816, 2328, 1656,
1535, 1487, 1305, 1159, 893, 707, 630. HRMS (ESI-TOF) (m/z):
+
(
1.1 equiv.), [CoCOCp*I
AcOH (20 mol%) were added. The reaction mixture was stirred at
0 ˚C for 12 h on a heating block, filtered through a pad of celite
2
] (10 mol%), AgSbF
6
(20 mol%) and
[M+H] calcd for C17
H
15
N
2
O
2
, 279.1128; found, 279.1130.
8-benzamido-6-methylquinoline N-oxide (Table 2, entry 3e).
5
Brown solid, Yield = 42.8 mg (77%). Mp 208-210 °C. Isolated
1
using ethyl acetate solvent. After that, filtrate was transferred to
round bottom flask and organic solvents were removed under re-
duced pressure. The residue was purified by flash chromatography
on silica gel (mesh 230–400) to give the desired product. Eluting
solvents for chromatography are indicated under the specific com-
pound headings.
from flash chromatography (35% EtOAc/n-hexane). H NMR (600
3
MHz, CDCl , δ): 15.16 (br, s, 1H, NH), 9.14 (s, 1H), 8.33 (d, J =
5.4 Hz, 1H), 8.07–8.09 (m, 2H), 7.70 (d, J = 8.4 Hz, 1H), 7.50–7.55
(m, 3H), 7.27 (s, 1H), 7.23 (dd, J = 8.4, 6.6 Hz, 1H), 2.52 (s, 3H).
1
3
1
C{ H} NMR (150 MHz, CDCl
3
, δ): 165.6, 140.5, 136.8, 135.2,
134.4, 132.5, 131.9, 129.8, 128.93, 128.87, 127.4, 121.5, 121.4,
–
1
Gram scale experiment for preparation of 3a. In a round-bottom
flask equipped with magnetic stir bar, quinoline N-oxide (1a)
120.8, 22.0. IR (ZnSe): νmax (cm ) 3116, 2918, 2850, 1653, 1573,
1481, 1371, 1296, 1138, 1041, 985, 879, 707, 682. HRMS (ESI-
+
(
1
1.810 g, 10 mmol) in HFIP (50 mL, 0.5 mL per mmol), 3-phenyl-
,4,2-dioxazol-5-one (2a) (1.793 g, 1.1 equiv.), [CoCp*(CO)I
(0.476 g, 10 mol%), AgSbF (0.687 g, 20 mol%) and AcOH (115
µL, 20 mol%) were added. The reaction mixture was stirred at 50
C for 12 h, filtered through a pad of celite using ethyl acetate sol-
TOF) (m/z): [M+H] calcd for C17
279.1133.
15 2 2
H N O , 279.1128; found,
2
]
6
8-benzamido-6-methoxyquinoline N-oxide (Table 2, entry 3f).
Brown solid, Yield = 41.7 mg (71%). Mp 200-204 °C. Isolated
1
˚
from flash chromatography (50% EtOAc/n-hexane). H NMR (600
vent. After that filtrate was transferred to round bottom flask and
organic solvents were removed under reduced pressure. The crude
product was purified by column chromatography on silica gel (230-
3
MHz, CDCl , δ): 15.28 (br, s, 1H, NH), 9.03–9.05 (m, 1H), 8.25–
8.27 (m, 1H), 8.07–8.09 (m, 2H), 7.68 (t, J = 7.2 Hz, 1H), 7.53–
7.56 (m, 1H), 7.50–7.53 (m, 2H), 7.21–7.25 (m, 1H), 6.82–6.83 (m,
13
1
4
00) with 60% EtOAc/n-hexane to obtain 1.617 gram of 3a, yield
1H), 3.95 (s, 3H). C{ H} NMR (150 MHz, CDCl
3
, δ): 165.8,
61%.
159.8, 136.1, 135.5, 135.1, 133.7, 131.9, 128.9, 128.4, 127.5,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 11
–
1
1
21.1, 110.3, 101.8, 55.9. IR (ZnSe): νmax (cm ) 3558, 2922, 2850,
8.06–8.08 (m, 2H), 7.88–7.89 (m, 2H), 7.79 (d, J = 8.4 Hz, 1H),
7.61–7.64 (m, 1H), 7.53–7.56 (m, 2H), 7.50–7.51 (m, 3H), 7.47–
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2337, 1620, 1548, 1423, 1174, 1031, 837, 642. HRMS (ESI-TOF)
+
13
1
(m/z): [M+H] calcd for C17
H
15
N
O
2 3
, 295.1077; found, 295.1069.
-benzamido-6-(tert-butyl)quinoline N-oxide (Table 2, entry 3g).
7.49 (m, 2H), 7.42 (d, J = 8.4 Hz, 1H). C{ H} NMR (150 MHz,
CDCl , δ): 165.7, 146.9, 135.4, 135.3, 133.4, 131.8, 131.7, 131.6,
8
3
Brown solid. Yield = 44.8 mg (70%), Mp 204–206 °C. Isolated
from flash chromatography (40% EtOAc/n-hexane). H NMR (600
129.9, 129.8, 129.5, 128.8, 128.6, 128.5, 127.6, 123.5, 122.4,
120.2. IR (ZnSe): νmax (cm ) 3064, 2962, 1660, 1552, 1479, 1352,
1
–1
MHz, CDCl
.36 (d, J = 6.0 Hz, 1H), 8.09–8.11 (m, 2H), 7.78 (d, J = 8.4 Hz,
1H), 7.53–7.54 (m, 1H), 7.50–7.52 (m, 2H), 7.45 (d, J = 1.8 Hz,
3
, δ): 15.15 (br, s, 1H, NH), 9.48 (d, J = 2.4 Hz, 1H),
1294, 1159, 1079, 848, 748, 677. HRMS (ESI–TOF) (m/z):
+
8
17 2 2
[M+H] calcd for C22H N O , 341.1285; found, 341.1276.
8-benzamido-2,6-dimethylquinoline N-oxide (Table 2, entry 3n).
Brown solid, Yield = 50.8 mg (87%). Mp 172–175 °C. Isolated
1
3
1
1H), 7.27 (dd, J = 8.4, 6.0 Hz, 1H), 1.45 (s, 9H). C{ H} NMR
150 MHz, CDCl , δ): 165.7, 153.4, 136.9, 135.3, 134.4, 132.4,
31.9, 129.8, 129.6, 128.9, 127.4, 120.6, 118.8, 117.8, 35.5, 31.1.
1
(
3
from flash chromatography (40% EtOAc/n-hexane). H NMR (600
1
MHz, CDCl
3
, δ): 15.37 (br, s, 1H, NH), 9.08 (d, J = 1.8 Hz, 1H),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
–
1
IR (ZnSe): νmax (cm ) 3082, 2958, 2326, 1664, 1523, 1481, 1357,
1
8.08–8.09 (m, 2H), 7.49–7.53 (m, 4H), 7.16–7.18 (m, 2H), 2.62 (s,
+
13
1
296, 1166, 1039, 862, 742. HRMS (ESI–TOF) (m/z): [M+H]
3H), 2.46 (s, 3H). C{ H} NMR (150 MHz, CDCl
3
, δ): 165.5,
calcd for C20 , 321.1598; found, 321.1599.
21 2 2
H N O
146.6, 138.9, 135.4, 133.9, 131.7, 131.1, 129.8, 128.8, 127.7,
–
1
8-benzamido-6-chloroquinoline N-oxide (Table 2, entry 3h).
Brown solid, Yield = 47.1 mg (79%). Mp 232–235 °C. Isolated
127.4, 122.8, 121.6, 121.3, 21.8, 19.1. IR (ZnSe): νmax (cm ) 3061,
2916, 2850, 2335, 1651, 1577, 1440, 1398, 1294, 1182, 1105, 1033,
1
+
from flash chromatography (30% EtOAc/n-hexane). H NMR (600
881, 707, 644. HRMS (ESI–TOF) (m/z): [M+H] calcd for
MHz, CDCl
.38 (dd, J = 6.0, 0.6 Hz, 1H), 8.06–8.08 (m, 2H), 7.71 (d, J = 8.4
Hz, 1H), 7.57 (t, J = 7.2 Hz, 1H), 7.52 (t, J = 7.2 Hz, 2H), 7.49 (d,
3
, δ): 15.23 (br, s, 1H, NH), 9.33 (d, J = 2.4 Hz, 1H),
C
18
H
17
N
2
O
2
, 293.1285; found, 293.1298.
8-benzamido-6-methoxy-2-methylquinoline N-oxide (Table 2, en-
try 3o). Brown solid, Yield = 51.7 mg (84%). Mp 200-203 °C. Iso-
8
13
1
1
J = 1.8 Hz, 1H), 7.32 (dd, J = 8.4, 6.0 Hz, 1H). C{ H} NMR (150
MHz, CDCl , δ): 165.8, 137.5, 136.2, 136.1, 134.7, 132.9, 132.3,
129.9, 128.9, 128.4, 127.5, 121.8, 120.6, 119.7. IR (ZnSe): νmax
lated from flash chromatography (60% EtOAc/n-hexane). H NMR
(600 MHz, CDCl , δ): 15.45 (br, s, 1H, NH), 8.94 (d, J = 3.0 Hz,
3
3
1H), 8.07–8.08 (m, 2H), 7.50–7.53 (m, 3H), 7.48 (d, J = 8.4 Hz,
1H), 7.14 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 2.4 Hz, 1H), 3.88 (s, 3H),
–
1
(
1
cm ) 3120, 2922, 2852, 2328, 1656, 1527, 1477, 1396, 1286,
+
13
1
165, 1097, 908, 835, 707. HRMS (ESI–TOF) (m/z): [M+Na]
calcd for C16 NaO , 321.0401; found, 321.0423.
-benzamido-6-(methoxycarbonyl)quinoline N-oxide (Table 2,
2.59 (s, 3H). C{ H} NMR (150 MHz, CDCl
3
, δ): 165.6, 158.8,
H11ClN
2
2
145.2, 135.6, 135.3, 132.2, 131.8, 128.8, 127.4, 127.35, 127.32,
–
1
8
123.2, 109.9, 101.9, 55.7, 18.9. IR (ZnSe): νmax (cm ) 3008, 2922,
entry 3i). Brown solid, Yield = 16.1 mg (25%). Mp 237–241 °C.
2848, 2339, 1660, 1573, 1454, 1327, 1288, 1180, 1049, 921, 867,
1
+
Isolated from flash chromatography (50% EtOAc/n-hexane). H
798, 651. HRMS (ESI–TOF) (m/z): [M+H] calcd for C18
H
17
N
2
O
3
,
NMR (600 MHz, CDCl
3
, δ): 15.02 (br, s, 1H, NH), 9.79 (d, J = 1.8
309.1234; found, 309.1236.
Hz, 1H), 8.50 (dd, J = 6.0, 0.6 Hz, 1H), 8.26 (d, J = 1.8 Hz, 1H),
8-benzamido-6-ethoxy-2-methylquinoline N-oxide (Table 2, entry
3p). Brown solid, Yield = 56.7 mg (88%). Mp 171–173 °C. Isolated
8
7
3
1
1
.07–8.08 (m, 2H), 7.94 (d, J = 8.4 Hz, 1H), 7.54–7.57 (m, 1H),
.50–7.53 (m, 2H), 7.39 (dd, J = 8.4, 6.0 Hz, 1H), 4.01 (s,
1
from flash chromatography (60% EtOAc/n-hexane). H NMR (600
1
3
1
H). C{ H} NMR (150 MHz, CDCl
3
, δ): 165.8, 165.7, 139.2,
3
MHz, CDCl , δ): 15.45 (br, s, 1H, NH), 8.99–9.02 (m, 1H), 8.09 (d,
35.3, 134.8, 132.8, 132.2, 132.0, 131.4, 130.8, 128.9, 127.5,
J = 7.2 Hz, 2H), 7.50–7.55 (m, 4H), 7.17–7.20 (m, 1H), 6.75–6.77
(m, 1H), 4.13–4.16 (m, 2H), 2.62 (s, 3H), 1.45–1.47 (m, 3H).
–1
24.5, 121.7, 118.8, 52.9. IR (ZnSe): νmax (cm ) 3120, 3076, 2920,
1
3
1
1728, 1653, 1537, 1409, 1286, 1174, 1093, 999, 879, 704, 655.
C{ H} NMR (150 MHz, CDCl
3
, δ): 165.7, 158.3, 145.1, 135.6,
+
HRMS (ESI–TOF) (m/z): [M+Na] calcd for C18
45.0846; found, 345.0845.
-benzamido-4-chloroquinoline N-oxide (Table 2, entry 3k).
14 2 4
H N NaO ,
135.4, 132.3, 131.8, 128.9, 127.5, 127.41, 127.36, 123.2, 110.4,
–
1
3
102.8, 64.1, 18.9, 14.8. IR (ZnSe): νmax (cm ) 3099, 2985, 2868,
8
2349, 1651, 1577, 1492, 1375, 1292, 1271, 1170, 1051, 869, 705,
+
Brown solid, Yield = 38.1 mg (64%). Mp 177–179 °C. Isolated
642. HRMS (ESI–TOF) (m/z): [M+H] calcd for C19
H
19
N
2
O
3
,
1
from flash chromatography (50% EtOAc/n-hexane). H NMR (600
323.1390; found, 323.1398.
MHz, CDCl
3
, δ): 15.19 (br, s, 1H, NH), 9.35–9.37 (m, 1H), 8.29–
8-benzamido-6-bromo-2-methylquinoline N-oxide (Table 2, entry
3q). Brown solid, Yield = 39.3 mg (55%). Mp 227–229 °C. Isolated
8.31 (m, 1H), 8.06 (d, J = 7.8 Hz, 2H), 7.87–7.89 (m, 1H), 7.71–
7.75 (m, 1H), 7.53–7.56 (m, 1H), 7.50–7.52 (m, 2H), 7.38–7.40 (m,
1
from flash chromatography (40% EtOAc/n-hexane). H NMR (600
1
3
1
1
1
1
1
H). C{ H} NMR (150 MHz, CDCl
3
, δ): 165.7, 136.7, 135.4,
3
MHz, CDCl , δ): 15.44 (br, s, 1H, NH), 9.43 (d, J = 2.4 Hz, 1H),
35.0, 133.7, 132.1, 131.6, 130.9, 129.7, 128.9, 127.5, 121.1,
20.5, 118.9. IR (ZnSe): νmax (cm ) 2897, 2850, 1674, 1579, 1381,
257, 1197, 1089, 920, 831, 794, 688. HRMS (ESI–TOF) (m/z):
8.08 (dd, J = 7.8, 1.2 Hz, 2H), 7.60 (d, J = 2.4 Hz, 1H), 7.55–7.58
(m, 2H), 7.53 – 7.55 (m, 2H), 7.31 (d, J = 8.4 Hz, 1H), 2.66 (s,
–
1
1
3
1
3H). C{ H} NMR (150 MHz, CDCl
3
, δ): 165.7, 147.9, 135.6,
+
[
M+H] calcd for C16
2 2
H12ClN O , 299.0582; found, 299.0586.
134.9, 132.1, 131.9, 130.3, 128.9, 127.5, 127.0, 124.0, 123.9,
–
1
8-benzamido-3-bromoquinoline N-oxide (Table 2, entry 3l).
122.9, 122.2, 19.3. IR (ZnSe): νmax (cm ) 2922, 1654, 1595, 1489,
Brown solid, Yield = 34.9 mg (51%). Mp 180–183 °C. Isolated
1355, 1280, 1176, 1043, 889, 761, 694. HRMS (ESI–TOF) (m/z):
1
+
from flash chromatography (30% EtOAc/n-hexane). H NMR (600
[M+H] calcd for C17
H
14BrN
2
O
2
, 357.0233; found, 357.0230.
MHz, CDCl
H), 8.47 (d, J = 1.2 Hz, 1H), 8.04–8.06 (m, 2H), 7.92 (d, J = 1.2
Hz, 1H), 7.61–7.64 (m, 1H), 7.54–7.57 (m, 1H), 7.50–7.53 (m, 2H),
3
, δ): 14.75 (br, s, 1H, NH), 9.25 (dd, J = 8.4, 1.2 Hz,
4-benzamidoacridine N-oxide (Table 2, entry 3s). Orange solid,
1
Yield = 32.0 mg (51%). Mp 195–197 °C. Isolated from flash chro-
1
matography (20% EtOAc/n-hexane). H NMR (600 MHz, CDCl
3
,
13
1
7
.41 (dd, J = 7.8, 0.6 Hz, 1H). C{ H} NMR (150 MHz, CDCl
3
,
δ): 15.55 (br, s, 1H, NH), 9.29 (d, J = 7.8 Hz, 1H), 8.83 (d, J = 9.0
Hz, 1H), 8.33 (s, 1H), 8.17–8.18 (m, 2H), 7.97 (d, J = 8.4 Hz, 1H),
δ): 165.7, 146.6, 138.6, 134.9, 132.2, 132.1, 130.83, 130.80, 130.1,
–
1
13
1
128.9, 127.5, 121.4, 119.7, 113.9. IR (ZnSe): νmax (cm ) 2964,
7.81–7.84 (m, 1H), 7.60–7.65 (m, 2H), 7.55–7.57 (m, 4H). C{ H}
NMR (150 MHz, CDCl , δ): 165.7, 140.2, 135.5, 134.1, 132.0,
131.9, 131.3, 129.3, 129.0, 128.9, 128.4, 128.1, 127.9, 127.6,
1660, 1552, 1479, 1352, 1294, 1159, 1072, 889, 748, 694. HRMS
3
+
(
ESI–TOF) (m/z): [M+H] calcd for C16
H
12BrN
2
O
2
, 343.0077;
–
1
found, 343.0072.
-benzamido-2-phenylquinoline N-oxide (Table 2, entry 3m).
Brown solid, Yield = 45.6 mg (67%). Mp 202–205 °C. Isolated
127.2, 122.8, 119.5, 119.1. IR (ZnSe): νmax (cm ) 3282, 2924,
8
2346, 1616, 1537, 1438, 1396, 1184, 1093, 896, 734, 653. HRMS
+
(ESI–TOF) (m/z): [M+H] calcd for C20
H
15
N
2
O
2
, 315.1128;
1
from flash chromatography (15% EtOAc/n-hexane). H NMR (600
MHz, CDCl , δ): 15.34 (br, s, 1H, NH), 9.32 (d, J = 8.4 Hz, 1H),
found, 315.1122.
3
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The Journal of Organic Chemistry
4
-benzamidophenanthridine N-oxide (Table 2, entry 3t). Brown
3
MHz, CDCl , δ): 169.2, 137.5, 134.5, 132.4, 131.0, 129.7, 129.3,
122.1, 120.7, 119.5, 26.0. IR (ZnSe): νmax (cm ) 3383, 2968, 1651,
1535, 1492, 1375, 1192, 815, 788, 626, 555.
–
1
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
solid, Yield = 45.2 mg (72%). Mp 217–219 °C. Isolated from flash
chromatography (60% EtOAc/n-hexane). H NMR (600 MHz,
1
CDCl
3
, δ): 15.41 (br, s, 1H, NH), 9.38 (dd, J = 7.8, 1.2 Hz, 1H),
.78 (s, 1H), 8.49 (d, J = 8.4 Hz, 1H), 8.28 (dd, J = 7.8, 0.6 Hz,
H), 8.11–8.12 (m, 2H), 7.78–7.81 (m, 3H), 7.68–7.71 (m, 1H),
8-(4-methylbenzamido)quinoline N-oxide (Table 3, entry 3za).
Brown solid, Yield = 50.0 mg (90%). Mp 193–195 °C. Isolated
from flash chromatography (70% EtOAc/n-hexane). H NMR (600
8
1
7
1
1
13
1
.52–7.56 (m, 3H). C{ H} NMR (150 MHz, CDCl
36.9, 136.1, 135.5, 131.9, 130.9, 130.4, 129.4, 128.9, 128.6,
3
, δ): 165.8,
3
MHz, CDCl , δ): 15.10 (br, s, 1H, NH), 9.28 (d, J = 7.8 Hz, 1H),
8.41 (d, J = 6.0 Hz, 1H), 7.98 (d, J = 7.8 Hz, 2H), 7.80 (d, J = 8.4
Hz, 1H), 7.61–7.63 (m, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.31 (d, J =
128.0, 127.6, 127.3, 126.5, 125.9, 122.8, 120.4, 116.9. IR (ZnSe):
–
1
13
1
ν
8
max (cm ) 3061, 2924, 2854, 1660, 1548, 1475, 1368, 1159, 1072,
89, 750, 694. HRMS (ESI–TOF) (m/z): [M+H]+ calcd for
, 315.1128; found, 315.1128.
-benzamidobenzo[f]quinoline N-oxide (Table 2, entry 3u).
Brown solid, Yield = 54.0 mg (86%). Mp 196–198 °C. Isolated
8.4 Hz, 2H), 7.28 (d, J = 6.6 Hz, 1H), 2.42 (s, 3H). C{ H} NMR
(150 MHz, CDCl , δ): 165.7, 142.4, 137.5, 135.0, 132.5, 132.4,
131.3, 129.9, 129.6, 129.5, 127.5, 122.1, 120.7, 119.6, 21.7. IR
3
20 15 2 2
C H N O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
–
1
5
(ZnSe): νmax (cm ) 3392, 2981, 1656, 1550, 1485, 1348, 1192,
+
1055, 817, 744, 653. HRMS (ESI–TOF) (m/z): [M+H] calcd for
1
from flash chromatography (70% EtOAc/n-hexane). H NMR (600
MHz, CDCl , δ): 15.30 (br, s, 1H, NH), 9.62 (s, 1H), 8.72 (d, J =
8.4 Hz, 1H), 8.55 (d, J = 6.6 Hz, 1H), 8.46 (d, J = 8.4 Hz, 1H), 8.12
C
17
H
15
N
2
O
2
, 279.1128; found, 279.1125.
3
8-(4-methoxybenzamido)quinoline N-oxide (Table 3, entry 3zb).
Brown solid, Yield = 52.9 mg (90%). Mp 164–166 °C. Isolated
1
(dd, J = 7.8, 1.2 Hz, 2H), 7.94 (d, J = 7.8 Hz, 1H), 7.68–7.70 (m,
from flash chromatography (90% EtOAc/n-hexane). H NMR (600
1
3
1
1
H), 7.61–7.64 (m, 1H), 7.52–7.57 (m, 4H). C{ H} NMR (150
, δ): 165.9, 138.5, 136.7, 135.3, 133.0, 132.8, 131.9,
31.3, 130.7, 129.5, 128.9, 127.4, 126.9, 125.1, 124.2, 123.0,
3
MHz, CDCl , δ): 15.04 (br, s, 1H, NH), 9.25 (d, J = 7.8 Hz, 1H),
MHz, CDCl
1
1
3
8.36 (d, J = 3.6 Hz, 1H), 8.03 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 7.8
Hz, 1H), 7.60–7.63 (m, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.28–7.31
–1
13
1
21.4, 119.6. IR (ZnSe): νmax (cm ) 2850, 1726, 1649, 1523, 1408,
(m, 1H), 6.99 (d, J = 8.4 Hz, 2H), 3.86 (s, 3H). C{ H} NMR (150
MHz, DMSO-d , δ): 163.9, 162.3, 138.3, 134.2, 132.2, 129.9,
129.7, 129.3, 128.9, 126.9, 122.5, 122.0, 117.9, 114.3, 55.6. IR
1355, 1274, 1176, 1080, 977, 881, 754, 671. HRMS (ESI–TOF)
(m/z): [M+H] calcd for C20
6
+
15 2 2
H N O , 315.1128; found, 315.1123.
–
1
10-benzamidobenzo[h]quinoline N-oxide (Table 2, entry 3v).
(ZnSe): νmax (cm ) 2916, 2850, 1658, 1579, 1460, 1371, 1249,
+
Brown solid, Yield = 54.6 mg (87%). Mp 218–220 °C. Isolated
from flash chromatography (80% EtOAc/n-hexane). H NMR (600
1176, 1024, 906, 779, 651. HRMS (ESI–TOF) (m/z): [M+H] calcd
1
15 2 3
for C17H N O , 295.1077; found, 295.1079.
MHz, CDCl
H), 8.32 (dd, J = 7.8, 1.2 Hz, 1H), 8.21–8.23 (m, 2H), 7.87–7.90
m, 2H), 7.81 (d, J = 8.4 Hz, 1H), 7.74 (dd, J = 7.8, 1.2 Hz, 1H),
7.55 (d, J = 4.8 Hz, 1H), 7.53–7.54 (m, 2H), 7.52 (d, J = 1.2 Hz,
3
, δ): 12.91 (br, s, 1H, NH), 8.70 (dd, J = 6.6, 1.2 Hz,
8-([1,1'-biphenyl]-4-carboxamido)quinoline N-oxide (Table 3,
entry 3zc). Brown solid, Yield = 61.9 mg (91%). Mp 201–203 °C.
1
(
1
Isolated from flash chromatography (50% EtOAc/n-hexane). H
3
NMR (600 MHz, CDCl , δ): 15.26 (br, s, 1H, NH), 9.31 (dd, J =
1
3
1
1
1
1
H), 7.50–7.51 (m, 1H). C{ H} NMR (150 MHz, CDCl
65.9, 140.0, 139.0, 138.0, 136.5, 135.7, 132.2, 131.6, 131.4,
29.9, 128.6, 128.1, 128.0, 125.9, 124.4, 124.2, 121.9, 117.9. IR
3
, δ):
8.4, 1.2 Hz, 1H), 8.43 (dd, J = 6.0, 1.2 Hz, 1H), 8.17 (dd, J = 6.6,
1.8 Hz, 2H), 7.82 (d, J = 7.8 Hz, 1H), 7.74 (dd, J = 6.6, 1.8 Hz, 2H),
7.63–7.66 (m, 3H), 7.52–7.54 (m, 1H), 7.48 (t, J = 7.8 Hz, 2H),
–
1
13
1
(ZnSe): νmax (cm ) 3066, 2922, 2850, 2339, 1658, 1566, 1485,
7.39 (t, J = 7.2 Hz, 1H), 7.31 (dd, J = 8.4, 6.0 Hz, 1H). C{ H}
NMR (150 MHz, CDCl , δ): 165.4, 144.7, 140.3, 137.5, 134.9,
133.9, 132.5, 131.3, 129.9, 129.5, 129.0, 128.1, 128.0, 127.6,
1
390, 1290, 1163, 1001, 916, 842, 796, 626. HRMS (ESI–TOF)
3
+
(m/z): [M+H] calcd for C20
15 2 2
H N O , 315.1128; found, 315.1133.
–
1
8-benzamido-4,7-dichloroquinoline N-oxide (Table 2, entry 3w).
Brown solid, Yield = 39.9 mg (60%). Mp 193–195 °C. Isolated
from flash chromatography (20% EtOAc/n-hexane). H NMR (600
127.4, 122.3, 120.8, 119.7. IR (ZnSe): νmax (cm ) 3564, 2918,
2850, 1653, 1541, 1485, 1384, 1257, 1165, 1089, 818, 742, 692.
1
+
HRMS (ESI–TOF) (m/z): [M+H] calcd for C22
H
17
N
2
O
2
,
MHz, CDCl
3
, δ): 13.28 (br, s, 1H, NH), 8.29 (d, J = 6.6 Hz, 1H),
.08–8.09 (m, 2H), 7.98 (d, J = 9.0 Hz, 1H), 7.81 (d, J = 9.0 Hz,
H), 7.55–7.58 (m, 1H), 7.49–7.52 (m, 2H), 7.39 (d, J = 6.6 Hz,
341.1285; found, 341.1288.
8
1
1
8-(4-chlorobenzamido)quinoline N-oxide (Table 3, entry 3zd).
Brown solid, Yield = 59.0 mg (99%). Mp 170–172 °C. Isolated
13
1
1
H). C{ H} NMR (150 MHz, CDCl
3
, δ): 164.8, 137.7, 135.9,
from flash chromatography (70% EtOAc/n-hexane). H NMR (600
MHz, CDCl , δ): 15.27 (br, s, 1H, NH), 9.24 (dd, J = 8.4, 1.2 Hz,
134.1, 132.9, 132.60, 132.57, 132.4, 131.4, 128.9, 128.30, 128.27,
3
–
1
121.7, 121.4. IR (ZnSe): νmax (cm ) 3523, 2922, 2326, 1672, 1510,
452, 1330, 1273, 1174, 1056, 921, 821, 792, 621. HRMS (ESI–
1H), 8.39 (d, J = 6.0 Hz, 1H), 8.01 (d, J = 8.4 Hz, 2H), 7.80 (d, J =
8.4 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.52–7.53 (m, 1H), 7.47 (dd,
1
+
13
1
TOF) (m/z): [M+H] calcd for C16
33.0193.
-amino-8-benzamidoquinoline N-oxide (Table 2, entry 3y).
H11Cl
2
N
2
O
2
, 333.0192, found
J = 6.6, 1.8 Hz, 2H), 7.32 (dd, J = 8.4, 6.0 Hz, 1H). C{ H} NMR
(150 MHz, DMSO-d , δ): 163.1, 138.3, 136.9, 133.8, 133.5, 132.2,
3
6
6
129.9, 129.8, 129.1, 128.8, 123.0, 122.1, 118.2. IR (ZnSe): νmax
–1
Brown solid, Yield = 11.2 mg (20%). Mp 124–126 °C. Isolated
from flash chromatography (50% EtOAc/n-hexane). H NMR (600
(cm ) 3070, 2920, 2852, 1662, 1541, 1485, 1350, 1259, 1163,
1
+
1022, 813, 742, 673. HRMS (ESI–TOF) (m/z): [M+H] calcd for
MHz, DMSO-d
.06 (d, J = 5.4 Hz, 1H), 7.84 (d, J = 7.2 Hz, 2H), 7.56 (d, J = 7.8
Hz, 1H), 7.49–7.52 (m, 1H), 7.46 (t, J = 7.2 Hz, 2H), 7.16 (dd, J =
6
, δ): 15.51 (br, s, 1H, NH), 8.49 (d, J = 2.4 Hz, 1H),
C
16
H12ClN
2
O
2
, 299.0582; found, 299.0594.
8
8-(3,5-dimethylbenzamido)quinoline N-oxide (Table 3, entry
3ze). Brown solid, Yield = 50.2 mg (86%). Mp 190–192 °C. Iso-
1
8
.4, 6.0 Hz, 1H), 6.48 (d, J = 2.4 Hz, 1H), 5.94 (br, s, 2H, NH
C{ H} NMR (150 MHz, DMSO-d
2
).
, δ): 164.1, 149.1, 134.9,
34.5, 134.1, 133.4, 132.0, 129.0, 127.2, 126.9, 123.6, 121.6,
lated from flash chromatography (50% EtOAc/n-hexane). H NMR
1
3
1
6
3
(600 MHz, CDCl , δ): 15.02 (br, s, 1H, NH), 9.27–9.29 (m, 1H),
1
8.42 (d, J = 6.0 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.68 (s, 2H),
7.61–7.64 (m, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.29 (dd, J = 8.4, 6.0
–1
1
09.0, 100.6. IR (ZnSe): νmax (cm ) 3593, 1726, 1641, 1541, 1409,
1
3
1
1365, 1240, 1151, 1039, 896, 734, 653. HRMS (ESI–TOF) (m/z):
Hz, 1H), 7.18 (s, 1H), 2.42 (s, 6H). C{ H} NMR (150 MHz,
CDCl , δ): 166.2, 138.5, 137.5, 135.3, 134.9, 133.6, 132.5, 131.4,
+
[M+H] calcd for C16
–acetamidoquinoline N–oxide (Table 3, entry 3z). Black solid,
Yield = 37.2 mg (92%). Isolated from flash chromatography (70%
H
14
N
3
O
2
, 280.1081; found, 280.1079.
3
2
0
–
8
129.9, 129.4, 125.3, 122.2, 120.7, 119.7, 21.6. IR (ZnSe): νmax (cm
1
) 3101, 2850, 2779, 1654, 1533, 1489, 1379, 1228, 1155, 1039,
920, 815, 786, 669. HRMS (ESI–TOF) (m/z): [M+Na] calcd for
1
+
EtOAc/n-hexane). H NMR (600 MHz, CDCl
NH), 9.01 (dd, J = 8.4, 1.2 Hz, 1H), 8.35 (dd, J = 8.4, 1.2 Hz, 1H),
.77 (d, J = 8.4 Hz, 1H), 7.54–7.57 (m, 1H), 7.46 (dd, J = 8.4, 1.2
3
, δ): 14.08 (br, s, 1H,
C
18
H
16NaN
2
O
2
, 315.1104; found, 315.1105.
8-(cyclopentanecarboxamido)quinoline N-oxide (Table 3, entry
3zf). Brown viscous, Yield = 39.7 mg (58%). Isolated from flash
7
1
3
1
Hz, 1H), 7.25–7.27 (m, 1H), 2.26 (s, 3H). C{ H} NMR (150
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The Journal of Organic Chemistry
Page 8 of 11
chromatography (80% EtOAc/n-hexane). 1H NMR (600 MHz,
CDCl , δ): 14.14 (br, s, 1H, NH), 9.08 (d, J = 7.8 Hz, 1H), 8.35 (d,
J = 6.0 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.54–7.57 (m, 1H), 7.45
d, J = 8.4 Hz, 1H), 7.25 (dd, J = 8.4 Hz, 6.0 Hz, 1H), 2.85 (p, J =
7.50 (m, 1H), 7.42–7.44 (m, 2H), 7.16–7.19 (m, 1H), 7.07 (d, J =
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
7.2 Hz, 1H), 6.71 (t, J = 4.8 Hz, 1H), 5.19–5.24 (m, 1H), 3.43–3.47
(m, 1H), 2.58 (d, J = 15.0 Hz, 1H), 1.32 (d, J = 6.6 Hz, 3H).
1
3
1
(
3
C{ H} NMR (150 MHz, CDCl , δ): 165.8, 159.0, 157.9, 136.2,
8
2
1
1
.4 Hz, 1H), 1.99–2.05 (m, 2H), 1.90–1.96 (m, 2H), 1.76–1.82 (m,
134.8, 133.1, 131.5, 128.5, 127.7, 127.4, 124.8, 123.6, 121.8,
1
3
1
–1
H), 1.61–1.67 (m, 2H). C{ H} NMR (150 MHz, CDCl
3
, δ):
111.6, 59.2, 36.1, 20.4. IR (ZnSe): νmax (cm ) 2926, 2850, 1658,
75.5, 137.4, 134.8, 132.4, 131.2, 129.8, 129.2, 121.8, 120.6,
1577, 1456, 1371, 1261, 1222, 1190, 974, 779, 696. HRMS (ESI–
–1
+
19.4, 48.4, 30.4, 26.0. IR (ZnSe): νmax (cm ) 2958, 2864, 1672,
TOF) (m/z): [M+Na] calcd for C20
H
18
N
4
NaO, 353.1373; found,
1581, 1489, 1369, 1290, 1159, 1091, 848, 746, 609. HRMS (ESI–
353.1379.
+
TOF) (m/z): [M+H] calcd for C15
H
17
N
2
O
2
, 257.1285; found,
N-(5-methyl-1-(pyrimidin-2-yl)indolin-7-yl)benzamide (Table 4,
1
5
2
57.1283.
-(cyclohexanecarboxamido)quinoline N-oxide (Table 3, entry
zg). Brown solid, Yield = 37.3 mg (69%). Mp 101–103 °C. Iso-
entry 6c). Brown solid, Yield = 46.2 mg (70%). Mp 174–176 °C.
1
8
Isolated from flash chromatography (20% EtOAc/n-hexane). H
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
3
NMR (600 MHz, CDCl , δ): 11.46 (br, s, 1H, NH), 8.41 (d, J = 4.8
1
lated from flash chromatography (60% EtOAc/n-hexane). H NMR
600 MHz, CDCl , δ): 14.12 (br, s, 1H, NH), 9.09 (d, J = 8.4 Hz,
Hz, 2H), 7.84–7.85 (m, 2H), 7.77 (s, 1H), 7.48 (t, J = 7.2 Hz, 1H),
7.41–7.43 (m, 2H), 6.88 (s, 1H), 6.67 (t, J = 4.8 Hz, 1H), 4.44 (t, J
(
3
1
3
1
1H), 8.35 (d, J = 6.0 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.54–7.57
(m, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.24–7.27 (m, 1H), 2.35–2.40
= 7.8 Hz, 2H), 3.05 (t, J = 7.8 Hz, 2H), 2.37 (s, 3H). C{ H}NMR
(150 MHz, CDCl , δ): 165.8, 159.4, 157.9, 146.6, 136.2, 136.1,
3
(
1
m, 1H), 2.06–2.08 (m, 2H), 1.82–1.85 (m, 2H), 1.69–1.71 (m, 1H),
134.7, 132.3, 131.4, 128.5, 127.4, 126.9, 123.9, 122.2, 111.3, 51.9,
1
3
1
–1
.53–1.59 (m, 2H), 1.31–1.38 (m, 2H), 1.25–1.29 (m, 1H). C{ H}
, δ): 175.5, 137.4, 134.8, 132.4, 131.2,
29.8, 129.3, 121.9, 120.6, 119.6, 47.7, 29.7, 25.9. IR (ZnSe): νmax
28.8, 21.1. IR (ZnSe): νmax (cm ) 2789, 1664, 1581, 1465, 1377,
NMR (150 MHz, CDCl
1
3
1267, 1184, 1080, 844, 790, 642. HRMS (ESI–TOF) (m/z):
+
[M+H] calcd for C20
H
19
N
4
O, 331.1553; found, 331.1548.
–1
(cm ) 3086, 2916, 2850, 1660, 1577, 1460, 1381, 1294, 1159, 933,
N-(5-bromo-1-(pyrimidin-2-yl)indolin-7-yl)benzamide (Table 4,
+
15
798, 696. HRMS (ESI–TOF) (m/z): [M+H] calcd for C16
H
19
N
2
O
2
,
entry 6d). Brown solid, Yield = 59.3 mg (75%). Mp 180-182 °C.
1
271.1441; found, 271.1450.
Isolated from flash chromatography (20% EtOAc/n-hexane). H
8
-(9H-carbazole-9-carboxamido)quinoline N-oxide (Table 3, en-
3
NMR (600 MHz, CDCl , δ): 11.60 (br, s, 1H, NH), 8.42 (d, J = 4.8
try 3zh). Brown solid, Yield = 45.9 mg (65%). Mp 190–192 °C.
Hz, 2H), 8.16 (s, 1H), 7.81 (d, J = 7.8 Hz, 2H), 7.48–7.51 (m, 1H),
7.42 (t, J = 7.8 Hz, 2H), 7.16 (d, J = 0.6 Hz, 1H), 6.72–6.74 (m,
1
Isolated from flash chromatography (90% EtOAc/n-hexane). H
1
3
1
NMR (600 MHz, CDCl
3
, δ): 14.91 (br, s, 1H, NH), 8.95 (d, J = 7.2
1H), 4.44–4.46 (m, 2H), 3.06–3.09 (m, 2H). C{ H} NMR (150
MHz, CDCl , δ): 165.8, 159.2, 157.9, 137.8, 135.8, 133.8, 131.7,
Hz, 1H), 8.33 (d, J = 5.4 Hz, 1H), 8.26 (d, J = 8.4 Hz, 2H), 8.03 (d,
J = 7.8 Hz, 2H), 7.78 (d, J = 8.4 Hz, 1H), 7.67 (t, J = 7.8 Hz, 1H),
3
128.6, 128.2, 127.4, 126.1, 124.1, 116.9, 111.9, 52.0, 28.6.IR
1
3
1
–1
7.50–7.54 (m, 3H), 7.35–7.37 (m, 2H), 7.23–7.25 (m, 1H). C{ H}
NMR (150 MHz, CDCl , δ): 150.6, 146.6, 140.6, 138.3, 137.2,
34.2, 132.4, 129.6, 129.4, 127.1, 125.6, 122.6, 122.4, 121.0,
(ZnSe): νmax (cm ) 2889, 1666, 1581, 1450, 1373, 1296, 1124,
+
3
1080, 910, 864, 790, 640, 599. HRMS (ESI–TOF) (m/z): [M+H]
1
1
1
4
calcd for C19H16BrN O, 395.0502; found, 395.0492.
–
1
20.8, 120.2, 120.0, 114.7. IR (ZnSe): νmax (cm ) 3097, 1687,
Synthesis of 2-benzamido-N-(tert-butyl)benzamide. To a solution
of N-(tert-butyl)benzamide (5e) (0.2 mmol) in HFIP (0.5 mL per
mmol) in a reaction vial euipped with magnetic stir bar, 3-Phenyl-
533, 1479, 1290, 1159, 935, 821, 740, 605. HRMS (ESI–TOF)
+
(m/z): [M+H] calcd for C22
H
16
N
3
O
2
, 354.1237; found, 354.1234.
Synthesis of various substituted N-(1-(pyrimidin-2-yl)indolin-7-
1,4,2-dioxazol-5-one 2a (1.1 equiv.), [CoCOCp*I
2
] (10 mol%),
yl)benzamides (6a-d). To a solution of various substituted 1-(py-
rimidin-2-yl)indoline (5a-d) (0.2 mmol) in HFIP (0.5 mL per
mmol) in a reaction vial equipped with magnetic stir bar, 3-Phenyl-
AgSbF (20 mol%) and AcOH (20 mol%) were added. The reaction
6
mixture was stirred at 50 ˚C for 12 h on a heating block, filtered
through a pad of celite using ethyl acetate solvent. After that filtrate
was transferred to round bottom flask and organic solvents were
removed under reduced pressure. The residue was purified by flash
chromatography on silica gel (mesh 230–400) to give the desired
product. Eluting solvents for chromatography are indicated under
the specific compound headings.
1
,4,2-dioxazol-5-one 2a (1.1 equiv.), [CoCOCp*I
2
] (10 mol%),
AgSbF (20 mol%) and AcOH (20 mol%) were added. The reaction
6
mixture was stirred at 50 ˚C for 12 h on a heating block, filtered
through a pad of celite using ethyl acetate solvent. After that filtrate
was transferred to round bottom flask and organic solvents were
removed under reduced pressure. The residue was purified by flash
chromatography on silica gel (mesh 230–400) to give the desired
product. Eluting solvents for chromatography are indicated under
the specific compound headings.
2-benzamido-N-(tert-butyl)benzamide (Table 4, entry 6e).8a
Brown solid, Yield = 34.9 mg (59%). Mp 185–187 °C. Isolated
1
from flash chromatography (25% EtOAc/n-hexane). H NMR (600
3
MHz, CDCl , δ): 11.92 (br, s, 1H, NH), 8.73 (d, J = 8.4 Hz, 1H),
Characterization Data. N-(1-(pyrimidin-2-yl)indolin-7-yl)ben-
8.02–8.03 (m, 2H), 7.53–7.55 (m, 1H), 7.50–7.52 (m, 2H), 7.46–
7.49 (m, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.03–7.05 (m, 1H), 6.19 (br,
15
zamide (Table 4, entry 6a). Brown solid, Yield = 48.0 mg (76%).
1
3
1
Mp 153–155 °C. Isolated from flash chromatography (10%
s, 1H, NH), 1.50 (s, 9H). C{ H} NMR (150 MHz, CDCl
3
, δ):
1
EtOAc/n-hexane). H NMR (600 MHz, CDCl
3
, δ): 11.42 (br, s, 1H,
169.2, 165.6, 139.6, 134.9, 132.3, 131.9, 128.9, 127.5, 126.7,
–
1
NH), 8.44 (d, J = 4.8 Hz, 2H), 7.93 (d, J = 8.4 Hz, 1H), 7.84–7.85
m, 2H), 7.47–7.50 (m, 1H), 7.41–7.44 (m, 2H), 7.15–7.17 (m, 1H),
122.9, 122.5, 121.8, 52.3, 28.9. IR (ZnSe): νmax (cm ) 3296, 2966,
(
1647, 1550, 1479, 1325, 1222, 1074, 885, 748, 653. HRMS (ESI–
+
7
7
.07 (dd, J = 7.2, 1.2 Hz, 1H), 6.70 (t, J = 4.8 Hz, 1H), 4.47 (t, J =
.8 Hz, 2H), 3.10–3.12 (m, 2H). C{ H} NMR (150 MHz, CDCl ,
3
TOF) (m/z): [M+Na] calcd for C18
319.1420.
20 2 2
H N NaO , 319.1417; found,
1
3
1
N-(2-(pyridin-2-yl)phenyl)benzamide (Table 4, entry 6f).21 To a
δ): 165.9, 159.5, 157.9, 136.3, 136.1, 134.7, 131.5, 128.6, 127.4,
–
1
27.3, 124.7, 123.9, 121.3, 111.6, 51.9, 28.9. IR (ZnSe): νmax (cm
solution of 2-phenylpyridine (5f) (0.2 mmol) in HFIP (0.5 mL per
mmol) in a reaction vial equipped with magnetic stir bar, 3-Phenyl-
1
) 3161, 2891, 1660, 1577, 1473, 1379, 1278, 1186, 1049, 991, 848,
+
781, 690. HRMS (ESI–TOF) (m/z): [M+H] calcd for C19
17.1397; found, 317.1395.
N-(2-methyl-1-(pyrimidin-2-yl)indolin-7-yl)benzamide (Table 4,
H
17
N
4
O,
1,4,2-dioxazol-5-one 2a (1.1 equiv.), [CoCOCp*I
2
] (10 mol%),
3
AgSbF (20 mol%) and AcOH (20 mol%) were added. The reaction
6
mixture was stirred at 50 ˚C for 12 h on a heating block, filtered
through a pad of celite using ethyl acetate solvent. After that filtrate
was transferred to round bottom flask and organic solvents were
removed under reduced pressure. The residue was purified by flash
chromatography on silica gel (mesh 230–400) to give the desired
1
5
entry 6b). Brown solid, Yield = 54.1 mg (82%). Mp 151–153 °C.
Isolated from flash chromatography (25% EtOAc/n-hexane). H
1
NMR (600 MHz, CDCl
3
, δ): 11.42 (br, s, 1H, NH), 8.45 (d, J = 4.8
Hz, 2H), 7.97 (d, J = 7.8 Hz, 1H), 7.86 (d, J = 7.2 Hz, 2H), 7.48–
ACS Paragon Plus Environment

Page 9 of 11
The Journal of Organic Chemistry
product. Eluting solvents for chromatography are indicated under
the specific compound headings. White solid, Yield = 19.2 mg
35%). Mp 114–117 °C. Isolated from flash chromatography (10%
NMR (600 MHz, CDCl
8.4 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 7.04 (dd, J = 8.4, 6.0 Hz, 1H),
6.94 (d, J = 7.8 Hz, 1H), 6.82 (br, s, 2H, NH ), 6.67 (d, J = 7.8 Hz,
3
1H). C{ H} NMR (150 MHz, CDCl , δ): 143.5, 135.6, 133.6,
3
, δ): 8.14 (d, J = 5.4 Hz, 1H), 7.51 (d, J =
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
2
1
13
1
EtOAc/n-hexane). H NMR (600 MHz, CDCl
NH), 8.80 (d, J = 8.4 Hz, 1H), 8.67 (d, J = 4.8 Hz, 1H), 8.03–8.05
m, 2H), 7.83– 7.86 (m, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.73 (dd, J
7.8, 1.8 Hz, 1H), 7.46 – 7.55 (m, 4H), 7.28–7.30 (m, 1H), 7.19–
3
, δ): 13.31 (br, s, 1H,
–
1
130.9, 129.5, 127.9, 120.5, 115.1 113.4. IR (ZnSe): νmax (cm )
(
3365, 3244, 3062, 2922, 1903, 1593, 1462, 1398, 1296, 1134, 1043,
+
=
964, 804, 740, 634. HRMS (ESI–TOF) (m/z): [M+H] calcd for
13
1
7
.22 (m, 1H). C{ H} NMR (150 MHz, CDCl
3
, δ): 165.7, 158.5,
C
9
H
9
N
2
O, 161.0709; found, 161.0695.
2
4
147.4, 138.3, 137.9, 135.9, 131.6, 130.4, 128.9, 128.7, 127.5,
N-(2-chloroquinolin-8-yl)benzamide (Scheme 6, 3ac). To an
–
1
125.7, 123.7, 123.1, 122.1, 122.0. IR (ZnSe): νmax (cm ) 2927,
oven–dried screw cap reaction vial charged with a spinvane mag-
netic stir–bar, 8-benzamidoquinoline N–oxide (3a, 0.1 mmol) and
thionyl chloride (2.0 mL) were added. The reaction mixture was
allowed to stir at 50 °C for 12 h on a heating block. After comple-
tion, the reaction mixture was collected in round bottom flask and
reaction vial was washed with DCM. Collected DCM fraction of
crude reaction mixture was evaporated under reduced pressure and
the products were isolated by flash chromatography using silica gel
(mesh 230–400). Eluting solvents for chromatography are indi-
cated under the specific compound headings. Off white solid, Yield
2
6
2
850, 2335, 1664, 1585, 1475, 1313, 1278, 1091, 947, 889, 754,
96. HRMS (ESI–TOF) (m/z): [M+H] calcd for C18H N O,
15 2
+
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
75.1179; found, 275.1153.
N-(benzo[h]quinolin-10-yl)benzamide (Table 4, entry 6g).21 To a
solution of benzo[h]quinoline (5g) (0.2 mmol) in HFIP (0.5 mL per
mmol) in a reaction vial equipped with magnetic stir bar, 3-Phenyl-
1,4,2-dioxazol-5-one 2a (1.1 equiv.), [CoCOCp*I
2
] (10 mol%),
AgSbF (20 mol%) and AcOH (20 mol%) were added. The reaction
6
mixture was stirred at 50 ˚C for 12 h on a heating block, filtered
through a pad of celite using ethyl acetate solvent. After that filtrate
was transferred to round bottom flask and organic solvents were
removed under reduced pressure. The residue was purified by flash
chromatography on silica gel (mesh 230–400) to give the desired
product. Eluting solvents for chromatography are indicated under
the specific compound headings. Brown solid, Yield = 32.2 mg
= 22.6 mg (80%). Mp 134–136 °C. Isolated from flash chromatog-
1
raphy (10% EtOAc/n-hexane). H NMR (600 MHz, CDCl
3
, δ):
10.29 (br, s, 1H, NH), 8.96–8.98 (m, 1H), 8.11 (d, J = 9.0 Hz, 1H),
8.06–8.07 (m, 2H), 7.55–7.61 (m, 4H), 7.52–7.53 (m, 1H), 7.43 (d,
1
3
1
J = 9.0 Hz, 1H). C{ H} NMR (150 MHz, CDCl
3
, δ): 165.6, 149.4,
139.4, 138.4, 135.0, 134.0, 132.1, 129.0, 128.0, 127.4, 126.7,
–
1
(
54%). Mp 158–160 °C. Isolated from flash chromatography (15%
122.9, 121.6, 118.0. IR (ZnSe): νmax (cm ) 3377, 3061, 1680, 1535,
1
EtOAc/n-hexane). H NMR (600 MHz, CDCl
NH), 9.37 – 9.38 (m, 1H), 8.94 (dd, J = 4.2, 1.8 Hz, 1H), 8.26–8.29
m, 3H), 7.84 (d, J = 9.0 Hz, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.67 (d,
3
, δ): 15.77 (br, s, 1H,
1475, 1388, 1251, 1118, 1097, 896, 746, 682. HRMS (ESI–TOF)
+
(m/z): [M+Na] calcd for C16
2
H11ClN NaO, 305.0452; found,
(
305.0454.
13
1
J = 8.4 Hz, 2H), 7.59–7.60 (m, 2H), 7.57–7.59 (m, 2H). C{ H}
NMR (150 MHz, CDCl , δ): 166.7, 148.0, 145.8, 139.9, 136.9,
36.7, 135.3, 131.6, 129.8, 129.3, 128.8, 127.8, 125.3, 123.4,
8-benzamido-2-(4-methoxyphenyl) quinoline N-oxide (Scheme 6,
2
5
3
3ad). To an oven–dried screw cap reaction vial charged with a
spinvane magnetic stir–bar, aryldiazonium tetrafluoroborate salt
(0.1 mmol), 8-benzamidoquinoline N-oxide (3a, 3 equiv.) and so-
dium acetate (2 equiv.) were added in MeCN (5 mL) and stir for 6
h at room temperature. After completion, reaction mixture was di-
luted with ethyl acetate and washed with brine solution three times.
1
1
1
–
1
20.9, 118.7, 118.1. IR (ZnSe): νmax (cm ) 2885, 1662, 1544, 1489,
342, 1288, 1182, 1093, 835, 709, 601. HRMS (ESI–TOF) (m/z):
+
[
M+H] calcd for C20
H
15
N
2
O, 299.1179; found, 299.1177.
22
N-(quinolin-8-yl)benzamide (Scheme 6, 3aa). To an oven–dried
screw cap reaction vial charged with a spinvane magnetic stir–bar,
8-benzamidoquinoline N–oxide (3a, 0.1 mmol), phenylboronic
acid (1.5 equiv.) and 0.5 mL DCE were added. The reaction mix-
ture was allowed to stir at 120 °C for 12 h on a heating block. After
completion, the reaction mixture was diluted with DCM and
washed with water three times. Combined organic layer was dried
over anhydrous sodium sulfate and evaporated under reduced pres-
sure and the products were isolated by flash chromatography using
silica gel (mesh 230–400). Eluting solvents for chromatography are
indicated under the specific compound headings. White solid,
2 4
Organic layer was dried over anhydrous Na SO and evaporated
under reduced pressure and the products were isolated by flash
chromatography using silica gel (mesh 230–400). Eluting solvents
for chromatography are indicated under the specific compound
headings. Orange solid, Yield = 19.6 mg (53%). Mp 184–186 °C.
1
Isolated from flash chromatography (40% EtOAc/n-hexane). H
3
NMR (600 MHz, CDCl , δ): 15.42 (br, s, 1H, NH), 9.31 (d, J = 8.4
Hz, 1H), 8.09 (d, J = 6.6 Hz, 2H), 7.92 (d, J = 9.0 Hz, 2H), 7.77 (d,
J = 8.4 Hz, 1H), 7.60–7.63 (m, 1H), 7.48–7.52 (m, 4H), 7.44 (d, J
1
3
1
= 8.4 Hz, 1H), 7.06 (d, J = 8.4 Hz, 2H), 3.90 (s, 3H). C{ H}NMR
(150 MHz, CDCl , δ): 165.8, 160.9, 146.8, 135.4, 135.2, 131.8,
131.5, 131.3, 129.3, 128.8, 128.5, 127.6, 125.4, 123.4, 122.4,
Yield = 14.1 mg (57%). Isolated from flash chromatography (10%
3
1
EtOAc/n-hexane). Mp 83–85 °C. H NMR (600 MHz, CDCl
3
, δ):
–
1
1
1
0.75 (br, s, 1H, NH), 8.94–8.96 (m, 1H), 8.84 (dd, J = 4.2, 1.8 Hz,
H), 8.17 (dd, J = 8.4, 1.2 Hz, 1H), 8.09–8.10 (m, 2H), 7.53–7.61
120.2, 114.1, 55.6. IR (ZnSe): νmax (cm ) 2850, 1660, 1577, 1485,
1485, 1381, 251, 1176, 974, 696. HRMS (ESI–TOF) (m/z):
13
1
+
(
m, 5H), 7.47 (dd, J = 8.4, 4.2 Hz, 1H). C{ H} NMR (150 MHz,
CDCl , δ): 165.6, 148.4, 146.6, 138.9, 136.5, 135.3, 134.7, 131.9,
128.9, 128.1, 127.6, 127.4, 121.8, 116.7. IR (ZnSe): νmax (cm )
350, 1670, 1523, 1483, 1388, 1267, 1128, 970, 898, 796, 673.
[M+H] calcd for C23
Deuterium labeling experiment. To a screw capped vial with a
stirbar quinoline N-oxide (0.1 mmol), [Cp*Co(CO)I (10 mol%),
AgSbF (20 mol%), CD CO D (20 mol%), HFIP-d (500 µL) and
CD OD (10 equiv.) were added. The reaction was stirred at 50 °C
19 2 3
H N O , 371.1390; found, 371.1385.
3
–
1
2 2
]
3
6
3
2
2
+
HRMS (ESI–TOF) (m/z): [M+Na] calcd for C16
71.0842; found, 271.0840.
-aminoquinoline N–oxide(Scheme 6, 3ab). To an oven-dried
H
12
N
2
NaO,
3
2
for 6 hours. After cooling to room temperature, the mixture was
dried under reduced pressure and extracted with EtOAc (3 x 10
mL). The combined organic phase was washed with saturated NaCl
solution (3 x 5 mL), dried over Na SO , and filtered. EtOAc was
2 4
removed under reduced pressure to obtain the crude product of C8
2
3
8
sealed tube charged with 8-benzamidoquinoline N–oxide (3a) (26.4
mg, 0.1 mmol, 100 mol %) and NaOH (224.0 mg, 5.6 mmol, 56
equiv.) was added EtOH (3 mL) at room temperature. The reaction
mixture was allowed to stir at 80 °C for 20 h on a heating block.
The reaction mixture was concentrated in vacuo. The reaction res-
idue was diluted with EtOAc and quenched with AcOH to adjust
deuterated quinoline N‐ oxide. The percentage of d‐ incorporation
1
was determined by H NMR. Peak areas at 8.72 ppm and 8.61 ppm
were compared to obtain the deuterium incorporation. Deuterium
incorporation was detected to be 40% by 1H NMR (Scheme 3a).
Parallel Reaction for KIE Study. In two different screw capped
pH = ~9. The organic layer was washed with H
2
O. The combined
organic layers were dried over Na SO4, filtered and concentrated
2
in vacuo. Yellow solid, Yield = 13.6 mg (85%). Mp 102–104 °C.
vial with a stirbar separately placed quinoline N-oxide (1a) and D
7
-
1
Isolated from flash chromatography (100% EtOAc/n-hexane). H
quinoline N-oxide (1a-D ), (0.1 mmol), [Cp*Co(CO)I ] (10
7
2
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mol%), AgSbF
6
(20 mol%), AcOH (20 mol%), HFIP were added,
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then both the mixtures were stirred at 50 °C for 6 hours on a heating
block at the same time. The k
1
H D
/k = 4.26 was calculated by H
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NMR spectroscopy (Scheme 3b).
Competitive Reaction for KIE Study. To a screw capped vial
with a stirbar consecutively placed 0.05 mmol of quinoline N-oxide
(
[
1a) and 0.05 mmol of
D
7
-quinoline N-oxide (1a-D
7
),
Cp*Co(CO)I ] (10 mol%), AgSbF
2
6
(20 mol%), AcOH (20 mol%),
HFIP were added, then the mixtures were stirred at 50 °C for 6
hours on a heating block. The k /k = 4.26 was calculated by H
H D
NMR. (Scheme 3b).
Competition experiment with quinoline N-oxide. To a screw
capped vial with a stirbar consecutively placed 0.05 mmol of quin-
oline N-oxide (1a) and 0.05 mmol of 6-methylquinoline N-oxide
1
0
1
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9
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9
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6, 47-77.
[Cp*Co(CO)I ] (10 mol%), AgSbF (20 mol%), AcOH (20 mol%),
2
6
3
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(
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2
6
4. (a) Kalsi, D.; Laskar, R. A.; Barsu, N.; Premkumar, J. R.; Sundararaju,
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mol%), HFIP were stirred at 50 °C for 12 hours. The product ratio
1
was calculated by H NMR. (Scheme 4a).
Competition experiment with dioxazolones. To a screw
capped vial with a stirbar consecutively placed 0.055 mmol of 3-
phenyl-1,4,2-dioxazol-5-one (2a) and 0.05 mmol of 3-p-
methylphenyl-1,4,2-dioxazol-5-one (2c), after that 0.1 mmol of
2 6
quinoline N-oxide (1a) [Cp*Co(CO)I ] (10 mol%), AgSbF (20
mol%), AcOH (20 mol%), HFIP were added. Then the mixtures
were stirred at 50 °C for 12 hours on a heating block. The product
1
ratio was calculated by H NMR. In another reaction vial, 0.05
3
029-3034; (e) You, C.; Pi, C.; Wu, Y.; Cui, X., Rh (III)-Catalyzed
Selective C8-H Acylmethylation of Quinoline N-oxides. Adv. Synth. Catal.
018, 360, 4068-4072;
mmol 3-phenyl-1,4,2-dioxazol-5-one (2a) and 0.05 mmol of 3-p-
chlorophenyl-1,4,2-dioxazol-5-one (2e), 0.1 mmol of quinoline N-
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2 6
] (10 mol%), AgSbF (20 mol%), AcOH
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Oxides at the C-8 Position Using a Cationic Rhodium(I) Catalyst. Adv.
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(20 mol%), HFIP were stirred at 50 °C on a heating block for 12
1
hours. The product ratio was calculated by H NMR. (Scheme 4b).
ASSOCIATED CONTENT
Supporting Information
Experimental procedures, details of optimization studies,
6
. Kwak, J.; Kim, M.; Chang, S., Rh(NHC)-Catalyzed Direct and Selective
Arylation of Quinolines at the 8-Position. J. Am. Chem. Soc. 2011, 133,
780-3783.
1
characterization data for all synthesized compounds including H
13
and C spectra. FAIR Data is available as Supporting Information
3
for Publication and includes the primary NMR FID files for
compounds [1y, 2g-j, 5a-d, 3a-i, 3k-q, 3s-w, 3y-z, 3za-zh, 6a-g,
7. (a) Hwang, H.; Kim, J.; Jeong, J.; Chang, S., Regioselective Introduction
of Heteroatoms at the C-8 position of Quinoline N-oxides: Remote C-H
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aa-3ad]
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0770-10776; (b) Dhiman, A. K.; Gupta, S. S.; Sharma, R.; Kumar, R.;
Sharma, U., Rh (III)-Catalyzed C (8)-H Activation of Quinoline N-Oxides:
Regioselective C-Br and C-N Bond Formation. J. Org. Chem. 2019, 84,
AUTHOR INFORMATION
1
8
2871-12880.
Corresponding
Author:
*upendra@ihbt.res.in;
. (a) Park, Y.; Park, K. T.; Kim, J. G.; Chang, S., Mechanistic Studies on
upendraihbt@gmail.com;
Web address: http://www.ihbt.res.in/en/staff/scientificstaff?
chronoform=sctdetail&task=detail&id=41
the Rh (III)-Mediated Amido Transfer Process Leading to Robust C-H
Amination with a New Type of Amidating Reagent. J. Am. Chem. Soc.
2015, 137, 4534-4542; (b) Hu, X.-H.; Yang, X.-F.; Loh, T.-P., Chelation-
Assisted
Amidobenziodoxolones:
Rhodium-Catalyzed
Direct3
Amidation
and
with
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2
Notes
C(sp )-H,
C(sp )-H,
Functionalizations. ACS Catal. 2016, 6, 5930-5934; (c) You, C.; Yuan, T.;
Huang, Y.; Pi, C.; Wu, Y.; Cui, X., Rhodium-Catalyzed Regioselective C8-
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The authors declare no competing financial interests
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