C-H Amidation and Amination of Arenes and Heteroarenes with Amide and Amine using Cu-MnO as a Reusable Catalyst under Mild Conditions

Article abstract of DOI:10.1021/acs.joc.0c02603

An atom-economical and efficient route for the direct amidation and amination of aryl C-H bonds using our synthesized recyclable heterogeneous Cu-MnO catalyst is reported here. The direct C-H amidation was carried out using a simple amide without any prea

Full text of DOI:10.1021/acs.joc.0c02603

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Article
C−H Amidation and Amination of Arenes and Heteroarenes with
Amide and Amine using Cu-MnO as a Reusable Catalyst under Mild
Conditions
Harshvardhan Singh, Chiranjit Sen, Eringathodi Suresh, Asit B. Panda,* and Subhash C. Ghosh*
Cite This: J. Org. Chem. 2021, 86, 3261−3275
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sı Supporting Information
ABSTRACT: An atom-economical and efficient route for the direct amidation and amination of aryl C−H bonds using our
synthesized recyclable heterogeneous Cu-MnO catalyst is reported here. The direct C−H amidation was carried out using a simple
amide without any preactivated coupling partner, and simple air was used as the sole oxidant. The reaction proceeds very smoothly
with a broad range of substrates containing numerous functional groups in very good to excellent yields. Direct C−H aminations
with a secondary amine were carried out under base-, ligand-, and external oxidant-free conditions in very good to excellent yields in
very mild conditions. Both the amidation and amination can be scaled up on a gram scale with similar yields. The major advantage is
that our catalyst is recyclable and reused several times without any significant loss of reactivity.
3
5−37
38,39
INTRODUCTION
stituted hydroxylamines, etc., using expensive Rh,
and Ir
Ru,
■
40−43
catalytic systems. All these reported processes
Incorporation of an amide moiety in organic molecules is one
of the most important transformations in organic synthesis.
The amide functional group is ubiquitous in natural products,
required preactivated coupling partners and mostly expensive
catalysts; thus, they are step and atom uneconomical.
Undeniably, cross-dehydrogenative coupling (CDC) for the
construction of C−N bonds is quite attractive since it is both
atom and step economical and proceeds without any
preactivation of either C−H or N−H reacting partners. It
only requires an oxidant for the sequential abstraction of a
hydrogen atom from both coupling partners. Comparing
aminations, direct amidation is more challenging due to the
pK narrowness of the amide as a coupling partner. Very few
examples are reported in the literature, and an intramolecular
Pd-catalyzed amidation was first reported by Buchwald using
Cu(OAc) as an oxidant. Daugulis used a Pd catalyst and
1
−7
polymers, and pharmaceuticals.
It was reported that about
5% of the known commercial drugs contain an amide
2
8
−10
group.
Thus, the development of methods for the
amidation of aromatics has received huge attention, focusing
on the discovery of highly efficient, atom economical, and
green conditions. Transition-metal-catalyzed cross-coupling
reactions are classical and efficient for the N-arylation of
amides, especially Buchwald−Hartwig amidation,
a cross-coupling between amides with aryl halides or pseudo
1
1−15
a
which is
halides using a palladium catalyst and expensive phosphine
44
1
6−21
2
ligands.
N-arylation of amides,
chelating diamine ligand and base.
coupling has also been applied for amidation, coupling with
Another pioneering work is the copper-catalyzed
22−29
the Goldberg reaction, using a
30−32
Received: November 2, 2020
Published: February 1, 2021
Chan−Lam oxidative
3
3,34
aryl boronic acids.
A prominent limitation of these
methods is the use of prefunctionalized substrates. In addition,
a range of amide precursors has been examined, such as
dioxazolones, benzoyl azides, N-hydroxycarbamates, N-sub-
©
2021 American Chemical Society
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3
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4
5
PhI(OAc) as oxidants. Yu and Che reported the intra-
prepared a manganese oxide-supported copper catalyst with
our reported procedure, where manganese oxide has dual
character as an ETM and support. It helps reduce copper to be
reoxidized and itself is oxidized by oxygen to complete the
cycle. As part of our ongoing research on C−H bond
2
molecular amidation of imine derivatives with primary
amides. Phthalimide as a coupling partner with PIDA as a
catalyst was independently reported by DeBoef and Sukbok
Chang. Jin Quan Yu reported the copper-catalyzed amidation
4
6
47
4
8
59−63
of aromatics with electron-deficient amides, but electron-
functionalization,
we herein wish to report the first
49
neutral carboxamides were not effective. Copper-catalyzed
amidation of 2-phenylpyridine with acyclic amides and imides
at a very high temperature (140 °C) and a longer reaction time
heterogeneous catalyst for the oxidative amidation of arenes
with a simple amide with key advantages such as the late-stage
introduction of the amide functionality in arenes, the
reusability of the catalyst, and the ligand-free and aerobic
conditions. The same catalyst is also effective for the amination
of arenes under milder reaction conditions.
50
(
24 h) was reported by Li and Chen et al. Thus, the
development of milder reaction conditions with a wide
substrate scope is quite challenging and highly demanding.
In terms of a green chemistry context, heterogeneous catalysis
is exciting due to the easy separation and the reusability of the
catalyst. Since we are working on heterogeneous catalysis, we
have designed and prepared several heterogeneous catalysts,
mainly focusing on the ease of preparation and the use of
inexpensive materials, and developed several morphological
CuOx-MnOy catalysts for numerous organic transformation
reactions.
Molecular oxygen is the most benign oxidant, but is rare and
kinetically unfavorable due to the high energy barrier for
electron transfer from a substrate to the oxidant. Backwell et al.
developed a new methodology by a biomimicking oxidative
process (Scheme 1). The use of a coupled catalytic system with
RESULTS AND DISCUSSION
■
We began our study by choosing the reaction of 8-
benzamidoquinoline (1a) and 2-pyrrolidinone (2a) in the
presence of our developed 5 wt % Cu on MnO and 2.0 equiv
of DMAP in toluene at 120 °C in a closed-carousel reaction
tube with air for 12 h. To our delight, the desired amidation
took place in the ortho-position of the phenyl ring, and the
desired product (3a) was obtained in a 43% yield (Table 1,
a
Table 1. Optimization of the Reaction Conditions
Scheme 1. Stepwise Electron-Transfer Pathway over the Cu-
MnO Catalyst
b
entry
catalyst
solvent
toluene
T (°C)
yield (%)
1
2
3
4
5
6
7
8
5% Cu-MnO
5% Cu-MnO
5% Cu-MnO
5% Cu-MnO
5% Cu-MnO
5% Cu-MnO
5% Cu-MnO
5% Cu-MnO
120
120
120
120
120
120
80
100
120
120
120
120
43
32
37
15
52
92
25
61
CH CN
3
NMP
THF
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
an electron-transfer mediator (ETM) facilitates the procedure
by transporting the electrons in a low energy pathway, which
increases the catalytic efficiency and the ease the oxidative
reactions. Based on this biomimetic oxidative concept, several
groups designed and developed a new copper/manganese
9
NR
NR
35
10
MnO
5% Cu-MnO
5% Cu-MnO
c
11
d
12
70
a
Reaction conditions are as follows: 1a (0.2 mmol), 2a (0.3 mmol, 1.5
equiv), Cu-MnO catalyst 25 mg (7.8 mol % Cu), and DMAP (2
5
1−54
oxide
systems.
and other transition metal/ETMs catalytic
Mizuno and co-workers reported copper
5
5−58
b
c
equiv) in 1 mL of solvent in air at 120 °C for 12 h. Isolated yield. In
the absence of DMAP. Catalyst loading was 12 mg.
d
hydroxide on manganese oxide-based OMS-2 for alkyne
5
1
homocoupling. Copper oxide supported by mesoporous
manganese oxide for the coupling of alkynes was developed by
entry 1). Encouraged by this result, we first screen the solvent
for this reaction. We found that the solvent played a crucial
role for the amidation, and DMSO was superior (92%) to all
5
2
S. L. Suib. P. Zhao et al. reported the OMS-2-supported
53,54
copper catalyst for the synthesis of heterocycles.
The redox
potential of the MnO /Mn O reaction is 1.04 V, which lies
the other solvents, including CH CN, NMP, THF, and DMF
2
2
3
3
between the redox potential of the CuO/Cu O (0.67 V)
(entries 2−6). Running the reaction at lower temperatures (80
and 100 °C) lowered the yield significantly (entries 7 and 8,
respectively). No reaction took place in the control experiment
in the absence of a catalyst and with simple MnO, revealing
that the presence of the Cu-MnO catalyst is essential for this
reaction (entries 9 and 10, respectively). Next, we checked the
role of DMAP. In absence of DMAP, the desired product was
obtained in a lower yield, which indicates that DMAP is
required for the reaction; other bases, such as Na CO , K CO ,
2
reaction and the O /H O (1.23 V) reaction. Thus, the large
2
2
gap of the redox potential between the substrate or reduced
catalyst with molecular oxygen can be avoided, and it has been
reported that reduced manganese oxide can be reoxidized by
simple oxygen.
Thus, preparing a CuOx/MnOy catalyst and performing an
oxidative reaction will accelerate the electron-transfer pathway
by lowering the redox energy barrier in a step-by-step way. We
hypothesized that our Cu-MnO catalyst could complete the
oxidative amidation reaction by helping the rapid electron-
transfer pathway in key reductive elimination steps. We have
2
3
2
3
and Et N, were less effective than DMAP (Table S1). The
3
reaction where the catalyst loading was lowered to 50% (12
mg) slightly decreased the yield (70%, entry 12).
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a
Table 2. Direct C−H Amidation of Benzamides
a
Reaction condition are as follows: 1 (0.2 mmol), 2 (0.3 mmol, 1.5 equiv), Cu-MnO catalyst (25 mg) and DMAP (2 equiv) in 1 mL of DMSO in
air at 120 °C for 12 h.
With the optimization conditions in hand, we next explored
the substrate scope and limitation. The reaction of 8-
aminoquinoline benzamides with different cyclic amides is
summarized in Table 2. The amidation reaction with γ-lactam
goes well with both the electron-rich and electron-poor
benzamide derivatives (entries 3a−3d, 85−93%). For the
unsymmetrical meta-substituted benzamides, amidation occurs
selectively at the less sterically hindered position (entry 3e,
Next, we checked the different functional groups substituted
(Me, OMe, F, and Cl) in 2, 5, and 6 positions of 8-amino
quinoline with 2a; for all derivatives, the amidation occurred
smoothly with excellent yields (85−93%, entries 3g−3j,
respectively). An excellent yield was also observed with the
1-naphthyl amide derivative (entry 3k). Further, very good to
excellent yields were observed for the amidations with δ-lactam
(2b) and ε-lactam (2c), and the electronic nature of the
phenyl ring was not so significant (entries 3l−3p). Moreover,
the reaction was successful with the thiophene derivatives; β-
lactam (2a), δ-lactam (2b), and ε-lactam (2c) reacted nicely,
8
1%), and other products were not observed even in the crude
NMR. ortho-Substituted (fluoro)benzamides reacted nicely
and provided the desired product in a 71% yield (entry 3f).
3
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a
Table 3. Direct C−H Amination of Benzamides
a
Reaction conditions are as follows: 1 (0.2 mmol), 4 (0.3 mmol, 1.5 equiv), and the Cu-MnO catalyst (15 mg, 4.7 mol % Cu) in 1 mL of toluene in
N at 100 °C for 6 h.
2
and a good yield of the desired product was obtained (65−
efficient method using simple Cu(OAc) or (CuOH) CO as
2 2 3
6
7%, entries 3q−3s, respectively). The single-crystal structure
the catalyst and air as a terminal oxidant with a wide range of
71
of 3r further confirmed the structure of the amidated product
and the α−C−H activation of the aryl ring.
amine coupling partners. Jana has reported the copper(II)-
2
mediated C(sp )−H amination of aminoquinoline benzamides
2
72
After the successful ortho-C(sp )−H amidation reaction of
with challenging electron-rich aniline derivatives. A similar
the aryl and heteroaryl compounds, we envisioned that our
catalyst would also work for the direct amination of aryl C−H
bonds. Notably, Yu and co-workers first reported the copper-
amination reaction was reported by Truong using a
heterogeneous Cu-MOF catalyst and N-methyl morpholine
75
oxide (NMO) as an oxidant. We optimized our reaction
conditions and were delighted to find that the amination works
under milder conditions than the amidation, in toluene at 100
°C for 6 h under an inert atmosphere with a lower catalyst (5
wt % Cu-MnO) loading (15 mg, 4.7 mol % Cu) and without
any additives. The C−H amination of 8-amino quinoline
benzamides with different cyclic and acyclic amines was next
investigated under the optimized reaction conditions. The
results are summarized in Table 3. Benzamides consisting of
both electron-donating and electron-withdrawing functional
64
catalyzed pyridine-directed C−H amination reaction. After
that, several groups have successfully reported the Cu-catalyzed
2
C(sp )−H amination with a different directing group, mostly
6
5−76
under homogeneous conditions.
In particular, the 8-
2
aminoquinoline-assisted amination of ortho-C(sp )−H bonds
of benzoic acid derivatives was first reported by Daugulis and
co-workers by employing simple Cu(OAc) as a catalyst and
2
N-methyl morpholine oxide (NMO) as an oxidant in the
70
presence of a Ag CO additive. The same group made an
2
3
exceptional advancement and reported a more general and
groups, such as OMe, Cl, F, and CF , on the para-position of
3
3
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the phenyl ring reacted very well with 4-methylpiperidine (4a)
and produced the corresponding aminated products in good to
excellent yields (Table 3, entries 5a−5e). We next investigated
other cyclic amines in combination with different benzamide
derivatives. 4-Phenylpiperidine (4b) reacts with benzamides
Table 4. Reusability of the Catalyst for Both Amidation (3a)
and Amination (5a)
(
(
1a), 4-methoxy benzamides (1b), and 4-chloro benzamides
1m) in excellent yields (92−96%, entries 5f−5h, respected).
As expected, the reaction of meta-Me-substituted benzamides
with 4-methylpiperidine proceeds well, similar to amidation,
and amination occurs selectively in the less sterically hindered
position (entry 5i). Next, morpholine (4c) as an amine was
tested and reacted with various functional group-substituted
benzamides, providing the ortho-aminated product in very
good to excellent yields (entries 5j−5n).
Reactions with naphthalene-1-amide proceed nicely, and the
C2-aminated product was observed selectively with morpho-
line and thiomorpholine (65% and 68%, respectively, entries
sphere was observed (see the Supporting Information for
details).
5
o and 5p). A heterocyclic substrate such as thiophene works
well, and a moderate yield of the desired product was obtained
46%, entry 5q). Other cyclic amines such as 1,2,3,4-
Next, we turned our attention to gain insight into the
reaction mechanism. First, we carried out the reaction in the
presence of radical scavengers such as TEMPO [(2,2,6,6-
tetramethylpiperidin-1-yl)oxyl] and BHT (butylated hydroxyl
toluene) and found that reactions proceeds well, confirming
that the reaction does not proceed through a radical pathway.
(
tetrahydroisoquinoline and 1-methyl piperazine are also
equally effective aminating agents (5r and 5s). To our delight,
acyclic N-methyl benzylamine was also found to be reactive,
and the desired product was obtained in a very good yield
(
71%, 5t). However, the amination reaction was not
(
Scheme 3a) The parallel KIE experiment was carried out next
compatible with a primary amine, tosylamide, and indole
under the optimized reaction conditions (entries 5u, 5v, and
by the intermolecular competitive reaction of two isotopomeric
substrates (1a and 1a-D, Scheme 3b), and the k /k value
H
D
5w). Both the amidation and amination reactions were scaled
observed was 1.04, indicating that C−H bond activation is not
the rate-determining step. Next, we carried out the reaction
under standard optimized conditions with several designed
substrates (6a−c). When N-methyl-N-(quinolin-8-yl)-
benzamide (6a), N-(naphthalene-1-yl)benzamide (6b), and
N-methoxybenzamide (6c) were examined under standard
conditions, no amidation product was obtained. These results
indicate that the presence of a secondary amide and a
quinoline moiety is important; thus, the presence of the N,N-
bidentate ligand is crucial for this reaction. It follows the
general transition-metal-catalyzed dehydrogenative amidation
pathway via a C−H activation step, as proposed by
up to a gram scale, and compounds 3a and 5a were successfully
synthesized in comparable yields (Scheme 2).
Scheme 2. Gram-Scale Synthesis of Amidated and Aminated
Products
44−46,49−51,77,78
others.
CONCLUSION
■
In conclusion, we have developed a very efficient and reusable
heterogeneous Cu-MnO catalyst for the C−H amidation and
amination of arenes and hetarenes with simple amides and
amines under mild reaction conditions. This is the first report
for the direct amidation of arenes with a heterogeneous
catalyst. Amidation reactions proceed under aerobic con-
ditions, and amination reactions do not need any additive.
Both reactions proceed well and give moderate to excellent
yields with a good functional group tolerance. The reaction is
scalable, and our catalyst showed very good reusability; up to
the fourth recycle, it exhibited a similar productivity.
We monitored the reaction progress after separating the
catalyst from the reaction mixture via cannula; no further
production of the product was observed, which indicates that
the active catalyst did not leach into the solution. The hot
filtration test further confirmed the heterogeneity of the
reaction. An ICP-AES analysis was carried out on the filtrate of
the standard reaction (synthesis of 3a), and a negligible
amount of Cu (<1 ppm) was leached. After the completion of
the reaction, the catalyst was simply filtered, washed with
acetone, and calcined at 350 °C in 5% hydrogen in nitrogen for
recycling; it exhibited a very good reusability for both the
reactions (Table 4). The small drop in yields after each cycle
was not due to the loss of Cu but was instead due to the
EXPERIMENTAL SECTION
■
General Methods and Materials. All reactions were carried out
in oven-dried glassware under standard reaction conditions. All
starting materials (8-aminoquinoline benzamides) were synthesized
using commercially available 8-aminoquinoline and other benzoyl
chloride derivatives. Amines and amides were also purchased from a
commercial source and used without further purification. All the
solvents were purchased from S. D. Fine Chemicals Ltd. India, dried
through the standard procedure, and stored under nitrogen. Analytical
60,61
sintering of impregnated copper.
We recorded EDX-SEM
images of the fresh and reused catalyst; in both cases, a
homogeneous distribution of Cu over the manganese oxide
3
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Scheme 3. Mechanistic Investigation
thin-layer chromatography (TLC) was performed on precoated silica
gel 60 F254 plates. Visualization on TLC was achieved by UV light
water (15 mL) and ethyl acetate (3 × 25 mL) and washed with a
brine solution (20 mL). The combined organic layer was dried over
Na SO . The organic part was removed under reduced pressure,
yielding a residue that was purified by flash column chromatography
using hexane/ethyl acetate (5:1) as an eluent to isolate the desired
product 4a. All other aminated products were purified by flash
chromatography using hexane/ethyl acetate as an eluent and prepared
following this general procedure.
(
254 nm). Flash column chromatography purification of the
compounds was carried out by gradient elution using ethyl acetate
EA) in light petroleum ether (PE) or hexane unless otherwise stated.
2
4
(
1
13
H and C NMR spectra recorded on a 600/151 and 500/126 MHz
NMR spectrometer, in CDCl3, unless otherwise stated, using either
TMS or the undeuterated solvent residual signal as the reference. The
following abbreviations were used to describe the peak splitting
patterns when appropriate: br = broad, s = singlet, d = doublet, t =
triplet, m = multiplet, and dd = doublet of the doublet. Coupling
constants J were reported in hertz (Hz). A Bruker D8 QUEST
instrument was used for crystal measurements. Mass spectral data
were obtained from the AESDCIF division of our Institution using the
electrospray ionization time-of-flight (ESI-TOF) mode on the mass
spectrometer.
Control Experiments Study for the Mechanism. A Control
Experiment in the Presence of a Radical Inhibitor. To a carousel
reaction tube equipped with a magnetic stir bar and charged with our
synthesized Cu-MnO (25 mg), N-(quinolin-8-yl)benzamide (1a, 0.2
mmol, 1 equiv), DMAP (2 equiv), and TEMPO (1 equiv) or BHT (1
equiv) in DMSO (1 mL) was added 2-pyrrolidinone (2a, 1.5 equiv)
under an air atmosphere. The closed tube was placed in a preheated
carousel reactor at 120 °C. After 12 h, product 3a was obtained in an
87% or 85% yield with TEMPO or BHT, respectively, which implied
General Procedure for the Amidation of 8-Aminoquinoline
Benzamides. Procedure. To a carousel reaction tube equipped with
a magnetic stir bar, our synthesized Cu-MnO (25 mg), N-(quinolin-8-
yl)benzamide (1a, 49.6 mg, 0.2 mmol, 1 equiv), and DMAP (48.9 mg,
that the reactions proceeded well and confirmed that the reaction
does not proceed through a radical pathway.
KIE Experiments. Two sets of independent reactions with 1a and
1a-D2 under the optimal reaction conditions were carried out. To a
10 mL carousel reaction tube charged with either 1a (49.6 mg, 0.2
mmol, 1.0 equiv) or 1a-D2 (50.0 mg, 0.2 mmol, 1.0 equiv), Cu-MnO
(25 mg), and DMAP (48.9 mg, 0.4 mmol) were added anhydrous
DMSO (1.0 mL) and 2-pyrrolidinone (2a, 1.5 equiv). Then, the
reaction mixture was stirred at 120 °C under air. A 0.1 mL aliquot was
withdrawn periodically and filtered through a small bed of silica-gel,
and the yield of the product was monitored by HPLC analysis. By
comparing the rate of two individual reactions, the kinetic isotope
2
equiv) were added DMSO (1 mL) and 2-pyrrolidinone (2a, 1.5
equiv) under an air atmosphere. The closed tube was placed in a
preheated carousel reactor at 120 °C for 12 h. After the reaction
reached completion, the reaction mixture was cooled to room
temperature. Subsequently, the crude mixture was diluted with water
(
15 mL), extracted with ethyl acetate (3 × 25 mL), and washed with a
brine solution (20 mL). The combined organic layer was dried over
Na SO . The organic part was removed under reduced pressure,
2
4
yielding residue that was purified by flash column chromatography
using hexane/ethyl acetate (5:2) as an eluent to isolate the desired
product 3a. All other amidated products were purified by flash
chromatography using hexane/ethyl acetate as an eluent and prepared
following this general procedure.
General Procedure for the Amination of 8-Aminoquinoline
Benzamides. Procedure. To a carousel reaction tube equipped with
a magnetic stir bar, our synthesized Cu-MnO (15 mg), and N-
effect (KIE) was determined as k /k = 1.04.
H D
Synthesis of N-(Quinolin-8-yl)benzamide. All amides (starting
material) were synthesized according to our previously reported
79
method.
Representative Procedure. A 100 mL round-bottom flask was
charged with 8-aminoquinoline (5.0 mmol), Et N (1.2 equiv), and
3
dichloromethane (12 mL) under an inert atmosphere. The
corresponding acid chloride (5.5 mmol) in dichloromethane was
added slowly at 0 °C. The mixture was stirred overnight at room
temperature. The reaction was quenched with 10 mL of a saturated
(
quinolin-8-yl)benzamide (1a, 49.6 mg, 0.2 mmol, 1 equiv) were
added dry toluene (1 mL) as a solvent and 4-methylpiperidine (4a,
.3 mmol, 1.5 equiv) under a nitrogen atmosphere. The closed tube
0
was placed in a preheated carousel reactor at 100 °C for 6 h. After the
reaction reached completion, the reaction mixture was cooled to room
temperature. Subsequently, the crude mixture was extracted with
NaHCO solution and extracted with dichloromethane (3 × 20 mL).
3
The combined organic layer was washed with brine and dried over
anhydrous Na SO . The solvent was removed under reduced
2
4
3
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pressure, and the pure product was isolated by flash chromatography
using hexane/ethyl acetate (5:1)
Synthesis of Spherical Cu-MnO Catalysts. Synthesis of
Spherical γ-MnO . Spherical γ-MnO was synthesized according to
2
2
7
6,77,80,81
our previously reported method.
Typical Synthetic Procedure. To a 40 mL beaker charged with
−
2
deionized water were added manganese acetate (2 g, 1.01 × 10
mol) and ethylene glycol (2 g, 1.04 x10− mol) to make the clear
2
2H), 7.47 (dd, J = 8.2, 4.3 Hz, 1H), 3.97 (t, J = 7.0 Hz, 2H), 2.48 (t, J
13 1
=
8.0 Hz, 2H), 2.17 (t, J = 7.5 Hz, 2H); C{ H} NMR (151 MHz,
solution under stirring conditions. Then, an aqueous solution of
ammonium carbonate (4 g, 0.025 mol) was added dropwise to the
premixed solution to make the total volume 40 mL. After stirring, the
resulting clear solution was transferred to a 60 mL Teflon-lined
stainless steel autoclave, sealed tightly, and heated at 150 °C for 15 h.
After that, the autoclave was allowed to cool, and the resultant
precipitates were washed with deionized water and ethanol by
centrifugation and dried at 70 °C for an hour. Finally, the dried
powder was calcined at 350 °C for 6 h under an air atmosphere.
Synthesis of Cu-MnO Catalysts. The impregnation method was
used for the preparation of Cu-impregnated MnO (Cu-MnO) using
Cu(OAc) ·H O and γ-MnO , followed by calcination under 5% H
CDCl ) δ 175.6, 164.5, 148.5, 138.7, 137.4, 137.1, 136.5, 134.5, 133.6
3
(q, J = 33.8 Hz), 130.3, 128.2, 127.5, 124.3 (q, J = 2.5 Hz), 124.0 (q, J
=
2.6 Hz), 123.4 (q, J = 273.3 Hz), 122.4, 122.0, 117.0, 51.1, 31.5,
1
9
1
9.0; F NMR (565 MHz, CDCl ) δ −68.43; HRMS (ESI-TOF) m/
3
+
z [M + H] calcd for C H F N O 400.1273, found 400.1259.
2
1
17
3
3
2
4
-Iodo-6-(2-oxopyrrodin-1-yl)-N-(quinoline-8-yl)benzamide (3d).
1
R = 0.28, light brown oil, hexane/EtOAc = 5:2, 80 mg, 85%: H
f
2
2
2
2
and 95% N condition.
2
Synthetic Procedure. Under stirring conditions, 500 mg of γ-
MnO and 67.5 mg (5 wt % with respect to MnO ) of copper Acetate
2
2
[
Cu(OAc) ·H O] were added to a methanol solution, followed by
2 2
NMR (600 MHz, CDCl ) δ 10.45 (s, 1H), 8.85 (d, J = 7.5 Hz, 1H),
3
sonication. The resultant slurry was evaporated to dryness with
continuous stirring (500 rpm) at 70 °C under atmospheric pressure.
The resultant dried powder was calcined at 350 °C for 6 h under 5%
H and 95% N .
8
7
=
.83−8.75 (m, 1H), 8.17 (d, J = 7.8 Hz, 1H), 7.80−7.76 (m, 1H),
.73 (s, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.59−7.53 (m, 2H), 7.45 (dd, J
8.2, 3.7 Hz, 1H), 3.90 (t, J = 6.9 Hz, 2H), 2.48 (t, J = 8.0 Hz, 2H),
13
1
2
2
2.17−2.08 (m, 2H); C{ H} NMR (151 MHz, CDCl ) δ 175.6,
3
Spectral Characterization Data of Amidation. 2-(2-Oxopyr-
1
1
64.9, 148.3, 138.7, 137.8, 136.8, 136.5, 136.1, 134.6, 133.4, 131.0,
28.1, 127.5, 122.2, 121.9, 116.9, 97.3, 51.3, 31.5, 19.0; HRMS (ESI-
rodin-1-yl)-N-(quinoline-8-yl)benzamide (3a). R = 0.29, yellow
f
+
TOF) m/z [M + Na] calcd for C H IN NaO 480.0185, found
2
0
16
3
2
4
80.0184.
5
-Methyl-2-(2-oxopyrrodin-1-yl)-N-(quinoline-8-yl)benzamide
(3e). R = 0.30, light yellow solid, mp 153−155 °C, hexane/EtOAc =
f
1
sticky gum, hexane/EtOAc = 5:2, 61 mg, 92%: H NMR (600 MHz,
CDCl ) δ 10.47 (s, 1H), 8.89 (d, J = 7.2 Hz, 1H), 8.80 (d, J = 2.8 Hz,
3
1
3
2
H), 8.21−8.14 (m, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.63−7.52 (m,
H), 7.49−7.42 (m, 2H), 7.37 (d, J = 7.9 Hz, 1H), 3.92 (t, J = 6.9 Hz,
1
3
1
H), 2.49 (t, J = 8.0 Hz, 2H), 2.14−2.09 (m, 2H); C{ H} NMR
1
5
:2, 56 mg, 81%: H NMR (500 MHz, CDCl ) δ 10.45 (s, 1H), 8.88
3
(151 MHz, CDCl ) δ 175.7, 165.7, 148.3, 138.8, 136.8, 136.5, 134.9,
3
(dd, J = 7.4, 1.2 Hz, 1H), 8.80 (dd, J = 4.2, 1.6 Hz, 1H), 8.16 (dd, J =
.3, 1.6 Hz, 1H), 7.72 (d, J = 1.4 Hz, 1H), 7.62−7.50 (m, 2H), 7.44
dd, J = 8.2, 4.2 Hz, 1H), 7.39−7.32 (m, 1H), 7.27−7.22 (m, 1H),
3.87 (t, J = 7.0 Hz, 2H), 2.47 (t, J = 8.1 Hz, 2H), 2.43 (s, 3H), 2.11−
.03 (m, 2H); C{ H} NMR (126 MHz, CDCl ) δ 175.8, 165.8,
148.3, 138.8, 137.9, 136.5, 134.9, 134.1, 133.7, 132.5, 130.3, 128.1,
27.6, 127.4, 122.0, 121.8, 116.9, 51.6, 31.6, 21.2, 19.0; HRMS (ESI-
1
5
34.0, 131.8, 129.8, 128.1, 127.8, 127.6, 127.4, 122.0, 121.8, 116.9,
8
(
+
1.5, 31.6, 19.0; HRMS (ESI-TOF) m/z [M + H] calcd for
C H N O 332.1399, found 332.1392.
20
18
3
2
4
-Methoxy-2-(2-oxopyrrolidin-1-yl)-N-(quinoline-8-yl)-
13
1
2
3
benzamide (3b). R = 0.25, yellow solid, mp 186−188 °C, hexane/
f
1
+
TOF) m/z [M + H] calcd for C H N O 346.1556, found
2
1
20
3
2
3
(3f). R = 0.28, light yellow solid, mp 218- 220 °C, hexane/EtOAc =
1
EtOAc = 5:2, 67 mg, 93%: H NMR (500 MHz, CDCl ) δ 10.49 (s,
3
1
H), 8.90 (d, J = 6.8 Hz, 1H), 8.80 (dd, J = 4.2, 1.6 Hz, 1H), 8.17
(
dd, J = 8.3, 1.5 Hz, 1H), 7.92 (d, J = 8.7 Hz, 1H), 7.62−7.51 (m,
2
6
2
1
1
H), 7.45 (dd, J = 8.2, 4.2 Hz, 1H), 6.96 (dd, J = 8.7, 2.5 Hz, 1H),
.87 (d, J = 2.5 Hz, 1H), 3.93−3.85 (m, 5H), 2.53 (t, J = 8.1 Hz, 2H),
.16−2.06 (m, 2H); C{ H} NMR (126 MHz, CDCl ) δ 175.8,
1
3
1
3
1
65.3, 162.3, 148.2, 138.8, 138.5, 136.5, 135.0, 131.6, 128.1, 127.6,
5:2, 50 mg, 71%: H NMR (600 MHz, CDCl
3
) δ 10.35 (s, 1H), 8.84
26.1, 121.8, 116.8, 113.2, 113.1, 55.8, 51.6, 31.7, 19.0; HRMS (ESI-
(d, J = 6.2 Hz, 1H), 8.80 (d, J = 4.2 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H),
7.57−7.54 (m, 2H), 7.49 (q, J = 7.7 Hz, 1H), 7.44 (dd, J = 8.2, 4.0
Hz, 1H), 7.17 (t, J = 8.5 Hz, 2H), 3.90 (t, J = 7.0 Hz, 2H), 2.42 (t, J =
+
TOF) m/z [M + K] calcd for C H N O K 400.1063, found
2
1
19
3
3
4
1
3
1
8.0 Hz, 2H), 2.12 (t, J = 7.5 Hz, 2H); C{ H} NMR (151 MHz,
benzamide (3c). R = 0.23, light yellow oil, hexane/EtOAc = 5:2, 71
CDCl ) δ 175.4, 161.4, 160.0 (d, J = 250.2 Hz), 148.6, 138.7 (d, J =
f
3
1
mg, 89%: H NMR (600 MHz, CDCl ) δ 10.47 (s, 1H), 8.89−8.83
5.6 Hz), 136.3, 134.6, 131.8 (d, J = 9.5 Hz), 128.1, 127.4, 123.7 (d, J
= 17.9 Hz), 123.3 (d, J = 2.4 Hz), 122.3, 121.9, 117.0, 115.4, 115.2,
3
(m, 1H), 8.80 (d, J = 4.4 Hz, 1H), 8.18 (d, J = 9.3 Hz, 1H), 8.02 (d, J
1
9
=
51.5, 31.4, 19.2; F NMR (565 MHz, CDCl ) δ −118.70 to −118.73
3
3
267
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Article
+
(
3
m); HRMS (ESI-TOF) m/z [M + Na] calcd for C H FN O Na
72.1124, found 372.1175.
(m, 1H), 7.47−7.40 (m, 2H), 7.35 (d, J = 7.9 Hz, 1H), 7.13 (dd, J =
8.7, 2.6 Hz, 1H), 3.93 (t, J = 7.0 Hz, 2H), 2.48 (t, J = 8.0 Hz, 2H),
2
0
16
3
2
1
3
1
N-(2-Methylquinoline-8-yl)-2-(2-oxopyrrodin-1-yl)benzamide
3g). R = 0.30, light yellow oil, hexane/EtOAc = 5:2, 59 mg, 85%: H
2.15 (q, J = 7.1 Hz, 2H); C{ H} NMR (126 MHz, CDCl
165.8, 161.1 (d, J = 246.3 Hz), 147.4, 136.9, 136.6 (d, J = 13.2 Hz),
36.0, 135.9 (d, J = 5.1 Hz), 133.5, 132.0, 129.6, 128.6 (d, J = 11.6
Hz), 127.7, 127.1, 122.7, 107.6 (d, J = 33.1 Hz), 104.7 (d, J = 22.5
3
) δ 175.6,
1
(
f
1
1
9
Hz), 51.4, 31.6, 19.0; F NMR (565 MHz, CDCl ) δ −114.79 to
3
−
114.82 (m); HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C H FN O Na 372.1124, found 372.1120.
2
0
16
3
2
2
-(2-Oxopyrrodin-1-yl)-N-(quinoline-8-yl)-1-naphthamide (3k).
1
R = 0.31, sticky yellow gum, hexane/EtOAc = 5:2, 61 mg, 80%: H
f
NMR (600 MHz, CDCl ) δ 10.48 (s, 1H), 8.93−8.81 (m, 1H), 8.04
3
(
d, J = 8.2 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.57 (t, J = 7.2 Hz, 1H),
7
7
.51−7.49 (m, 2H), 7.44 (t, J = 7.5 Hz, 1H), 7.40 (d, J = 7.9 Hz, 1H),
.32 (d, J = 8.2 Hz, 1H), 3.89 (t, J = 6.9 Hz, 2H), 2.73 (s, 3H), 2.45
t, J = 8.0 Hz, 2H), 2.04 (t, J = 7.5 Hz, 2H); 13C{ H} NMR (151
1
(
MHz, CDCl ) δ 175.5, 165.8, 157.7, 138.0, 137.0, 136.5, 134.2, 134.2,
3
1
3
31.8, 129.8, 127.8, 127.5, 126.5, 126.2, 122.7, 121.8, 116.7, 51.5,
1.7, 25.2, 19.2; HRMS (ESI-TOF) m/z [M + H] calcd for
+
NMR (500 MHz, CDCl ) δ 10.35 (s, 1H), 9.02 (dd, J = 7.3, 1.3 Hz,
3
C H N O 346.1556, found 346.1565.
1H), 8.75 (dd, J = 4.1, 1.5 Hz, 1H), 8.20−8.11 (m, 2H), 8.00 (d, J =
8.7 Hz, 1H), 7.91−7.89 (m, 1H), 7.65−7.59 (m, 2H), 7.56−7.51 (m,
2H), 7.47−7.40 (m, 2H), 3.91 (t, J = 6.9 Hz, 2H), 2.37 (t, J = 8.0 Hz,
21
20
3
2
N-(5-Chloroquinoline-8-yl)-2-(2-oxopyrrodin-1-yl)benzamide
(3h). R = 0.28, light yellow solid, mp 208- 210 °C, hexane/EtOAc =
f
1
3
1
2
1
1
1
H), 2.04 (t, J = 7.5 Hz, 2H); C{ H} NMR (126 MHz, CDCl ) δ
3
75.7, 166.1, 148.8, 138.8, 136.3, 134.6, 133.8, 132.8, 132.8, 131.3,
31.0, 128.3, 128.2, 127.7, 127.4, 126.9, 125.4, 125.1, 122.5, 121.9,
17.0, 51.6, 31.3, 19.5; HRMS (ESI-TOF) m/z [M + H] calcd for
+
C H N O 382.1556, found 382.1545.
2
4
20
3
2
2
-(2-Oxopiperidin-1-yl)-N-(quinoline-8-yl)benzamide (3l). R =
f
1
0
.28, sticky gum, hexane/EtOAc = 5:2, 61 mg, 88%: H NMR (500
1
5
8
7
7
2
1
1
:2, 68 mg, 93%: H NMR (600 MHz, CDCl ), δ 10.41 (s, 1H),
3
.84−8.83 (m, 2H), 8.63−8.47 (m, 1H), 7.90 (d, J = 6.8 Hz, 1H),
.63 (d, J = 8.2 Hz, 1H), 7.59−7.54 (m, 2H), 7.44 (t, J = 7.5 Hz, 1H),
.36 (d, J = 7.9 Hz, 1H), 3.91 (t, J = 7.1 Hz, 2H), 2.48 (t, J = 8.0 Hz,
H), 2.17−2.07 (m, 2H); C{ H} NMR (151 MHz,) δ 175.6, 165.7,
49.0, 139.3, 136.9, 134.1, 133.8, 133.5, 131.9, 129.6, 127.7, 127.4,
27.2, 126.1, 124.7, 122.6, 116.8, 51.4, 31.6, 19.0; HRMS (ESI-TOF)
m/z [M + H] calcd for C H ClN O 366.1009, found 366.0995.
1
3
1
+
2
0
17
3
2
MHz, CDCl ) δ 10.40 (s, 1H), 8.91 (dd, J = 7.2, 1.2 Hz, 1H), 8.81
3
N-(6-Methoxyquinolin-8-yl)-2-(2-oxopyrrolidin-1-yl-)benzamide
(
dd, J = 4.2, 1.6 Hz, 1H), 8.16 (dd, J = 8.3, 1.5 Hz, 1H), 7.88 (dd, J =
(
3i). R = 0.24, light yellow solid, mp 164 °C, hexane/EtOAc = 5:2, 62
f
7.6, 1.2 Hz, 1H), 7.63−7.51 (m, 3H), 7.45 (td, J = 8.2, 2.6 Hz, 2H),
7
1
1
1
.31 (d, J = 7.9 Hz, 1H), 3.71 (s, 2H), 2.50 (t, J = 6.3 Hz, 2H), 1.90−
1
3
1
.79 (m, 4H); C{ H} NMR (126 MHz, CDCl ) δ 171.1, 165.9,
3
48.4, 141.2, 138.8, 136.3, 134.9, 134.8, 131.9, 129.5, 128.8, 128.1,
28.0, 127.4, 122.0, 121.8, 116.9, 52.53, 32.74, 23.37, 21.35; HRMS
+
(
ESI-TOF) m/z [M + H] calcd for C H N O 346.1556, found
2
1
20
3
2
3
46.1555.
2
-(2-Oxopiperidin-1-yl)-N-(quinoline-8-yl)-4-(trifluoromethyl)-
benzamide (3m). R = 0.25, light yellow solid, mp 140−142 °C,
f
1
mg, 87%: H NMR (500 MHz, CDCl ) δ 10.43 (s, 1H), 8.69−8.56
3
(
m, 2H), 8.03 (dd, J = 8.3, 1.5 Hz, 1H), 7.91 (dd, J = 7.7, 1.4 Hz,
1
2
2
1
1
H), 7.55 (td, J = 7.7, 1.5 Hz, 1H), 7.47−7.33 (m, 3H), 6.82 (d, J =
.6 Hz, 1H), 3.94 (s, 3H), 3.90 (t, J = 7.0 Hz, 2H), 2.48 (t, J = 8.0 Hz,
1
3
1
H), 2.14−2.06 (m, 2H); C{ H} NMR (126 MHz, CDCl ) δ 175.7,
3
65.7, 158.7, 145.7, 136.9, 135.8, 135.4, 135.1, 133.8, 131.9, 129.8,
29.1, 127.8, 127.4, 122.3, 109.4, 100.2, 55.8, 51.5, 31.6, 19.0; HRMS
+
1
(ESI-TOF) m/z [M + H] calcd for C H N O 362.1505, found
hexane/EtOAc = 5:2, 66 mg, 80%: H NMR (500 MHz, CDCl
) δ
3
2
1
20
3
3
3
62.1510.
10.41 (s, 1H), 8.88 (dd, J = 6.0, 2.9 Hz, 1H), 8.80 (dd, J = 4.2, 1.7 Hz,
1H), 8.17 (dd, J = 8.3, 1.7 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.71
(dd, J = 8.0, 0.9 Hz, 1H), 7.60−7.55 (m, 3H), 7.45 (dd, J = 8.3, 4.2
Hz, 1H), 3.75 (s, 2H), 2.48 (t, J = 6.5 Hz, 2H), 1.93 (dt, J = 8.6, 5.9
N-(6-fluoroquinoline-8-yl)-2-(2-oxopyrrodin-1-yl)benzamide (3j).
1
R = 0.29, light yellow oil, hexane/EtOAc = 5:2, 59 mg, 85%: H
f
1
3
1
Hz, 2H), 1.87−1.80 (m, 2H); C{ H} NMR (126 MHz, CDCl ) δ
3
1
1
2
71.1, 164.63, 148.6, 141.7, 138.5 (q, J = 38.6 Hz), 136.4, 134.5,
33.7 (q, J = 33.6 Hz), 130.0, 128.1, 127.4, 125.9, 124.9, 123.4 (q, J =
1
9
72.6 Hz), 122.4, 121.9, 117.0, 52.4, 32.7, 23.3, 21.2; F NMR (565
+
MHz, CDCl ) δ −68.38; HRMS (ESI-TOF) m/z [M + H] calcd for
C H F N O 414.1429, found 414.1440.
3
2
2
19
3
3
2
2
-(2-Oxoazepan-1-yl)-N-(quinoline-8-yl)benzamide (3n). Rf =
0
.25, light yellow solid, mp 160 °C, hexane/EtOAc = 5:2, 63 mg,
90%: H NMR (600 MHz, CDCl ) δ 10.54 (s, 1H), 8.92 (d, J = 7.5
1
NMR (600 MHz, CDCl ) δ 10.49 (s, 1H), 8.78−8.68 (m, 2H), 8.09
3
3
(
dd, J = 8.3, 1.2 Hz, 1H), 7.90 (dd, J = 7.6, 1.0 Hz, 1H), 7.61−7.52
Hz, 1H), 8.84−8.79 (m, 1H), 8.17 (d, J = 8.3 Hz, 1H), 7.93 (d, J =
3
268
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Article
1
7
.7 Hz, 1H), 7.60−7.52 (m, 3H), 7.47−7.41 (m, 2H), 7.30 (d, J = 7.9
5:2, 46 mg, 65%: H NMR (500 MHz, CDCl
3
) δ 10.71 (s, 1H), 8.94
Hz, 1H), 3.91−3.64 (m, 2H), 2.71 (s, 2H), 1.89−1.66 (m, 6H);
(dd, J = 7.3, 1.6 Hz, 1H), 8.82 (dd, J = 4.2, 1.5 Hz, 1H), 8.19 (dd, J =
8.2, 1.5 Hz, 1H), 7.63−7.52 (m, 3H), 7.49 (dd, J = 8.2, 4.2 Hz, 1H),
.02 (d, J = 5.2 Hz, 1H), 3.72 (t, J = 5.6 Hz, 2H), 2.81 (t, J = 6.5 Hz,
H), 2.13−2.01 (m, 4H); C{ H} NMR (126 MHz, CDCl ) δ 171.8,
59.4, 148.1, 140.8, 138.8, 136.8, 134.7, 134.1, 129.7, 128.2, 127.7,
27.7, 122.1, 121.8, 117.6, 52.7, 33.1, 23.3, 21.7; HRMS (ESI-TOF)
m/z [M + H] calcd for C19
-(2-Oxoazepan-1-yl)-N-(quinoline-8-yl)thiophene-2-carboxa-
mide (3s). R = 0.24, sticky gum, hexane/EtOAc = 5:2, 47 mg, 66%:
13
1
C{ H} NMR (151 MHz, CDCl ) δ 176.9, 165.7, 148.5, 142.3,
3
7
2
1
1
1
1
38.9, 136.4, 134.9, 133.8, 131.8, 130.1, 128.9, 128.1, 127.8, 127.5,
1
3
1
22.1, 121.8, 117.0, 53.7, 37.6, 30.0, 28.1, 23.3; HRMS (ESI-TOF)
3
+
m/z [M + H] calcd for C H N O 360.1712, found 360.1701.
2
2
22
3
2
4
-Methoxy-2-(2-oxoazepan-1-yl)-N-(quinoline-8-yl)benzamide
1
+
(3o). R = 0.23, yellow oil, hexane/EtOAc = 5:2, 69 mg, 89%: H
H
17
N
3
O
2
S 352.1120, found 352.1126.
f
3
f
NMR (600 MHz, CDCl ) δ 10.58 (s, 1H), 8.92 (d, J = 7.5 Hz, 1H),
3
8
1
.81 (d, J = 3.6 Hz, 1H), 8.17 (d, J = 8.1 Hz, 1H), 7.97 (d, J = 8.5 Hz,
H), 7.62−7.50 (m, 2H), 7.45 (dd, J = 8.2, 4.2 Hz, 1H), 7.00−6.93
1
H NMR (600 MHz, CDCl ) δ 10.86 (s, 1H), 8.91 (dd, J = 7.5, 1.2
3
(
(
m, 1H), 6.79 (s, 1H), 3.98 (d, J = 22.5 Hz, 1H), 3.88 (s, 3H), 3.59
s, 1H), 2.77 (d, J = 35.7 Hz, 2H), 2.00−1.68 (m, 6H); C{ H}
Hz, 1H), 8.84 (dd, J = 4.2, 1.5 Hz, 1H), 8.20 (dd, J = 8.3, 1.4 Hz,
1H), 7.59−7.53 (m, 3H), 7.49 (dd, J = 8.2, 4.2 Hz, 1H), 7.03 (d, J =
5.2 Hz, 1H), 3.95 (s, 2H), 3.00 (d, J = 8.3 Hz, 2H), 1.94−1.78 (m,
1
3
1
NMR (151 MHz, CDCl ) δ 176.8, 165.0, 162.2, 148.3, 143.9, 138.9,
3
1
3
1
1
1
36.4, 135.1, 132.0, 128.1, 127.5, 125.7, 121.7, 121.7, 116.9, 114.8,
13.0, 77.3, 77.1, 76.9, 55.7, 53.6, 37.6, 30.0, 28.0, 23.3; HRMS (ESI-
6H); C{ H} NMR (151 MHz, CDCl ) δ 177.3, 159.3, 148.3, 142.1,
3
138.9, 136.8, 134.7, 132.9, 129.4, 128.3, 128.2, 127.8, 122.0, 121.8+,
117.3, 53.6, 37.4, 30.1, 28.3, 23.6; HRMS (ESI-TOF) m/z [M + H]
calcd for C H N O S 366.1276, found 366.1275.
+
TOF) m/z [M + Na] calcd for C H N O Na 412.1637, found
2
3
23
3
3
412.1640.
2
0
19
3
2
2
-(2-Oxoazepan-1-yl)-N-(quinoline-8-yl)-1-naphthamide (3p). Rf
Spectral Characterization Data of Amination. 2-(4-Methyl-
1
82
=
0.26, sticky gum, hexane/EtOAc = 5:2, 62 mg, 76%: H NMR (600
piperidin-1-yl)-N-(quinolin-8-yl)benzamide (5a). R = 0.72, white
f
1
MHz, CDCl ) δ 10.39 (s, 1H), 9.05 (d, J = 8.0 Hz, 1H), 8.81−8.72
solid, mp = 98−100 °C, hexane/EtOAc = 5:1, 66 mg, 96%: H NMR
3
(
m, 1H), 8.16 (d, J = 7.9 Hz, 1H), 8.10 (d, J = 7.7 Hz, 1H), 7.97 (d, J
(600 MHz, CDCl ) δ 12.78 (s, 1H), 9.17 (d, J = 7.4 Hz, 1H), 8.84 (s,
3
=
8.7 Hz, 1H), 7.91−7.88 (m, 1H), 7.66−7.57 (m, 2H), 7.55−7.49
1H), 8.15 (dd, J = 29.1, 7.4 Hz, 2H), 7.57 (dd, J = 10.2, 5.1 Hz, 1H),
7.50 (d, J = 7.8 Hz, 1H), 7.42 (d, J = 4.3 Hz, 2H), 7.24−7.14 (m,
2H), 3.36 (d, J = 10.3 Hz, 2H), 2.77 (t, J = 11.1 Hz, 2H), 1.70−1.60
(
m, 2H), 7.42 (dd, J = 8.3, 3.9 Hz, 1H), 7.33 (d, J = 9.0 Hz, 1H), 3.77
(d, J = 21.1 Hz, 2H), 2.51 (d, J = 34.8 Hz, 2H), 1.88−1.73 (m, 4H),
1
3
1
13
1
1
1
1
5
.61−1.42 (m, 2H); C{ H} NMR (151 MHz, CDCl ) δ 177.0,
66.6, 148.8, 139.4, 138.8, 136.1, 134.9, 132.8, 132.6, 131.2, 131.2,
28.2, 128.1, 127.5, 127.3, 126.8, 126.1, 125.6, 122.4, 121.9, 117.1,
(m, 4H), 1.42 (s, 1H), 0.76 (d, J = 5.7 Hz, 3H); C{ H} NMR (151
3
MHz, CDCl
) δ 166.2, 152.6, 147.9, 139.1, 136.3, 136.0, 132.2, 131.9,
3
128.7, 128.4, 127.6, 123.5, 121.6, 121.4, 119.3, 117.8, 54.7, 33.5, 30.5,
21.7; HRMS (ESI-TOF) m/z [M + H]+ calcd for C22H N O
24 3
346.1919, found 346.1913.
4-Methoxy-2-(4-methylpiperidin-1-yl)-N-(quinolin-8-yl)-
benzamide (5b). R = 0.62, white solid, mp 148 °C, hexane/EtOAc =
f
+
3.4, 37.5, 30.1, 28.5, 23.3; HRMS (ESI-TOF) m/z [M + H] calcd
for C H N O 410.1869, found 410.1858.
26
23
3
2
3
-(2-Oxopyrrodin-1-yl)-N-(quinoline-8-yl)thiophene-2-carboxa-
mide (3q). R = 0.25, white solid, mp 198 °C, hexane/EtOAc = 5:2,
f
1
4
5 mg, 67%: H NMR (500 MHz, CDCl ) δ 10.68 (s, 1H), 8.91 (dd,
3
1
J = 7.4, 1.5 Hz, 1H), 8.80 (dd, J = 4.2, 1.6 Hz, 1H), 8.20 (dd, J = 8.3,
5:1, 71 mg, 95%: H NMR (600 MHz, CDCl
3
) δ 12.69 (s, 1H), 9.15
1
.6 Hz, 1H), 7.63−7.53 (m, 3H), 7.48 (dd, J = 8.2, 4.2 Hz, 1H), 7.10
(d, J = 7.9 Hz, 1H), 8.86 (d, J = 5.1 Hz, 1H), 8.19−8.13 (m, 2H),
7.58 (t, J = 8.0 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.44 (dd, J = 8.1,
4.5 Hz, 1H), 6.75 (d, J = 2.1 Hz, 1H), 6.71 (dd, J = 8.1, 2.1 Hz, 1H),
3.86 (s, 3H), 3.38 (d, J = 11.6 Hz, 2H), 2.81−2.70 (m, 2H), 1.71−
1.67 (m, 2H), 1.62 (d, J = 10.9 Hz, 2H), 1.50−1.43 (m, 1H), 0.78 (d,
(
d, J = 5.3 Hz, 1H), 3.94 (t, J = 7.0 Hz, 2H), 2.71 (t, J = 8.1 Hz, 2H),
.46−2.31 (m, 2H).; C{ H} NMR (126 MHz, CDCl ) δ 176.2,
59.4, 148.0, 138.8, 136.8, 136.5, 134.6, 133.4, 129.5, 128.3, 127.8,
1
3
1
2
1
1
3
26.3, 122.0, 121.8, 117.3, 51.0, 31.3, 19.0; HRMS (ESI-TOF) m/z
+
13
1
[
M + H] calcd for C H N O S 338.0963, found 338.0970.
J = 6.4 Hz, 3H); C{ H} NMR (151 MHz, CDCl ) δ 166.0, 162.8,
3
1
8
15
3
2
3
-(2-Oxopiperidin-1-yl)-N-(quinoline-8-yl)thiophene-2-carboxa-
154.5, 147.9, 139.1, 136.4, 136.3, 133.8, 128.4, 127.7, 121.6, 121.4,
121.4, 117.8, 107.7, 106.2, 55.5, 54.8, 33.5, 30.6, 21.7; HRMS (ESI-
mide (3r). R = 0.26, white solid, mp 178−180 °C, hexane/EtOAc =
f
3
269
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J. Org. Chem. 2021, 86, 3261−3275

The Journal of Organic Chemistry
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Article
+
TOF) m/z [M + Na] calcd for C H N O Na 398.1844, found
2
3
25
3
2
398.1856.
4
-Chloro-2-(4-methylpiperidin-1-yl)-N-(quinolin-8-yl)benzamide
f
(
5c). R = 0.65, white solid, mp 170−172 °C, hexane/EtOAc = 5:1, 64
Hz, 2H); 13C{ H} NMR (151 MHz, CDCl ) δ 166.3, 152.2, 148.6,
1
3
1
1
48.4, 136.6, 132.3, 132.0, 128.9, 128.3, 127.8, 127.6, 127.4, 126.9,
26.2, 123.7, 121.8, 121.4, 119.2, 117.8, 116.7, 55.1, 42.4, 32.9;
+
1
HRMS (ESI-TOF) m/z [M + H] calcd for C H N O 408.2076,
found 408.2075.
2
7
26
3
mg, 85%: H NMR (600 MHz, CDCl ) δ 12.56 (s, 1H), 9.12 (d, J =
7
=
(
3
.2 Hz, 1H), 8.91−8.79 (m, 1H), 8.17 (d, J = 7.8 Hz, 1H), 8.09 (d, J
8.2 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.46
dd, J = 8.1, 4.4 Hz, 1H), 7.19 (d, J = 2.0 Hz, 1H), 7.16 (dd, J = 8.1,
4
-Methoxy-2-(4-phenylpiperidin-1-yl)-N-(quinolin-8-yl)-
benzamide (5g). R = 0.76, white solid, mp 166 °C, hexane/EtOAc =
f
2
2
3
1
1
.1 Hz, 1H), 3.37 (d, J = 11.4 Hz, 2H), 2.77 (td, J = 11.4, 3.4 Hz,
H), 1.68−1.62 (m, 4H), 1.48−1.44 (m, 1H), 0.78 (d, J = 6.6 Hz,
H); 13C{ H} NMR (151 MHz, CDCl ) δ 165.3, 153.6, 148.1, 139.0,
1
3
37.9, 136.5, 135.8, 133.3, 128.4, 127.7, 127.3, 123.6, 121.9, 121.6,
19.9, 117.9, 54.7, 33.4, 30.5, 21.7; HRMS (ESI-TOF) m/z [M +
+
Na] calcd for C H N ONa 402.1349, found 402.1361.
22
22
3
4
-Fluoro-2-(4-methylpiperidin-1-yl)-N-(quinolin-8-yl)benzamide
(
5d). R = 0.60, white solid, mp 148−150 °C, hexane/EtOAc = 5:1, 56
f
1
1
0:1, 84 mg, 96%: H NMR (600 MHz, CDCl ) δ 12.64 (s, 1H), 9.14
3
(
d, J = 7.7 Hz, 1H), 8.83−8.80 (m, 1H), 8.21−8.18 (m, 1H), 8.15 (d,
J = 9.1 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.53 (d, J = 8.3 Hz, 1H),
7
2
3
2
.44 (dd, J = 8.2, 3.7 Hz, 1H), 7.13−7.09 (m, 3H), 6.82 (dd, J = 6.2,
.7 Hz, 2H), 6.79 (d, J = 2.1 Hz, 1H), 6.73 (dd, J = 8.1, 2.1 Hz, 1H),
.88 (s, 3H), 3.54 (d, J = 11.6 Hz, 2H), 2.90 (t, J = 11.3 Hz, 2H),
.60−2.56 (m, 1H), 2.20−2.13 (m, 2H), 1.83 (d, J = 12.3 Hz, 2H);
1
13
1
mg, 78%: H NMR (600 MHz, CDCl ) δ 12.55 (s, 1H), 9.13 (d, J =
C{ H} NMR (151 MHz, CDCl ) δ 166.0, 162.8, 154.1, 148.5,
3
3
8
8
6
.0 Hz, 1H), 8.85 (d, J = 5.1 Hz, 1H), 8.17−8.14 (m, 2H), 7.58 (t, J =
.0 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.44 (dd, J = 8.2, 3.7 Hz, 1H),
.93−6.84 (m, 2H), 3.37 (d, J = 11.5 Hz, 2H), 2.74 (td, J = 11.6, 2.6
145.9, 139.2, 136.6, 136.1, 133.8, 128.5, 128.3, 127.8, 126.9, 126.2,
121.7, 121.5, 121.3, 117.8, 107.8, 106.1, 55.6, 55.1, 42.4, 32.8; HRMS
+
(ESI-TOF) m/z [M + H] calcd for C H N O 438.2182, found
2
8
28
3
2
Hz, 2H), 1.73−1.57 (m, 4H), 1.48−1.42 (m, 1H), 0.77 (d, J = 6.6 Hz,
438.2189.
4-Chloro-2-(4-phenylpiperidin-1-yl)-N-(quinolin-8-yl)benzamide
H); 13C{ H} NMR (151 MHz, CDCl ) δ 165.3, 165.1 (d, J = 251.9
1
3
3
1
Hz), 154.8 (d, J = 8.6 Hz), 148.0, 139.0, 136.4, 135.8, 134.1 (d, J =
(5h). R = 0.76, sticky gum, hexane/EtOAc = 10:1, 83 mg, 94%: H
f
1
0.1 Hz), 128.4, 127.7, 125.0 (d, J = 2.3 Hz), 121.7, 121.5, 117.8,
10.2 (d, J = 21.2 Hz), 106.8 (d, J = 23.1 Hz), 54.7, 33.3, 30.4, 21.6;
1
19
F NMR (565 MHz, CDCl ) δ −113.65 to −113.69 (m); HRMS
3
+
(ESI-TOF) m/z [M + H] calcd for C H N O 364.1825, found
2
2
22
3
3
64.1833.
4
-Trifluoromethyl-2-(4-methylpiperidin-1-yl)-N-(quinolin-8-yl)-
benzamide (5e). R = 0.58, sticky gum, hexane/EtOAc = 5:1, 59 mg,
f
NMR (600 MHz, CDCl ) δ 12.51 (s, 1H), 9.11 (dd, J = 7.6, 0.9 Hz,
3
1
8
7
8
3
H), 8.82 (dd, J = 4.1, 1.5 Hz, 1H), 8.21 (dd, J = 8.2, 1.5 Hz, 1H),
.07 (d, J = 8.3 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.57−7.54 (m, 1H),
.46 (dd, J = 8.2, 4.2 Hz, 1H), 7.23 (d, J = 1.9 Hz, 1H), 7.18 (dd, J =
.3, 1.9 Hz, 1H), 7.12−7.09 (m, 3H), 6.80 (dd, J = 6.4, 2.9 Hz, 2H),
.54 (d, J = 11.8 Hz, 2H), 2.92 (dd, J = 11.8, 10.5 Hz, 2H), 2.60−2.55
1
3
1
(
m, 1H), 2.15−2.09 (m, 2H), 1.83 (d, J = 12.3 Hz, 2H); C{ H}
1
7
1%: H NMR (600 MHz, CDCl ) δ 12.56 (s, 1H), 9.13 (d, J = 7.6
3
NMR (151 MHz, CDCl ) δ 165.3, 153.2, 148.6, 145.7, 139.0, 138.0,
3
Hz, 1H), 8.86 (d, J = 3.5 Hz, 1H), 8.23 (d, J = 8.0 Hz, 1H), 8.18 (d, J
8.1 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.47
dd, J = 8.2, 4.3 Hz, 1H), 7.45−7.41 (m, 2H), 3.42 (d, J = 11.3 Hz,
1
1
36.6, 135.6, 133.3, 128.5, 128.4, 127.8, 127.4, 126.8, 126.3, 123.7,
=
22.0, 121.5, 119.8, 117.8, 54.9, 42.2, 32.8; HRMS (ESI-TOF) m/z
(
+
[M + H] calcd for C H ClN O 442.1686, found 442.1680.
2
7
25
3
2
0
1
1
1
2
H), 3.03−2.69 (m, 2H), 1.67−1.64 (m, 4H), 1.51−145 (m, 1H),
5
-Methyl-2-(4-methylpiperidin-1-yl)-N-(quinolin-8-yl)benzamide
1
3
1
.78 (d, J = 6.6 Hz, 3H); C{ H} NMR (151 MHz, CDCl ) δ 165.1,
3
(5i). R = 0.65, white solid, mp 162−164 °C, hexane/EtOAc = 5:1, 60
f
52.8, 148.2, 139.0, 136.5, 135.5, 133.7 (q, J = 32.0 Hz), 132.6, 131.9,
28.4, 127.7 (q, J = 50.4 Hz), 123.9 (q, J = 273.0 Hz), 122.1, 121.6,
19.9 (q, J = 3.0 Hz), 117.9, 116.2 (q, J = 3.7 Hz), 54.6, 33.4, 30.4,
1.6; 19F NMR (565 MHz, CDCl ) δ −68.45; HRMS (ESI-TOF) m/
3
+
z [M + H] calcd for C H F N O 414.1793, found 414.1812.
2
3
23
3
3
2
-(4-Phenylpiperidin-1-yl)-N-(quinolin-8-yl)benzamide (5f). R =
f
1
0
.82, sticky gum, hexane/EtOAc = 10:1, 75 mg, 92%: H NMR (600
MHz, CDCl ) δ 12.70 (s, 1H), 9.15 (d, J = 7.1 Hz, 1H), 8.84−8.81
3
1
(
m, 1H), 8.26−8.13 (m, 3H), 7.50−7.44 (m, 3H), 7.27 (d, J = 8.0 Hz,
mg, 83%: H NMR (600 MHz, CDCl ) δ 12.89 (s, 1H), 9.16 (d, J =
3
1H), 7.21 (t, J = 7.5 Hz, 1H), 7.11 (dd, J = 6.1, 3.8 Hz, 3H), 6.80 (dd,
7.1 Hz, 1H), 8.89−8.83 (m, 1H), 8.18−8.12 (m, 1H), 8.01 (d, J = 1.8
Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.44 (dd, J
= 8.3, 3.8 Hz, 1H), 7.25 (dd, J = 7.9, 2.0 Hz, 1H), 7.14 (d, J = 8.1 Hz,
J = 6.2, 2.8 Hz, 2H), 3.55 (d, J = 11.7 Hz, 2H), 2.95 (dd, J = 17.7, 6.2
Hz, 2H), 2.60−2.56 (m, 1H), 2.18−2.11 (m, 2H), 1.83 (d, J = 12.1
3
270
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J. Org. Chem. 2021, 86, 3261−3275

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1
H), 3.33 (d, J = 11.6 Hz, 2H), 2.76 (td, J = 11.9, 1.9 Hz, 2H), 2.36
(
s, 3H), 1.72−1.66 (m, 2H), 1.64−1.59 (m, 2H), 1.48−1.42 (m, 1H),
1
3
1
0
1
1
.79 (d, J = 6.7 Hz, 3H); C{ H} NMR (151 MHz, CDCl ) δ 166.4,
3
50.3, 148.0, 139.2, 136.3, 136.2, 133.1, 132.8, 132.4, 128.4, 127.7,
21.6, 121.4, 119.4, 117.9, 54.9, 33.6, 30.6, 21.7, 20.8; HRMS (ESI-
+
TOF) m/z [M + Na] calcd for C H N ONa 382.1895, found
2
3
25
3
3
.11 (m, 4H); 13C{ H} NMR (151 MHz, CDCl ) δ 165.5, 163.0,
1
3
3
8
2
f
153.1, 148.1, 138.9, 136.5, 135.9, 134.1, 128.4, 127.7, 121.7, 121.6,
21.6, 117.7, 108.4, 106.2, 66.2, 55.6, 54.0; HRMS (ESI-TOF) m/z
1
solid, mp = 118 °C, hexane/EtOAc = 5:1, 57 mg, 85%: H NMR (600
1
+
[
M + H] calcd for C H N O 364.1661, found 364.1667.
21 22 3 3
2
-Chloro-6-morpholino-4-nitro-N-(quinolin-8-yl)benzamide
(
5n). R = 0.21, white solid, mp 198−200 °C, hexane/EtOAc = 5:1, 76
f
MHz, CDCl ) δ 12.68 (s, 1H), 9.13 (dd, J = 7.7, 1.3 Hz, 1H), 8.87
3
(
1
(
(
dd, J = 4.2, 1.7 Hz, 1H), 8.22−8.17 (m, 2H), 7.60 (t, J = 7.9 Hz,
H), 7.55 (dd, J = 8.2, 1.3 Hz, 1H), 7.53−7.47 (m, 2H), 7.29−7.23
1
13 1
mg, 92%: H NMR (600 MHz, CDCl ) δ 11.93 (s, 1H), 9.09−9.02
m, 2H), 4.00−3.95 (m, 4H), 3.18−3.14 (m, 4H); C{ H} NMR
3
(
m, 1H), 8.90 (d, J = 3.2 Hz, 1H), 8.87 (d, J = 5.2 Hz, 1H), 8.31 (dd,
151 MHz, CDCl ) δ 165.9, 151.2, 148.3, 139.0, 136.5, 135.7, 132.5,
3
J = 8.8, 2.6 Hz, 1H), 8.22 (dd, J = 8.1, 1.8 Hz, 1H), 7.66−7.55 (m,
1
5
3
32.3, 129.0, 128.5, 127.7, 124.4, 121.9, 121.8, 119.3, 117.9, 66.3,
4.0; HRMS (ESI-TOF) m/z [M + H]+ calcd for C H N O
2H), 7.52 (dd, J = 8.2, 3.7 Hz, 1H), 7.25 (d, J = 9.0 Hz, 1H), 3.90 (t, J
2
0
20
3
2
1
3
1
=
4.6 Hz, 4H), 3.26 (t, J = 4.6 Hz, 4H); C{ H} NMR (151 MHz,
34.1556, found 334.1563.
-Methyl-2-morpholino-N-(quinolin-8-yl)benzamide (5k). Rf =
8
2
CDCl ) δ 163.8, 155.8, 148.5, 143.2, 138.5, 136.7, 134.6, 129.1, 128.4,
4
3
1
28.0, 127.7, 127.2, 122.5, 122.0, 118.9, 117.9, 65.9, 53.3; HRMS
0
.34, white solid, mp = 177−180 °C, hexane/EtOAc = 5:1, 58 mg,
+
(ESI-TOF) m/z [M + Na] calcd for C H ClN O Na 435.0836,
20 17 4 4
found 435.0843.
8
3
2
-Morpholino-N-(quinolin-8-yl)-1-naphthamide (5o). Rf =
1
0
.33, sticky gum, hexane/EtOAc = 5:1, 50 mg, 65%: H NMR (600
1
8
3%: H NMR (600 MHz, CDCl ) δ 12.79 (s, 1H), 9.13 (d, J = 8.1
3
Hz, 1H), 8.91−8.82 (m, 1H), 8.17 (d, J = 7.8 Hz, 1H), 8.03 (d, J =
.7 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.47
dd, J = 8.4, 4.0 Hz, 1H), 7.30 (dd, J = 8.1, 1.7 Hz, 1H), 7.16 (d, J =
1
(
MHz, CDCl ) δ 10.64 (s, 1H), 9.12 (d, J = 7.4 Hz, 1H), 8.77−8.70
3
8
.1 Hz, 1H), 4.00−3.96 (m, 4H), 3.13−3.09 (m, 4H), 2.38 (s, 3H);
(
m, 1H), 8.27 (d, J = 8.5 Hz, 1H), 8.21−8.17 (m, 1H), 7.93 (d, J =
1
3
1
C{ H} NMR (151 MHz, CDCl ) δ 165.9, 148.9, 148.2, 139.0,
3
8.8 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.57
1
1
36.5, 135.8, 134.1, 133.0, 132.7, 128.6, 128.4, 127.7, 121.8, 121.7,
19.5, 117.9, 66.3, 54.1, 20.8; HRMS (ESI-TOF) m/z [M + H] calcd
(
d, J = 8.1 Hz, 1H), 7.52−7.49 (m, 1H), 7.45−7.39 (m, 3H), 3.65−
+
13 1
3
.59 (m, 4H), 3.27−3.20 (m, 4H); C{ H} NMR (151 MHz,
for C H N O 348.1712, found 348.1726.
21
22
3
2
CDCl ) δ 166.7, 147.3, 146.5, 137.6, 135.63, 134.1, 130.8, 130.4,
3
8
2
4
-Fluoro-2-morpholino-N-(quinolin-8-yl)benzamide (5l). Rf =
129.5, 127.4, 127.1, 126.7, 126.6, 126.1, 124.1, 124.0, 121.0, 120.8,
+
0.32, white solid, mp = 174−176 °C, hexane/EtOAc = 5:1, 55 mg,
1
17.9, 115.9, 66.1, 52.0; HRMS (ESI-TOF) m/z [M + H] calcd for
C H N O 384.1712, found 384.1716.
2
4
22
3
2
2
-Thiomorpholino-N-(quinolin-8-yl)naphthamide (5p). R = 0.34,
f
1
white solid, mp 140−141 °C, hexane/EtOAc = 5:1, 54 mg, 68%: H
1
7
9%: H NMR (600 MHz, CDCl ) δ 12.47 (s, 1H), 9.10 (d, J = 8.0
3
Hz, 1H), 8.87 (dd, J = 4.2, 1.7 Hz, 1H), 8.31−8.11 (m, 2H), 7.60 (t, J
7.9 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 8.1, 4.5 Hz,
H), 6.93 (dd, J = 12.5, 5.6 Hz, 2H), 4.11−3.65 (m, 4H), 3.33−2.93
NMR (600 MHz, CDCl ) δ 10.52 (s, 1H), 9.13 (d, J = 7.1 Hz, 1H),
3
=
8.77−8.69 (m, 1H), 8.24 (d, J = 8.6 Hz, 1H), 8.19 (d, J = 7.9 Hz,
1H), 7.93 (d, J = 8.9 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.66 (t, J = 7.8
Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.51 (t, J = 7.4 Hz, 1H), 7.46−7.39
1
m, 4H); 13C{ H} NMR (151 MHz, CDCl ) δ 165.3 (d, J = 252.9
1
(
3
1
3
1
Hz), 165.0, 153.4 (d, J = 8.4 Hz), 148.3, 138.9, 136.6, 135.6, 134.5 (d,
J = 10.0 Hz), 128.5, 127.7, 125.2 (d, J = 2.5 Hz), 122.0, 121.8, 117.8,
(m, 3H), 3.50−3.46 (m, 4H), 2.64−2.60 (m, 4H); C{ H} NMR
(151 MHz, CDCl ) δ 167.6, 148.6, 148.3, 138.6, 136.6, 135.1, 131.7,
3
1
9
1
11.1 (d, J = 21.4 Hz), 106.8 (d, J = 23.3 Hz), 66.1, 53.9; F NMR
131.2, 130.6, 128.4, 128.1, 128.0, 127.7, 127.5, 125.2, 125.2, 122.0,
121.9, 119.9, 116.9, 55.4, 28.2; HRMS (ESI-TOF) m/z [M + H]+
calcd for C H N OS 400.1484, found 400.1500.
(
565 MHz, CDCl ) δ −113.32 to −113.36 (m); HRMS (ESI-TOF)
3
+
m/z [M + Na] calcd for C H FN O Na 374.1281, found 374.1296.
2
0
18
3
2
24 22
3
8
2
82
4
-Methoxy-2-morpholino-N-(quinolin-8-yl)benzamide (5m). Rf
3-(Morpholino)-N-(quinolin-8-yl)thiophenecarboxamide (5q).
0.31, white solid, mp = 147−149 °C, hexane/EtOAc = 5:1, 64 mg,
R = 0.29, white solid, mp = 169−171 °C, hexane/EtOAc = 5:1, 31
f
1
1
mg, 46%: H NMR (500 MHz, CDCl ) δ 12.60 (s, 1H), 9.04 (dd, J =
3
3
Hz, 1H), 8.88−8.84 (m, 1H), 8.23−8.13 (m, 2H), 7.58 (t, J = 8.0 Hz,
H), 7.51 (d, J = 8.0 Hz, 1H), 7.46 (dd, J = 8.2, 3.7 Hz, 1H), 6.77
dd, J = 6.1, 2.4 Hz, 2H), 4.00−3.96 (m, 4H), 3.87 (s, 3H), 3.15−
7.6, 1.4 Hz, 1H), 8.94 (dd, J = 4.2, 1.7 Hz, 1H), 8.20 (dd, J = 8.3, 1.7
Hz, 1H), 7.62−7.46 (m, 4H), 7.21 (d, J = 5.3 Hz, 1H), 4.20−4.10 (m,
1
(
1
3
1
4H), 3.16−3.07 (m, 4H); C{ H} NMR (126 MHz, CDCl ) δ 160.8,
3
3
271
https://dx.doi.org/10.1021/acs.joc.0c02603
J. Org. Chem. 2021, 86, 3261−3275

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
ASSOCIATED CONTENT
sı Supporting Information
■
*
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02603.
Experimental methods; optimization of the reaction
conditions; and copies of NMR, XRD, SEM, and XPS
images of the fresh and reused catalyst(PDF)
1
1
52.3, 148.2, 139.1, 136.6, 135.8, 130.4, 130.3, 128.4, 127.7, 122.3,
21.9, 121.7, 118.16, 66.6, 54.5; HRMS (ESI-TOF) m/z [M + H]
+
calcd for C H N O S 340.1120, found 340.1089.
18
18
3
2
2
-(3,4-Dihydroisoquinoin-2(1H)-yl)-N-(quinolin-8-yl)benzamide
1
Accession Codes
(
5r). R = 0.38, sticky gum, hexane/EtOAc = 5:1, 44 mg, 58%: H
f
CCDC 2034527−2034529 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: + 44 1223 336033.
AUTHOR INFORMATION
■
NMR (600 MHz, CDCl ) δ 13.46 (s, 1H), 9.06 (d, J = 7.8 Hz, 1H),
3
Corresponding Authors
8
(
=
.34 (dd, J = 7.9, 1.6 Hz, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.78−7.73
m, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.44 (d, J
8.1 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 7.5 Hz, 1H),
.19−7.10 (m, 4H), 6.99 (d, J = 7.2 Hz, 1H), 4.46 (s, 2H), 3.42 (t, J =
Subhash C. Ghosh − Central Salt and Marine Chemicals
Research Institute (CSIR-CSMCRI), Bhavnagar, Gujarat
7
5
3
64002, India; Academy of Scientific and Innovative
1
3
1
.9 Hz, 2H), 2.95 (t, J = 5.8 Hz, 2H), 2.16 (s, 2H); C{ H} NMR
Research (AcSIR), Ghaziabad, Uttar Pradesh 201002,
India; orcid.org/0000-0002-6528-1582;
151 MHz,) δ 165.3, 151.6, 147.7, 139.3, 136.0, 135.8, 134.8, 134.8,
32.4, 132.2, 129.1, 128.8, 128.0, 127.4, 126.3, 126.3, 125.9, 124.8,
Email: scghosh@csmcri.res.in
21.6, 121.3, 121.1, 117.7, 54.7, 52.8, 31.1, 28.8; HRMS (ESI-TOF)
+
Asit B. Panda − Central Salt and Marine Chemicals Research
Institute (CSIR-CSMCRI), Bhavnagar, Gujarat 364002,
India; Academy of Scientific and Innovative Research
2
5
21
3
2
-(4-Methylpiperazin-1-yl)-N-(quinolin-8-yl)benzamide (5s). R =
f
1
0
.22, sticky gum, hexane/EtOAc = 5:2, 42 mg, 61%: H NMR (600
(
AcSIR), Ghaziabad, Uttar Pradesh 201002, India;
orcid.org/0000-0002-4141-6286; Email: abpanda@
csmcri.res.in
Authors
Harshvardhan Singh − Central Salt and Marine Chemicals
Research Institute (CSIR-CSMCRI), Bhavnagar, Gujarat
MHz, CDCl ) δ 12.59 (s, 1H), 9.14 (d, J = 8.1 Hz, 1H), 8.92−8.89
3
364002, India; Academy of Scientific and Innovative
(
m, 1H), 8.21−8.18 (m, 1H), 8.17−8.14 (m, 1H), 7.61 (t, J = 7.7 Hz,
H), 7.55 (d, J = 7.9 Hz, 1H), 7.49 (dd, J = 7.9, 4.9 Hz, 2H), 7.26 (t, J
4.0 Hz, 2H), 7.23 (t, J = 7.5 Hz, 1H), 3.21 (s, 4H), 2.72 (d, J = 4.1
Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
Chiranjit Sen − Central Salt and Marine Chemicals Research
Institute (CSIR-CSMCRI), Bhavnagar, Gujarat 364002,
India; Academy of Scientific and Innovative Research
(AcSIR), Ghaziabad, Uttar Pradesh 201002, India
Eringathodi Suresh − Central Salt and Marine Chemicals
Research Institute (CSIR-CSMCRI), Bhavnagar, Gujarat
1
=
1
3
1
Hz, 4H), 2.20 (s, 3H); C{ H} NMR (151 MHz, CDCl ) δ 166.1,
3
1
1
51.4, 148.3, 139.1, 136.5, 135.8, 132.4, 132.2, 128.9, 128.5, 127.8,
24.1, 121.8, 121.6, 119.3, 117.9, 54.2, 53.6, 45.9; HRMS (ESI-TOF)
+
m/z [M + H] calcd for C H N O: 347.1872, found 347.1875.
2
1
23
4
8
2
2
-(Benzyl(methyl)amino)-N-(quinolin-8-yl)benzamide (5t). Rf
=
0.40, light yellow sticky gum, hexane/EtOAc = 5:1, 52 mg, 71%:
364002, India; Academy of Scientific and Innovative
Research (AcSIR), Ghaziabad, Uttar Pradesh 201002,
India; orcid.org/0000-0002-1934-6832
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02603
Notes
The authors declare no competing financial interest.
1
ACKNOWLEDGMENTS
H NMR (600 MHz, CDCl ) δ 13.83 (s, 1H), 9.07 (d, J = 7.6 Hz,
H), 8.75 (d, J = 3.6 Hz, 1H), 8.27 (d, J = 7.8 Hz, 1H), 8.15 (d, J =
.3 Hz, 1H), 7.59 (t, J = 7.9 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.42
■
0
3
We are thankful to the SERB, DST, India (EMR/2016/
02427), for the financial support for this work. The authors
1
8
also acknowledge the AESD&CIF of CSIR-CSMCRI for
constant analytical support. CSIR-CSMCRI Communication
no. 176/2020.
(
3
(
dd, J = 8.2, 4.1 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.22−7.19 (m,
H), 7.15 (d, J = 8.0 Hz, 1H), 7.12−7.05 (m, 3H), 4.32 (s, 2H), 2.93
s, 3H); 1 C{ H} NMR (151 MHz, CDCl ) δ 165.3, 150.7, 148.2,
3
1
3
1
1
39.7, 136.4, 136.2, 136.2, 131.8, 129.7, 129.1, 128.3, 128.09, 127.7,
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■
+
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