Copper-Catalyzed Intermolecular C(sp2)-H Amination with Electrophilic O-Benzoyl Hydroxylamines

Electrophilic O ‑Benzoyl Hydroxylamines

Article

Copper-Catalyzed Intermolecular C(sp )−H Amination with

Wei-Hao Rao,* Qi Li, Li-Li Jiang, Xue-Wan Deng, Pan Xu, Fang-Yuan Chen, Ming Li,

and Guo-Dong Zou

Cite This: J. Org. Chem. 2021, 86, 10580 −10590

Read Online

ACCESS

Metrics & More

Article Recommendations

sı Supporting Information

ABSTRACT: A copper-catalyzed intermolecular electrophilic amination of benzamides with O-benzoyl hydroxylamines was

achieved with the assistance of an 8-aminoquinolyl group. With this protocol, good compatibility was observed for a variety of aryl

amides and heteroaryl amides, and excellent tolerance with various functional groups was achieved. Signiﬁcantly, the monoaminated

product was overwhelmingly delivered under the simple reaction conditions. Preliminary mechanistic investigations suggested that a

radical pathway should be excluded and C−H activation be potentially the rate-determining step.

INTRODUCTION

Koley and coworkers reported pyrimidyl or pyridyl group-

directed copper-catalyzed ortho C−H diarylamination of

indoles, indolines, anilines, and N-aryl-7-azaindoles with diaryl

■

Over the past decades, C−H amination has received

considerable attention. To achieve excellent regioselectivity

and reactivity, the strategy of auxiliary-assisted transition-metal

catalysis tends to be adopted. Compared with directed C−H

amines. Moreover, copper, nickel, or cobalt-catalyzed

(electrochemical) versions of aromatic C−H amination with

nucleophilic amines have been developed.

amination under precious metal catalysis, base-metal copper

has shown excellent catalytic performance due to low cost and

low toxicity. In this area, Yu and Chatani’s group

independently developed copper-mediated selective C−H

amination of 2-phenylpyridines with tosylamines and aniline-

In contrast to directed nucleophilic amination versions,

copper-catalyzed electrophilic amination of C(sp )−H bonds

is still underexplored. Yu et al. developed an eﬃcient copper-

mediated C−H amination reaction with oximes as amino

12a

a3b

donors to introduce free NH groups directly. Very recently,

s.,

Nicholas’s group have later developed a similar C−H

Jana et al. reported a practical copper-catalyzed, 2-picolinamide

amination protocol. Inspired by these seminal works, several

diﬀerent approaches for aromatic C−H amination or

amidation with nucleophilc amino sources including tosyla-

mides, aromatic amides, aromatic or alkyl amines, anilines, and

azides have been later reported. For example, Zhu’s group

accomplished several elegant works on pyridine-directed

directed ortho C−H amination of anilines with hydroxylami-

nes.

These electrophilic aminations proceed smoothly

without any external oxidant or additives. Early in 2014, an

elegant work on iron-catalyzed ortho-amination of 8-amino-

quinolyl aromatic carboxamides with N-chloroamines was

described by Nakamura’s group (Scheme 1B). However, the

use of air and moisture-sensitive phenyl magnesium bromide

and incompatibility of ortho-substituted benzamides, to some

extent, hampered its practicability. Enlightened by these

elegant works, we envisioned that an electrophilic amination

copper-mediated aryl C−H amination with azides. Daugulis’s

group pioneered 8-aminoquinolyl or picolinyl group-directed

copper-mediated/catalyzed arene C−H amination with a series

of nucleophilic amines (Scheme 1A) and recently realized N-

aminopyridinium ylide-directed copper-promoted amination of

benzamides with pyrazoles, imidazoles, and sulfonamides.

protocol for C(sp )−H of benzamides would be realized by

using hydroxylamines with the strategy of directed copper-

Jana and coworkers later developed a copper-mediated

intermolecular C(sp )−H amination of benzamides with

Received: May 26, 2021

Published: July 27, 2021

electron-rich anilines. Yu and Dai accomplished several

examples of directed copper-mediated ortho-C−H amination/

amidation of benzamides with a broad array of nucleophilic

amine donors. Chen and Carretero’s group independently

accomplished picolinamide-directed copper-catalyzed amina-

tion of aromatic C−H bonds with simple amines. Recently,

2021 American Chemical Society

J. Org. Chem. 2021, 86, 10580−10590

0580

The Journal of Organic Chemistry

Article

Scheme 1. Diﬀerent Scenario of Copper-Catalyzed Electrophilic Amination of C(sp )−H Bonds

catalyzed C−H activation, in virtue of the signiﬁcant success of

several solvents in the presence of catalytic copper acetate and

electrophilic hydroxylamines in the amination reaction. We

here report a copper-catalyzed intermolecular electrophilic

excess Na CO (entries 1−6). Experiments showed that

amide-type solvent was generally superior to other tested

solvents, and DMAc aﬀorded the desired product 3a in 64%

yield (entry 2). After the extensive screening of various copper

salts (entries 7 and 10), we were pleased to ﬁnd that product

3a could be produced in 66% yield in the presence of CuI as a

catalyst. To our delight, the desired product 3a could be

aﬀorded in 78% yield (74% isolated yield) when the loading

amount of CuI was increased to 25 mol %. Further

amination of C(sp )−H with hydroxylamines with the

assistance of an 8-aminoquinolyl group (Scheme 1C).

Signiﬁcantly, mono-selective ortho-amination was obtained

and compatibility of ortho-substituted benzamides was

observed with the protocol.

RESULTS AND DISCUSSION

■

(

experiments showed that Na CO worked better than other

We commenced our optimization study with the reaction of N-

quinolin-8-yl)benzamide (1a) and O-benzoyl hydroxylmor-

tested bases (entries 11−15). Overall, the desired product 3a

was obtained in 74% yield with 25 mol % CuI in DMAc at 80

pholine (2a) as model substrates (Table 1). We ﬁrst evaluated

C for 2 h (entry 9).

With the optimized conditions in hand, we explored the

Table 1. Optimization of the Reaction Conditions

aromatic amide scope. As shown in Scheme 2, a broad variety

of aromatic amides were compatible with the protocol. Para-

substituted aromatic amides generally proceeded smoothly.

Amination of electron-rich or -deﬁcient substrates aﬀorded the

desired products 3b-3k in moderate to high yields. The

amination reaction of ortho-substituted benzamides generally

proceeded at a higher temperature (3l-3o), presumably caused

by a high steric hindrance arising from the ortho-substituents.

Meta-substituents including methyl (3p), chloro (3r), bromo

(3s), and triﬂuoromethyl (3t) groups at the aromatic ring

could be also well tolerated. Notably, the selective mono-

amination occurred exclusively at the ortho site. Meanwhile,

amination of benzamide with a small ﬂuoro substituent at the

meta site delivered regioisomers 3q with a 1:1 regioselectivity.

The amination reaction of electron-rich 2-naphthamide

occurred at the C3 site of the naphthyl ring to aﬀord the

amination product 3u in moderate yield. The protocol could

be extended to the ortho-amination of 1-naphthamide, and the

corresponding product 3v was obtained in 64% yield.

Moreover, heteroaromatic amides including nicotinamide,

isonicotinamide, thiophene-2-carboxamide, and thiophene-3-

carboxamide could be selectively aminated at the ortho site to

aﬀord the corresponding product 3w−3z in 52%−61% yields.

Subsequently, we turned our attention to examine the scope

of electrophilic O-benzoyl hydroxylamines (Scheme 3). The

catalytic amination of 1b with these O-benzoyl hydroxyl-

amines, derived from 6-membered cyclic amines including

piperidines and piperazine proceeded smoothly to provide the

entry

Cu salts

base

solvent

yield (%)

Cu(OAc)₂

Na CO

DMF

DMAc

NMP

trace

Na CO

^C^u⁽^O^A^c⁾2

Na CO

DCE

^C^u⁽^O^A^c⁾2

Na CO

toluene

dioxane

DMAc

DMF

DMAc

^C^u⁽^O^A^c⁾2

Na CO

CuBr

CuI

Na CO

78(74)

Na CO

Cu (OH) CO

Na CO

CuI

Li CO

trace

CuI

K CO

K PO

NaOAc

KOAc

Reaction conditions: 1a (0.3 mmol), Cu salts (0.03 mmol, 10 mol

), base (0.6 mmol, 2 equiv), 2a (0.45 mmol, 1.5 equiv) in 3 mL of

solvent at 80 °C for 2 h under nitrogen. Yield determined by H

NMR using CH Br as the internal standard. With 25 mol % CuI.

Isolated yield in parentheses.

0581

J. Org. Chem. 2021, 86, 10580−10590

The Journal of Organic Chemistry

Article

Scheme 2. Ortho-C−H Amination of Substituted 8-Aminoquinonyl Benzamides with 2a

Unless otherwise mentioned, all of the reactions were carried out with 1 (0.3 mmol), 2a (0.45 mmol), CuI (25 mol %), Na CO (0.6 mmol) in

the DMAc (3.0 mL) at 80 °C for 2 h under N . Isolated yields. Under 100 °C.

desired aminated product 4a−4e in acceptable to good yields.

realized under basic conditions to provide the carboxylic acid 5

in 89% isolated yield.

Notably, the ester, ketal, and Boc groups are well tolerated. A

-membered cyclic azepane donor coupled well with 1b to give

Considering that the preparation of O-benzoyl hydroxyl-

amines required an additional synthetic step, we wondered

whether the one-pot amination of benzamides with the

combination of morpholine and BzOOBz was feasible. With

this in mind, the ortho-amination of 1a with the combination

of morpholine and BzOOBz instead of 2a was performed

the aminated product 4f in 50% yield. However, a 5-membered

cyclic pyrrolidine donor (4g) was not tolerated. The reactions

with acyclic diethyl amine- and dipropyl amine-derived O-

benzoyl hydroxylamines (4h-4i) could also render the

installation of the dialkyl amine units, albeit in low yields.

A gram-scale synthesis of 3a was carried out, and 3a was

isolated in 69% yield along with 20% recovery of 1a (Scheme

(

Scheme 5). Unfortunately, the yield of 3a was only 30% based

on crude H NMR analysis (see Supporting Information for

details), which suggested that O-benzoyl hydroxylamines was

superior to the combination of morpholine and BzOOBz in the

amination reaction.

a), demonstrating the potential application of the protocol

into large-scale production. To examine the viability of this

transformation, the removal of 8-aminoquinolyl directing

group was conducted (Scheme 4b). The amide cleavage was

0582

J. Org. Chem. 2021, 86, 10580−10590

The Journal of Organic Chemistry

Article

Scheme 3. Scope of O-Benzoyl Hydroxylamines

Reaction conditions: 1b (0.3 mmol), 2 (0.45 mmol), CuI (25 mol %), Na CO (0.6 mmol) in the DMAc (3.0 mL) at 80 °C for 2 h under N .

Isolated yields.

Scheme 4. Gram-Scale Synthesis of 3a and Removal of 8-

Aminoquinoline Auxiliary

(2a) aﬀorded a 1.8:1 ratio of the products, which showed that

the electron-deﬁcient amide was favored. The 1.75:1 ratio of

products 4c and 3b in the competitive coupling reaction of O-

benzoyl hydroxylmorpholine (2a) and O-benzoyl hydroxylpi-

peridine (2b) with 4-methylbenzoic amide derivative (1b)

showed that less electrophilic O-benzoyl hydroxylpiperidine

(

2b) was favored. Furthermore, intramolecular and intermo-

lecular KIE were determined to be 3.8 and 4.0, respectively

(

Scheme 6c,d), indicating that C−H cleavage could potentially

be involved in the rate-determining step.

In summary, we developed a copper-catalyzed intermolec-

ular electrophilic amination of benzamides with O-benzoyl

hydroxylamines. The amination occurred at the ortho site

selectively with the assistance of a 8-aminoquinolyl group. A

variety of aryl amides and heteroaryl amides are compatible

with the protocol, and excellent tolerance with various

functional groups was achieved. Signiﬁcantly, the monoami-

nated product was overwhelmingly delivered under the simple

reaction conditions.

Scheme 5. Amination of 1a with the Combination of

Morpholine and BzOOBz

EXPERIMENTAL SECTION

■

General Information. NMR spectra were recorded on a JNM-

ECZ600R/S3 at 600 MHz (for H NMR) and 150 MHz (for

NMR) using TMS as the internal standard. Chemical shifts are given

relative to the residual solvents of CDCl (7.26 ppm for H NMR,

7.16 ppm for C{ H} NMR) unless otherwise noted. HRMS for

new compounds were recorded on a MicroMass Waters Xevo G2-XS

QTof, Xinyang Normal University. Melting points were measured on

a SGW X-4A melting point apparatus and are uncorrected. For

column chromatography, silica gel (300−400 mesh) was used as the

stationary phase. Unless otherwise noted, all commercial materials

were used without further puriﬁcation. Solvents were used after

puriﬁcation directed by Puriﬁcation of Laboratory Chemicals, 6th Ed.

Synthesis of Starting Materials. The benzamides 1a−1z were

synthesized from the corresponding carboxylic acids and 8-amino-

To further get insight into the reaction mechanism,

preliminary mechanistic investigations were conducted. Radical

scavenger experiments with 1.0 or 2.0 equiv of TEMPO or 2.0

equiv of BHT as a radical inhibitor showed that the

transformation was not completely inhibited (Scheme 6a),

suggesting that a radical pathway should not be involved in the

amination process. Subsequent competition experiments were

performed to probe the reactivity of substrates (Scheme 6b).

Competitive reaction of benzamide (1a) and 3-methylbenzoic

amide derivatives (1p) with O-benzoyl hydroxylmorpholine

quinoline according to the literature. All O-benzoyl hydroxylamines

2 were synthesized from the corresponding amines and benzoyl

peroxide according to the literature. 1a-d and 1a-d were prepared

0583

J. Org. Chem. 2021, 86, 10580−10590

The Journal of Organic Chemistry

Article

Scheme 6. Mechanistic Investigations

according to the literature. All of the NMR spectra of the known

compounds were in accordance with the data in the literature.

General Procedure for the Ortho-Amination of Benzamides.

Take the reaction of 1a with 2a for example: To a 30 mL Schlenk

ﬂask were added 1a (75 mg, 0.3 mmol), CuI (14 mg, 0.075 mmol), 2a

69% yield and the residual starting material 1a (0.25 g) as a white

solid in 20% yield.

Removal of the 8-Aminoquinolyl Auxiliary. The removal of 8-

aminoquinolyl auxiliary was conducted according the literature.

30 mL Schlenk ﬂask equipped with a stir bar was charged with 3a

(100 mg, 0.3 mmol), NaOH (180 mg, 4.5 mmol), and EtOH (3 mL).

The resulting mixture was stirred at 130 °C (oil bath). After 3 days,

the reaction mixture was cooled down to room temperature, diluted

with 50 mL ethyl acetate, and washed with HCl (4 × 20 mL of 0.5 N

aqueous solution). The aqueous layers were combined and extracted

with EtOAc (3 × 20 mL). Combined organic layers were dried over

(

93 mg, 0.45 mmol, 1.5 equiv), Na CO (64 mg, 0.6 mmol, 2 equiv),

and DMAc (3.0 mL). The ﬂask was then charged with N via two-

times N vacuum exchanges, and the mixture was stirred at 80 °C (oil

bath) for 2 h. After being allowed to cool to room temperature, the

reaction was diluted with DCM (10 mL) and treated with saturated

2 3

aqueous solution of Na S. Then, the mixture was stirred at room

temperature for 10 min and was ﬁltered through a short pad of Celite,

which was washed with copious DCM. Evaporation of the organic

solvent and puriﬁcation by silica gel column chromatography

petroleum ether: EtOAc = 4:1) gave the desired product 3a as a

white solid (74 mg) in 74% yield.

Gram-Scale Synthesis of 3a. To a 100 mL vial were added 1a

1.24 g, 5 mmol), CuI (0.237 g, 1.25 mmol), 2a (1.55 g, 0.45 mmol,

.5 equiv), Na CO (1.06 mg, 10 mmol, 2 equiv), and DMAc (50

mL). The ﬂask was then charged with N via two-times N -vacuum

MgSO . Evaporation of the organic solvent and puriﬁcation by silica

gel column chromatography (petroleum ether: EtOAc = 7:1) gave the

desired product 5 as a yellowish oil (55 mg) in 89% yield.

Mechanistic Investigation. Radical Scavenger Experiment. To

a 30 mL Schlenk ﬂask were added 1a (75 mg, 0.3 mmol), CuI (14 mg,

(

.075 mmol), 2a (93 mg, 0.45 mmol, 1.5 equiv), Na CO (64 mg, 0.6

2 3

(

mmol, 2 equiv), TEMPO (1.0 or 2.0 equiv), or BHT (2.0 equiv) and

DMAc (3.0 mL). The ﬂask was then charged with N via two-times

N -vacuum exchanges, and the mixture was stirred at 80 °C (oil bath)

exchanges, and the mixture was stirred at 80 °C (oil bath) for 2 h.

After being allowed to cool to room temperature, the reaction was

diluted with DCM (10 mL) and treated with saturated aqueous

for 2 h. After being allowed to cool to room temperature, the reaction

was diluted with DCM (10 mL) and treated with saturated aqueous

solution of Na S. Then, the mixture was stirred at room temperature

for 10 min and was ﬁltered through a short pad of Celite, which was

washed with copious DCM. Evaporation of the organic solvent and

puriﬁcation by silica gel column chromatography (petroleum ether:

EtOAc = 4:1) gave the desired product 3a as a white solid (1.15 g) in

for 10 min and was ﬁltered through a short pad of Celite, which was

washed with copious DCM. Evaporation of the organic solvent

aﬀorded the crude product, and subsequent H NMR analysis of the

crude product with CH Br as an internal standard gave a 33% yield

0584

J. Org. Chem. 2021, 86, 10580−10590

The Journal of Organic Chemistry

Article

of 3a with 1.0 equiv of TEMPO, a 31% yield of 3a with 2.0 equiv of

TEMPO, and a trace of 3a with 2.0 equiv of BHT, respectively.

Competition experiments of 1a and 1p with 2a: To a 30 mL

Schlenk ﬂask were added 1a (25 mg, 0.1 mmol), 1p (26 mg, 0.1

mmol), CuI (10 mg, 0.05 mmol), 2a (62 mg, 0.3 mmol, 1.5 equiv),

Na CO (43 mg, 0.4 mmol, 2 equiv), and DMAc (2.0 mL). The ﬂask

4-Methyl-2-morpholino-N-(quinolin-8-yl)benzamide (3b). The

compound 3b was prepared according to the GP and puriﬁed by

silica column chromatography in petroleum ether:ethyl acetate = 6:1.

3b was obtained as a white solid (73 mg, 70%). This compound is

known. Melting point: 184−185 °C. H NMR (600 MHz,

Chloroform-d) δ 12.69 (s, 1H), 9.13 (dd, J = 7.8, 1.2 Hz, 1H),

8.86 (dd, J = 4.2, 1.8 Hz, 1H), 8.16 (dd, J = 8.4, 1.2 Hz, 1H), 8.09 (d,

J = 7.8 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H),

7.46 (dd, J = 8.4, 4.2 Hz, 1H), 7.10−6.98 (m, 2H), 3.97 (t, J = 4.2 Hz,

was then charged with N via two-times N vacuum exchanges, and

the mixture was stirred at 80 °C (oil bath) for 2 h. After being allowed

to cool to room temperature, the reaction was diluted with DCM (10

H), 3.13 (t, J = 4.2 Hz, 4H), 2.41 (s, 3H). C{ H} NMR (150

mL) and treated with saturated aqueous solution of Na S. Then, the

MHz, Chloroform-d) δ 165.9, 151.2, 148.2, 143.0, 138.9, 136.5, 135.8,

mixture was stirred at room temperature for 10 min and was ﬁltered

through a short pad of Celite, which was washed with copious DCM.

Evaporation of the organic solvent aﬀorded the crude product, and

32.3, 128.4, 127.7, 126.1, 125.2, 121.7, 121.7, 120.1, 117.8, 66.2,

54.0, 21.7. HRMS (ESI-TOF): m/z calcd for C H N O [M + H]

21 22 3 2

348.1707, found 348.1710.

subsequent H NMR analysis of the crude product gave a 1.8:1 ratio

-(tert-Butyl)-2-morpholino-N-(quinolin-8-yl)benzamide (3c).

of products 3a and 3p.

The compound 3c was prepared according to the GP and puriﬁed

by silica column chromatography in petroleum ether:ethyl acetate =

Competition Experiment of 2a and 2b with 1b. To a 30 mL

Schlenk ﬂask were added 1b (53 mg, 0.2 mmol), CuI (10 mg, 0.05

mmol), 2a (62 mg, 0.3 mmol, 1.5 equiv), 2b (62 mg, 0.3 mmol, 1.5

equiv), Na CO (43 mg, 0.4 mmol, 2 equiv), and DMAc (2.0 mL).

:1. 3c was obtained as a white solid (62 mg, 53%). This compound is

known. Melting point: 132−134 °C. H NMR (600 MHz,

Chloroform-d) δ 12.71 (s, 1H), 9.13 (d, J = 7.8 Hz, 1H), 8.87 (dd,

J = 4.2, 1.2 Hz, 1H), 8.19 (d, J = 7.8 Hz, 1H), 8.13 (d, J = 7.8 Hz,

The ﬂask was then charged with N₂via two-times N₂vacuum

exchanges, and the mixture was stirred at 80 °C (oil bath) for 2 h.

After being allowed to cool to room temperature, the reaction was

diluted with DCM (10 mL) and treated with saturated aqueous

H), 7.60 (t, J = 7.8 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.48 (dd, J =

.4, 4.2 Hz, 1H), 7.32−7.27 (m, 2H), 3.99 (t, J = 4.2 Hz, 4H), 3.18 (t,

J = 4.2 Hz, 4H), 1.37 (s, 9H). C{ H} NMR (150 MHz,

Chloroform-d) δ 165.9, 156.1, 151.0, 148.2, 139.0, 136.5, 135.9,

solution of Na S. Then, the mixture was stirred at room temperature

for 10 min and was ﬁltered through a short pad of Celite, which was

32.0, 128.4, 127.7, 126.1, 121.7, 121.6, 121.5, 117.9, 116.3, 66.3,

washed with copious DCM. Evaporation of the organic solvent

54.1, 35.3, 31.3. HRMS (ESI-TOF): m/z calcd for C24

H] 390.2176, found 390.2174.

[M +

aﬀorded the crude product, and subsequent H NMR analysis of the

crude product gave a 1.75:1 ratio of products 4c and 3b.

Intramolecular KIE Experiment. To a 30 mL Schlenk ﬂask were

-Methoxy-2-morpholino-N-(quinolin-8-yl)benzamide (3d).

Compound 3d was prepared according to the GP and puriﬁed by

silica column chromatography in petroleum ether:ethyl acetate = 6:1.

added 1a-d (100 mg, 0.4 mmol), CuI (19 mg, 0.1 mmol), 2a (124

mg, 0.6 mmol, 1.5 equiv), Na CO (168 mg, 0.8 mmol, 2.0 equiv),

d was obtained as a white solid (74 mg, 68%). This compound is

and DMAc (4.0 mL). The ﬂask was then charged with N via twice

known. Melting point: 171−173 °C. H NMR (600 MHz,

Chloroform-d) δ 12.62 (s, 1H), 9.12 (dd, J = 7.8, 1.2 Hz, 1H),

N -vacuum exchanges, and the mixture was stirred at 80 °C (oil bath)

for 12 min. After being allowed to cool to room temperature, the

reaction was diluted with DCM (15 mL) and treated with saturated

.86 (dd, J = 4.2, 1.8 Hz, 1H), 8.23−8.10 (m, 2H), 7.58 (t, J = 7.8 Hz,

H), 7.51 (d, J = 8.4 Hz, 1H), 7.46 (dd, J = 8.4, 4.2 Hz, 1H), 6.77−

.75 (m, 2H), 3.97 (t, J = 4.2 Hz, 4H), 3.87 (s, 3H), 3.12 (t, J = 4.2

aqueous solution of Na S. Then, the mixture was stirred at room

temperature for 10 min and was ﬁltered through a pad of Celite,

which was washed with copious DCM. Evaporation of the organic

solvent and puriﬁcation by ﬂash chromatography (toluene: EtOAc =

Hz, 4H). C{ H} NMR (150 MHz, Chloroform-d) δ 165.5, 163.0,

53.1, 148.1, 138.9, 136.5, 135.9, 134.1, 128.4, 127.7, 121.7, 121.6,

21.6, 117.8, 108.4, 106.2, 66.2, 55.6, 54.0. HRMS (ESI-TOF): m/z

6:1) gave the desired product in 10% yield. The KIE value was

calcd for C H N O [M + H] 364.1656, found 364.1653.

calculated to be K /K = 3.8.

3-Morpholino-N-(quinolin-8-yl)-[1,1′-biphenyl]-4-carboxamide

Intermolecular KIE Experiment. To a 30 mL Schlenk ﬂask were

added 1a-d (50.6 mg, 0.2 mmol), 1a (50.0 mg, 0.2 mmol), CuI (19

(

3e). Compound 3e was prepared according to the GP and puriﬁed

by silica column chromatography in petroleum ether:ethyl acetate =

mg, 0.1 mmol), 2a (124 mg, 0.6 mmol, 1.5 equiv), Na CO (168 mg,

5:1. 3e was obtained as a white solid (86 mg, 70%). This compound is

11a

0.8 mmol, 2.0 equiv), and DMAc (4.0 mL). The ﬂask was then

known.

Melting point: 168−170 °C. H NMR (600 MHz,

charged with N via two-times N vacuum exchanges, and the mixture

Chloroform-d) δ 12.73 (s, 1H), 9.17 (dd, J = 7.8, 1.2 Hz, 1H),

8.89 (dd, J = 4.2, 1.8 Hz, 1H), 8.28 (d, J = 7.8 Hz, 1H), 8.19 (dd, J =

8.4, 1.8 Hz, 1H), 7.68−7.64 (m, 2H), 7.61 (t, J = 7.8 Hz, 1H), 7.55

(d, J = 8.4 Hz, 1H), 7.52−7.47 (m, 4H), 7.46 (d, J = 1.8 Hz, 1H),

7.44−7.39 (m, 1H), 4.00 (t, J = 4.2 Hz, 4H), 3.23 (t, J = 4.2 Hz, 4H).

was stirred at 80 °C (oil bath) for 12 min. After being allowed to cool

to room temperature, the reaction was diluted with DCM (15 mL)

and treated with saturated aqueous solution of Na S. Then, the

mixture was stirred at room temperature for 10 min and was ﬁltered

through a pad of Celite, which was washed with copious DCM.

Evaporation of the organic solvent and puriﬁcation by ﬂash

chromatography (toluene:EtOAc = 8:1) gave the desired product in

C{ H} NMR (150 MHz, Chloroform-d) δ 165.6, 151.6, 148.2,

145.4, 140.3, 138.9, 136.5, 135.7, 132.8, 129.0, 128.4, 128.2, 127.7,

127.6, 127.3, 123.0, 121.9, 121.7, 118.2, 117.9, 66.2, 54.1. HRMS

2% yield. The KIE value was calculated to be K /K = 4.0.

Characterization of Compounds. 2-Morpholino-N-(quinolin-

-yl)benzamide (3a). The compound 3a was prepared according to

(ESI-TOF): m/z calcd for C H NaN O [M + Na] 432.1682,

26 23

found 432.1683.

4-Fluoro-2-morpholino-N-(quinolin-8-yl)benzamide (3f). Com-

pound 3f was prepared according to the GP and puriﬁed by silica

column chromatography in petroleum ether:ethyl acetate = 4:1. 3f

was obtained as a white solid (77 mg, 73%). This compound is

the GP and puriﬁed by silica column chromatography in petroleum

ether:ethyl acetate = 4:1. 3a was obtained as a white solid (74 mg,

4%). This compound is known. Melting point: 122−124 °C. H

NMR (600 MHz, Chloroform-d) δ 12.67 (s, 1H), 9.13 (d, J = 7.8

known. Melting point: 177−179 °C. H NMR (600 MHz,

Chloroform-d) δ 12.5 (s, 1H), 9.09 (dd, J = 7.8, 1.2 Hz, 1H), 8.88

(d, J = 2.4 Hz, 1H), 8.20 (dd, J = 8.4, 1.8 Hz, 1H), 8.17 (dd, J = 9.6,

6.6 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.56 (dd, J = 7.8, 1.2 Hz, 1H),

7.50 (dd, J = 8.4, 4.2 Hz, 1H), 6.94 (m, J = 7.8 Hz, 1H), 6.93 (dd, J =

6.6, 2.4 Hz, 1H), 3.96 (t, J = 4.2 Hz, 4H), 3.14 (t, J = 4.2 Hz, 4H).

Hz,1H), 8.82 (dd, J = 3.6, 1.8 Hz, 1H), 8.19 (dd, J = 7.8, 1.8 Hz, 1H),

.11 (dd, J = 8.4, 1.2 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.49 (d, J =

.8 Hz, 1H), 7.46 (td, J = 7.8, 1.2 Hz, 1H), 7.41 (dd, J = 8.4, 4.2 Hz,

H), 7.23 (d, J = 7.2 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 3.93 (t, J = 4.2

Hz, 4H), 3.10 (t, J = 4.2 Hz, 4H). C{ H} NMR (150 MHz,

Chloroform-d) δ 165.6, 151.1, 148.1, 138.7, 136.3, 135.5, 132.3,

C{ H} NMR (150 MHz, Chloroform-d) δ 165.1 (d, J = 251.25 Hz,

32.1, 128.8, 128.2, 127.5, 124.2, 121.7, 121.6, 119.2, 117.7, 66.0,

1C), 164.8, 153.3 (d, J = 8.4 Hz, 1C), 148.2, 138.7, 136.5, 135.4,

134.4 (d, J = 9.9 Hz, 1C), 128.4, 127.6, 125.0, 121.9, 121.7, 117.7,

111.0 (d, J = 21.15 Hz, 1C), 106.7 (d, J = 23.25 Hz, 1C), 66.0, 53.8.

3.8. HRMS (ESI-TOF): m/z calcd for C H N O [M + H]

34.1550, found 334.1550.

0585

J. Org. Chem. 2021, 86, 10580−10590

The Journal of Organic Chemistry

Article

53.7. HRMS (ESI-TOF): m/z calcd for C H N O_[_M₊_H_]+

379.1401, found 379.1405.

F NMR (565 MHz, Chloroform-d) δ −106.3. HRMS (ESI-TOF):

m/z calcd for C H FNaN O [M + Na] 374.1275, found 374.1276.

-Chloro-2-morpholino-N-(quinolin-8-yl)benzamide (3g). Com-

2-Methyl-6-morpholino-N-(quinolin-8-yl)benzamide (3l). Com-

pound 3l was prepared according to the GP and puriﬁed by silica

column chromatography in petroleum ether:ethyl acetate = 4:1. 3l

was obtained as a white solid (67 mg, 65%). This compound is

pound 3g was prepared according to the GP and puriﬁed by silica

column chromatography in petroleum ether:ethyl acetate = 6:1. 3 g

was obtained as a white solid (72 mg, 65%). This compound is

known. Melting point: 148−150 °C. H NMR (600 MHz,

Chloroform-d) δ 12.47 (s, 1H), 9.08 (dd, J = 7.8, 1.8 Hz, 1H),

.86 (dd, J = 4.2, 1.8 Hz, 1H), 8.18 (d, J = 7.8 Hz, 1H), 8.10 (d, J =

.4 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.48

dd, J = 8.4, 4.2 Hz, 1H), 7.21 (dd, J = 8.4, 1.8 Hz, 1H), 7.19 (d, J =

.8 Hz, 1H), 3.94 (t, J = 4.2 Hz, 4H), 3.13 (t, J = 4.2 Hz, 4H).

C{ H} NMR (150 MHz, Chloroform-d) δ 164.8, 152.2, 148.3,

38.8, 138.2, 136.6, 135.4, 133.5, 128.4, 127.7, 127.4, 124.4, 122.1,

21.8, 119.8, 117.8, 66.1, 53.8. HRMS (ESI-TOF): m/z calcd for

C H ClN O [M + H] 368.1160, found 368.1156.

known. Melting point: 126−128 °C. H NMR (600 MHz,

Chloroform-d) δ 10.62 (s, 1H), 9.00 (dd, J = 7.8, 1.8 Hz, 1H),

8.77 (dd, J = 4.2, 1.8 Hz, 1H), 8.18 (dd, J = 8.4, 1.8 Hz, 1H), 7.64−

7.58 (m, 1H), 7.55 (dd, J = 8.4, 1.2 Hz, 1H), 7.45 (dd, J = 8.4, 4.2 Hz,

1H), 7.31 (t, J = 7.8 Hz, 1H), 7.01 (d, J = 7.8 Hz, 1H), 6.98 (d, J = 7.8

Hz, 1H), 3.51 (t, J = 4.2 Hz, 4H), 3.08 (t, J = 4.2 Hz, 4H), 2.50 (s,

(

3H). C{ H} NMR (150 MHz, Chloroform-d) δ 168.0, 150.1, 148.3,

138.6, 138.4, 136.5, 135.0, 131.9, 130.2, 128.3, 127.6, 126.0, 121.8,

116.7, 116.5, 67.0, 53.1, 20.5. HRMS (ESI-TOF): m/z calcd for

[M + H] 348.1707, found 348.1712.

-Bromo-2-morpholino-N-(quinolin-8-yl)benzamide (3h). Com-

2-Fluoro-6-morpholino-N-(quinolin-8-yl)benzamide (3m). Com-

pound 3h was prepared according to the GP and puriﬁed by silica

column chromatography in petroleum ether:ethyl acetate = 4:1. 3h

was obtained as a white solid (93 mg, 75%). This compound is

known. Melting point: 148 °C (decomp). H NMR (600 MHz,

Chloroform-d) δ 12.47 (s, 1H), 9.08 (dd, J = 7.8, 1.2 Hz, 1H), 8.87

pound 3m was prepared according to the GP and puriﬁed by silica

column chromatography in petroleum ether:ethyl acetate = 4:1. 3m

was obtained as a white solid (65 mg, 62%). Melting point: 145−147

°C. H NMR (600 MHz, Chloroform-d) δ 10.93 (s, 1H), 8.99 (d, J =

7.8 Hz, 1H), 8.78 (dd, J = 4.2, 1.8 Hz, 1H), 8.17 (dt, J = 8.4, 1.8 Hz,

1H), 7.58 (td, J = 7.8, 3.0 Hz, 1H), 7.54 (dt, J = 8.4, 1.8 Hz, 1H), 7.45

(dd, J = 8.4, 4.2 Hz, 1H), 7.40−7.33 (m, 1H), 6.89−6.85 (m, 2H),

(

dd, J = 4.2, 1.8 Hz, 1H), 8.20 (dd, J = 8.4, 1.8 Hz, 1H), 8.02 (d, J =

.4 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.56 (dd, J = 8.4, 1.8 Hz, 1H),

.50 (dd, J = 8.4, 4.2 Hz, 1H), 7.39 (dd, J = 8.4, 1.8 Hz, 1H), 7.36 (d,

3.64 (t, J = 3.6 Hz, 4H), 3.12 (t, J = 3.6 Hz, 4H). C{ H} NMR (150

MHz, Chloroform-d) δ 162.9, 161.6 (d, J = 251.25 Hz, 1C), 151.5 (d,

J = 4.2 Hz, 1C), 148.3, 138.5, 136.5, 134.6, 131.8 (d, J = 10.5 Hz, 1C),

J = 2.4 Hz, 1H), 3.95 (t, J = 4.8 Hz, 4H), 3.15 (t, J = 4.8 Hz, 4H).

C{ H} NMR (150 MHz, Chloroform-d) δ 164.9, 152.1, 148.3,

28.2, 127.6, 122.1, 121.8, 119.1 (d, J = 13.8 Hz, 1C), 117.0, 114.0,

11.0 (d, J = 22.5 Hz, 1C), 66.6, 52.9. F NMR (565 MHz,

38.8, 136.6, 135.3, 133.7, 128.4, 127.8, 127.7, 127.4, 126.7, 122.8,

22.1, 121.8, 117.8, 66.0, 53.9. HRMS (ESI-TOF): m/z calcd for

Chloroform-d) δ −113.2. HRMS (ESI-TOF): m/z calcd for

C H BrN O [M + H] 412.0655 found 412.0653.

Methyl-3-morpholino-4-(quinolin-8-ylcarbamoyl)benzoate (3i).

Compound 3i was prepared according to the GP and puriﬁed by

silica column chromatography in petroleum ether:ethyl acetate = 4:1.

19FN

[M + H] 352.1456, found 352.1449.

2-Chloro-6-morpholino-N-(quinolin-8-yl)benzamide (3n). Com-

pound 3n was prepared according to the GP and puriﬁed by silica

column chromatography in petroleum ether:ethyl acetate = 6:1. 3n

was obtained as a white solid (55 mg, 50%). Melting point: 116−118

i was obtained as a white solid (82 mg, 70%). This compound is

known. Melting point: 183−185 °C. H NMR (600 MHz,

Chloroform-d) δ 12.57 (s, 1H), 9.08 (d, J = 7.8 Hz, 1H), 8.85 (dd,

J = 4.2, 1.8 Hz, 1H), 8.20 (d, J = 7.8 Hz, 1H), 8.16 (d, J = 8.4 Hz,

°C. H NMR (600 MHz, Chloroform-d) δ 12.68 (s, 1H), 9.13 (dd, J

= 7.8, 1.2 Hz, 1H), 8.87 (dd, J = 4.2, 1.8 Hz, 1H), 8.19 (dd, J = 3.6,

1.8 Hz, 1H), 8.18 (dd, J = 4.2, 1.8 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H),

7.54 (dd, J = 7.8, 1.2 Hz, 1H), 7.51 (dd, J = 7.8, 1.8 Hz, 1H), 7.48

(dd, J = 8.4, 4.2 Hz, 1H), 7.28−7.22 (m, 2H), 3.97 (t, J = 4.2 Hz,

H), 7.89 (s, 1H), 7.87 (dd, J = 7.8, 1.2 Hz, 1H), 7.62−7.55 (m, 1H),

.53 (d, J = 8.4 Hz, 1H), 7.46 (ddd, J = 8.4, 4.2, 1.8 Hz, 1H), 3.93 (t, J

4.2 Hz, 4H), 3.16 (t, J = 4.2 Hz, 4H). C{ H} NMR (150 MHz,

Chloroform-d) δ 166.4, 164.9, 151.0, 148.3, 138.8, 136.5, 135.2,

4H), 3.15 (t, J = 4.2 Hz, 4H). C{ H} NMR (150 MHz, Chloroform-

d) δ 165.9, 151.2, 148.2, 138.9, 136.5, 135.7, 132.5, 132.3, 129.0,

33.4, 132.8, 132.3, 128.4, 127.6, 125.1, 122.2, 121.8, 120.4, 117.9,

6.1, 53.8, 52.5. HRMS (ESI-TOF): m/z calcd for C H N O [M +

128.4, 127.7, 124.4, 121.9, 121.7, 119.3, 117.9, 66.3, 54.0. HRMS

H] 392.1605, found 392.1597.

-Morpholino-N-(quinolin-8-yl)-4-(triﬂuoromethyl)benzamide

3j). Compound 3j was prepared according to the GP and puriﬁed by

silica column chromatography in petroleum ether:ethyl acetate = 4:1.

j was obtained as a white solid (75 mg, 62%). This compound is

(ESI-TOF): m/z calcd for C20

H19ClN O

[M + H] 368.1160, found

368.1170.

(

2-Morpholino-N-(quinolin-8-yl)-6-(triﬂuoromethyl)benzamide

(3o). Compound 3o was prepared according to the GP and puriﬁed

by silica column chromatography in petroleum ether:ethyl acetate =

4:1. 3o was obtained as a white solid (55 mg, 46%). Melting point:

known. Melting point: 172−174 °C. H NMR (600 MHz,

Chloroform-d) δ 12.45 (s, 1H), 9.09 (dd, J = 7.8, 1.8 Hz, 1H),

135−137 °C. H NMR (600 MHz, Chloroform-d) δ 10.26 (s, 1H),

.86 (dd, J = 4.2, 1.8 Hz, 1H), 8.24 (d, J = 7.8 Hz, 1H), 8.19 (dd, J =

.4, 1.8 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.56 (dd, J = 8.4, 1.2 Hz,

H), 7.49 (dd, J = 7.8, 1.8 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.45 (s,

H), 3.94 (t, J = 4.2 Hz, 4H), 3.18 (t, J = 4.2 Hz, 4H). C{ H} NMR

150 MHz, Chloroform-d) δ 164.6, 151.4, 148.4, 138.8, 136.6, 135.1,

8.91 (dd, J = 7.8, 1.8 Hz, 1H), 8.75 (dd, J = 4.2, 1.8 Hz, 1H), 8.20

(dd, J = 8.4, 1.8 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.58 (dd, J = 8.4,

1.8 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.46

(dd, J = 8.4, 4.2 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 3.53 (t, J = 4.2 Hz,

(

4H), 3.09 (t, J = 4.2 Hz, 4H). C{ H} NMR (150 MHz, Chloroform-

d) δ 165.4, 151.0, 148.4, 138.5, 136.6, 134.6, 131.9, 130.7, 129.6 (q, J

= 31.5 Hz, 1C), 128.3, 127.7, 124.0, 123.7 (d, J = 272.7 Hz, 1C),

33.9 (q, J = 32.1 Hz, 1C), 132.9, 132.1, 128.4, 127.6, 123.7, 122.3,

21.9, 121.0, 120.7, 117.9, 116.0, 66.1, 53.7. F NMR (565 MHz,

Chloroform-d) δ −62.75. HRMS (ESI-TOF): m/z calcd for

C H NaF N O [M + Na] 424.1243, found 424.1249.

122.2, 121.9, 121.6 (q, J = 4.65 Hz, 1C), 117.0, 67.0, 53.1. F NMR

(565 MHz, Chloroform-d) δ −58.75. HRMS (ESI-TOF): m/z calcd

-Morpholino-4-nitro-N-(quinolin-8-yl)benzamide (3k). Com-

for C21H

18NaF

[M + Na] 424.1243, found 424.1249.

pound 3k was prepared according to the GP and puriﬁed by silica

column chromatography in petroleum ether:ethyl acetate = 4:1. 3k

5-Methyl-2-morpholino-N-(quinolin-8-yl)benzamide (3p). Com-

pound 3p was prepared according to the GP and puriﬁed by silica

column chromatography in petroleum ether:ethyl acetate = 4:1. 3p

was obtained as a white solid (78 mg, 75%). This compound is

known. Melting point: 149−151 °C. H NMR (600 MHz,

Chloroform-d) δ 12.80 (s, 1H), 9.13 (dd, J = 7.8, 1.2 Hz, 1H),

8.87 (dd, J = 4.2, 1.8 Hz, 1H), 8.18 (dd, J = 8.4, 1.8 Hz, 1H), 8.03 (d,

J = 2.4 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.54 (dd, J = 8.4, 1.2 Hz,

1H), 7.47 (dd, J = 8.4, 4.2 Hz, 1H), 7.30 (dd, J = 8.4, 2.4 Hz, 1H),

7.16 (d, J = 8.4 Hz, 1H), 4.07−3.86 (m, 4H), 3.25−3.03 (m, 4H),

was obtained as a yellowish solid (52 mg, 46%). Melting point: 116−

(

18 °C. H NMR (600 MHz, Chloroform-d) δ 12.37 (s, 1H), 9.06

dd, J = 7.2, 1.8 Hz, 1H), 8.87 (dd, J = 4.2, 1.8 Hz, 1H), 8.29−8.24

m, 1H), 8.21 (dd, J = 8.4, 1.8 Hz, 1H), 8.05 (s, 1H), 8.04 (dd, J =

.8, 2.4 Hz, 1H), 7.64−7.57 (m, 2H), 7.51 (dd, J = 8.4, 4.2 Hz, 1H),

13 1

.01−3.74 (m, 4H), 3.29−2.96 (m, 4H). C{ H} NMR (150 MHz,

Chloroform-d) δ 163.9, 151.9, 150.2, 148.5, 138.7, 136.7, 134.8,

34.5, 133.4, 128.5, 127.7, 122.7, 122.0, 118.6, 118.0, 114.3, 66.0,

0586

J. Org. Chem. 2021, 86, 10580−10590

The Journal of Organic Chemistry

Article

.38 (s, 3H). ¹³C{ H} NMR (150 MHz, Chloroform-d) δ 165.9,

Chloroform-d) δ 12.36 (s, 1H), 9.09 (dd, J = 7.8, 1.2 Hz, 1H),

8.87 (d, J = 2.4 Hz, 1H), 8.41 (d, J = 2.4 Hz, 1H), 8.21 (dd, J = 8.4,

1.8 Hz, 1H), 7.73 (dd, J = 8.4, 2.4 Hz, 1H), 7.65−7.60 (m, 1H), 7.58

(dd, J = 8.4, 1.8 Hz, 1H), 7.51 (dd, J = 8.4, 4.2 Hz, 1H), 7.31 (d, J =

8.4 Hz, 1H), 3.95 (t, J = 4.2 Hz, 4H), 3.21 (t, J = 4.2 Hz, 4H).

48.9, 148.2, 139.0, 136.5, 135.8, 134.1, 133.0, 132.7, 128.6, 128.4,

27.7, 121.8, 121.7, 119.5, 117.9, 66.3, 54.1, 20.8. HRMS (ESI-TOF):

m/z calcd for C H N O [M + H] 348.1707, found 348.1710.

-Fluoro-2-morpholino-N-(quinolin-8-yl)benzamide (3q). Com-

pound 3q was prepared according to the GP and puriﬁed by silica

column chromatography in petroleum ether:ethyl acetate = 4:1. 3q

was obtained as a white solid (38 mg, 36%). This compound is

known. Melting point: 158−159 °C. H NMR (600 MHz,

Chloroform-d) δ 12.91 (s, 1H), 9.10 (dd, J = 7.8, 1.8 Hz, 1H),

.88 (dd, J = 4.2, 1.8 Hz, 1H), 8.19 (dd, J = 8.4, 1.8 Hz, 1H), 7.95

dd, J = 9.6, 3.0 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.56 (dd, J = 7.8,

.2 Hz, 1H), 7.49 (dd, J = 8.4, 4.2 Hz, 1H), 7.26 (dd, J = 9.0, 4.8 Hz,

H), 7.19 (ddd, J = 9.0, 7.2, 3.0 Hz, 1H), 4.00 (t, J = 4.2 Hz, 4H),

C{ H} NMR (150 MHz, Chloroform-d) δ 164.6, 153.8, 148.4,

138.8, 136.7, 135.1, 129.7 (d, J = 3.5 Hz, 1C), 129.30, 129.1 (d, J =

.6 Hz, 1C), 128.5, 127.7, 126.1 (q, J = 33.2 Hz, 1C), 125.8, 125.0 (q,

J = 270.3 Hz, 1C), 123.2, 122.3, 121.9, 119.3, 117.9, 66.1, 53.7.

NMR (565 MHz, Chloroform-d) δ −62.08. HRMS (ESI-TOF): m/z

(

calcd for C H NaF N O [M + Na] 424.1243, found 424.1249.

-Morpholino-N-(quinolin-8-yl)-2-naphthamide (3u). Com-

pound 3u was prepared according to the GP and puriﬁed by silica

column chromatography in petroleum ether: ethyl acetate = 5:1. 3u

was obtained as a white solid (67 mg, 58%). This compound is

.11 (t, J = 4.2 Hz, 4H). C{ H} NMR (150 MHz, Chloroform-d) δ

64.2, 159.7 (d, J = 242.7 Hz, 1C), 148.3, 147.4, 139.0, 136.6, 135.5,

31.0 (d, J = 6.9 Hz, 1C), 128.5, 127.7, 122.3, 121.8, 121.6 (d, J = 8.0

known. Melting point: 212−214 °C. H NMR (600 MHz,

Chloroform-d) δ 10.66 (s, 1H), 9.13 (dd, J = 7.8, 1.2 Hz, 1H),

Hz, 1C), 119.1 (d, J = 22.5 Hz, 1C), 118.8 (d, J = 24.2 Hz, 1C),

.74 (dd, J = 4.2, 1.8 Hz, 1H), 8.29 (d, J = 9.0 Hz, 1H), 8.20 (dd, J =

.4, 1.8 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H),

18.3, 66.2, 54.3. ¹F NMR (565 MHz, Chloroform-d) δ −117.50.

HRMS (ESI-TOF): m/z calcd for C H FN O [M + H] 352.1456,

7.65 (t, J = 7.8 Hz, 1H), 7.58 (dd, J = 7.8, 1.2 Hz, 1H), 7.52 (ddd, J =

found 352.1449.

.4, 6.6, 1.2 Hz, 1H), 7.45 (dd, J = 7.8, 4.2 Hz, 1H), 7.44−7.42 (m,

-Fluoro-2-morpholino-N-(quinolin-8-yl)benzamide (3q′). Com-

1H), 7.41 (d, J = 9.0 Hz, 1H), 3.63 (t, J = 4.2 Hz, 4H), 3.24 (t, J = 4.2

pound 3q′ was prepared according to the GP and puriﬁed by silica

column chromatography in petroleum ether:ethyl acetate = 4:1. 3q′

was obtained as a white solid (39 mg, 37%). This compound is

Hz, 4H). C{ H} NMR (150 MHz, Chloroform-d) δ 167.7, 148.3,

147.5, 138.6, 136.5, 135.1, 131.8, 131.4, 130.4, 128.3, 128.1, 127.7,

27.6, 127.0, 125.1, 125.0, 122.0, 121.9, 118.8, 116.8, 67.1, 53.0.

known. Melting point: 131−133 °C. H NMR (600 MHz,

Chloroform-d) δ 12.73 (s, 1H), 9.07 (dd, J = 7.8, 1.8 Hz, 1H),

.89 (dd, J = 4.2, 1.8 Hz, 1H), 8.20 (dd, J = 8.4, 1.8 Hz, 1H), 8.09 (d,

J = 7.8 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.57 (dd, J = 8.4, 1.8 Hz,

H), 7.49 (dd, J = 8.4, 4.2 Hz, 1H), 7.29 (td, J = 8.4, 5.4 Hz, 1H),

.24 (ddd, J = 12.6, 7.8, 1.8 Hz, 1H), 4.07 (t, J = 4.2 Hz, 4H), 3.36 (t,

J = 4.2 Hz, 4H). C{ H} NMR (150 MHz, Chloroform-d) δ 164.5,

61.0 (d, J = 250.5 Hz, 1C), 148.2, 139.2, 137.1 (d, J = 9.9 Hz, 1C),

36.6, 135.5, 133.3 (d, J = 2.7 Hz, 1C), 128.4, 127.6, 126.8 (d, J = 8.9

HRMS (ESI-TOF): m/z calcd for C H N O [M + H] 384.1707,

found 384.1704.

-Morpholino-N-(quinolin-8-yl)-1-naphthamide (3v). Com-

pound 3v was prepared according to the GP and puriﬁed by silica

column chromatography in petroleum ether:ethyl acetate = 6:1. 3v

was obtained as a brown oil (74 mg, 64%). H NMR (600 MHz,

Chloroform-d) δ 10.67 (s, 1H), 9.13 (dd, J = 7.8, 1.2 Hz, 1H), 8.74

(

dd, J = 4.2, 1.8 Hz, 1H), 8.29 (d, J = 8.4 Hz, 1H), 8.19 (dd, J = 8.4,

.8 Hz, 1H), 7.94 (d, J = 9.0 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.65

t, J = 7.8 Hz, 1H), 7.58 (dd, J = 8.4, 1.2 Hz, 1H), 7.52 (ddd, J = 8.4,

6.6, 1.2 Hz, 1H), 7.45 (dd, J = 8.4, 4.2 Hz, 1H), 7.44−7.42 (m, 1H),

(

Hz, 1C), 122.4, 121.8, 120.2 (d, J = 21.8 Hz, 1C), 118.9, 66.5, 52.0,

2.0. ¹⁹F NMR (565 MHz, Chloroform-d) δ −117.5. HRMS (ESI-

TOF): m/z calcd for C H FN O_[_M₊_H_]+ 352.1456, found

.41 (d, J = 9.0 Hz, 1H), 3.63 (t, J = 4.2 Hz, 4H), 3.24 (t, J = 4.2 Hz,

H). C{ H} NMR (150 MHz, Chloroform-d) δ 167.7, 148.3, 147.5,

38.6, 136.5, 135.1, 131.8, 131.4, 130.4, 128.3, 128.1, 127.7, 127.6,

352.1449.

-Chloro-2-morpholino-N-(quinolin-8-yl)benzamide (3r). Com-

pound 3r was prepared according to the GP and puriﬁed by silica

column chromatography in petroleum ether:ethyl acetate = 4:1. 3r

was obtained as a white solid (72 mg, 65%). This compound is

Melting point: 147−149 °C. H NMR (600 MHz,

Chloroform-d) δ 12.64 (s, 1H), 9.08 (dd, J = 7.6, 1.4 Hz, 1H),

.86 (dd, J = 4.1, 1.6 Hz, 1H), 8.21−8.17 (m, 2H), 8.16 (d, J = 2.7

Hz, 1H), 7.59 (t, J = 7.9 Hz, 1H), 7.55 (d, J = 7.4 Hz, 1H), 7.48 (dd, J

8.2, 4.2 Hz, 1H), 7.43 (dd, J = 8.6, 2.7 Hz, 1H), 7.17 (d, J = 8.6 Hz,

H), 4.11−3.74 (m, 5H), 3.22−2.98 (m, 5H). C{ H} NMR (150

MHz, Chloroform-d) δ 164.3, 149.7, 148.3, 138.8, 136.6, 135.3, 132.2,

32.1, 130.4, 130.1, 128.4, 127.6, 122.2, 121.8, 121.0, 118.0, 66.1,

6.0. HRMS (ESI-TOF): m/z calcd for C H ClN O [M + H]

68.1160, found 368.1170.

-Bromo-2-morpholino-N-(quinolin-8-yl)benzamide (3s). Com-

pound 3s was prepared according to the GP and puriﬁed by silica

column chromatography in petroleum ether:ethyl acetate = 8:1. 3s

was obtained as a white solid (85 mg, 69%). Melting point: 155−157

C. H NMR (600 MHz, Chloroform-d) δ 12.58 (s, 1H), 9.08 (dd, J

7.8, 1.8 Hz, 1H), 8.85 (dd, J = 4.2, 1.8 Hz, 1H), 8.29 (d, J = 2.4 Hz,

H), 8.18 (dd, J = 8.4, 1.8 Hz, 1H), 7.61−7.58 (m, 1H), 7.58−7.56

m, 1H), 7.54 (dd, J = 8.4, 1.2 Hz, 1H), 7.47 (dd, J = 8.4, 4.2 Hz,

27.0, 125.1, 125.0, 121.9, 121.8, 118.8, 116.8, 67.1, 53.0. HRMS

(ESI-TOF): m/z calcd for C H N O [M + H] 384.1707, found

11a

384.1706.

known.

-Morpholino-N-(quinolin-8-yl)nicotinamide (3w). Compound

w was prepared according to the GP and puriﬁed by silica column

chromatography in petroleum ether:ethyl acetate = 1:3. 3w was

obtained as an oﬀ-white solid (52 mg, 52%). This compound is

known. Melting point: 188−190 °C. H NMR (600 MHz,

Chloroform-d) δ 11.69 (s, 1H), 9.05 (s, 1H), 9.02 (dd, J = 7.8, 1.8

Hz, 1H), 8.82 (dd, J = 4.2, 1.8 Hz, 1H), 8.56 (d, J = 5.4 Hz, 1H), 8.18

(dd, J = 8.4, 1.8 Hz, 1H), 7.60−7.56 (m, 1H), 7.55 (dd, J = 8.4, 1.8

Hz, 1H), 7.48 (dd, J = 8.4, 4.2 Hz, 1H), 6.98 (d, J = 5.4 Hz, 1H),

.98−3.74 (m, 4H), 3.32−3.08 (m, 4H). C{ H} NMR (151 MHz,

Chloroform-d) δ 164.5, 153.0, 152.8, 148.4, 138.5, 136.6, 134.8,

28.3, 127.7, 123.5, 122.2, 121.9, 117.4, 112.6, 65.9, 52.3. HRMS

(

ESI-TOF): m/z calcd for C H N O [M + H] 335.1503, found

19 19 4 2

335.1510.

(

-Morpholino-N-(quinolin-8-yl)isonicotinamide (3x). Compound

x was prepared according to the GP and puriﬁed by silica column

chromatography in petroleum ether:ethyl acetate = 1:1. 3x was

obtained as a yellowish solid (56 mg, 56%). This compound is

H), 7.10 (d, J = 8.4 Hz, 1H), 3.95 (d, J = 4.2 Hz, 4H), 3.10 (d, J =

.2 Hz, 4H). ¹³C{ H} NMR (150 MHz, Chloroform-d) δ 164.2,

50.1, 148.3, 138.8, 136.6, 135.3, 135.1, 135.0, 130.7, 128.4, 127.6,

known. Melting point: 217−219 °C. H NMR (600 MHz,

Chloroform-d) δ 12.52 (s, 1H), 9.07 (dd, J = 7.2, 2.4 Hz, 1H),

.87 (dd, J = 4.2, 1.8 Hz, 1H), 8.62 (s, 1H), 8.55 (d, J = 4.8 Hz, 1H),

.20 (dd, J = 8.4, 1.8 Hz, 1H), 7.97 (d, J = 4.8 Hz, 1H), 7.65−7.55

22.2, 121.8, 121.2, 118.0, 117.6, 66.1, 53.9. HRMS (ESI-TOF): m/z

calcd for C H BrN O [M + H] 412.0655 found 412.0644.

-Morpholino-N-(quinolin-8-yl)-5-(triﬂuoromethyl)benzamide

3t). Compound 3t was prepared according to the GP and puriﬁed by

silica column chromatography in petroleum ether:ethyl acetate = 4:1.

t was obtained as a white solid (75 mg, 62%). This compound is

(m, 2H), 7.50 (dd, J = 8.4, 4.2 Hz, 1H), 4.10−3.82 (m, 4H), 3.38−

13 1

(

3.11 (m, 4H). C{ H} NMR (150 MHz, Chloroform-d) δ 163.6,

148.5, 146.3, 145.2, 142.5, 138.8, 136.6, 135.4, 134.9, 128.4, 127.6,

124.7, 122.6, 121.9, 118.1, 66.1, 53.6. HRMS (ESI-TOF): m/z calcd

known. Melting point: 144−146 °C. H NMR (600 MHz,

for C H N O [M + H] 335.1503, found 335.1506.

0587

J. Org. Chem. 2021, 86, 10580−10590

The Journal of Organic Chemistry

Article

-Morpholino-N-(quinolin-8-yl)thiophene-2-carboxamide (3y).

TOF): m/z calcd for C H NaN O [M + Na] 368.1733, found

22 23 3 1

Compound 3y was prepared according to the GP and puriﬁed by

368.1733.

silica column chromatography in petroleum ether:ethyl acetate = 4:1.

4-Methyl-2-(2-methylpiperidin-1-yl)-N-(quinolin-8-yl)benzamide

(4d). Compound 4d was prepared according to the GP and puriﬁed

by silica column chromatography in petroleum ether:ethyl acetate =

y was obtained as an oﬀ-white solid (55 mg, 54%). This compound

is known. Melting point: 170−171 °C. H NMR (600 MHz,

Chloroform-d) δ 12.60 (s, 1H), 9.04 (dd, J = 7.8, 1.2 Hz, 1H), 8.93

:1. 4d was obtained as an oﬀ-white solid (50 mg, 46%). Melting

point: 196−198 °C. H NMR (600 MHz, Chloroform-d) δ 13.72 (s,

(dd, J = 4.2, 1.8 Hz, 1H), 8.19 (dd, J = 8.4, 1.8 Hz, 1H), 7.58 (t, J =

H), 9.14 (dd, J = 7.8, 1.2 Hz, 1H), 8.86 (dd, J = 4.2, 1.8 Hz, 1H),

.29 (d, J = 8.4 Hz, 1H), 8.16 (dd, J = 8.4, 1.8 Hz, 1H), 7.59 (t, J =

.8 Hz, 1H), 7.54 (dd, J = 7.8, 1.2 Hz, 1H), 7.52 (d, J = 5.4 Hz, 1H),

.50 (dd, J = 8.4, 4.2 Hz, 1H), 7.20 (d, J = 5.4 Hz, 1H), 4.15 (t, J =

7.8 Hz, 1H), 7.52 (dd, J = 7.8, 1.2 Hz, 1H), 7.46 (dd, J = 8.4, 4.2 Hz,

H), 7.21 (s, 1H), 7.11 (d, J = 7.8 Hz, 1H), 3.28−3.18 (m, 1H), 3.16

dt, J = 11.4, 3.6 Hz, 1H), 2.76 (td, J = 11.4, 2.4 Hz, 1H), 2.23−2.11

(m, 1H), 2.06−1.95 (m, 1H), 1.87−1.82 (m, 2H), 1.56−1.44 (m,

.2 Hz, 4H), 3.11 (t, J = 4.2 Hz, 4H). C{ H} NMR (150 MHz,

(

Chloroform-d) δ 160.7, 152.3, 148.1, 139.0, 136.5, 135.8, 130.3,

30.2, 128.4, 127.7, 122.3, 121.8, 121.7, 118.1, 66.6, 54.4. HRMS

(ESI-TOF): m/z calcd for C H NaN O S [M + Na] 362.0934,

18 17 3 2

(

H), 1.29−1.19 (m, 1H), 1.05 (d, J = 6.6 Hz, 3H). C{ H} NMR

found 362.0927.

150 MHz, Chloroform-d) δ 165.7, 152.1, 147.7, 142.7, 139.7, 136.7,

-Morpholino-N-(quinolin-8-yl)thiophene-3-carboxamide (3z).

36.3, 131.9, 128.4, 127.7, 127.6, 126.2, 123.7, 121.6, 121.5, 118.8,

Compound 3z was prepared according to the GP and puriﬁed by

silica column chromatography in petroleum ether:ethyl acetate = 4:1.

6.7, 33.1, 24.4, 25.8, 21.6, 19.5. HRMS (ESI-TOF): m/z calcd for

C H N O [M + H] 360.2070, found 360.2079.

z was obtained as a white solid (62 mg, 61%). Melting point: 151−

tert-Butyl-4-(5-methyl-2-(quinolin-8-ylcarbamoyl)phenyl)-

153 °C. H NMR (600 MHz, Chloroform-d) δ 12.35 (s, 1H), 9.06

piperazine-1-carboxylate (4e). Compound 4e was prepared

according to the GP and puriﬁed by silica column chromatography

in petroleum ether:ethyl acetate = 4:1. 4e was obtained as a white

(dd, J = 7.8, 1.2 Hz, 1H), 8.89 (dd, J = 4.2, 1.8 Hz, 1H), 8.17 (dd, J =

.4, 1.8 Hz, 1H), 7.57 (d, J = 6.0 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H),

.51 (dd, J = 8.4, 1.2 Hz, 1H), 7.48 (dd, J = 8.4, 4.2 Hz, 1H), 7.00 (d,

solid (100 mg, 75%). Melting point: 146−148 °C. H NMR (600

J = 5.4 Hz, 1H), 4.11 (t, J = 4.2 Hz, 4H), 3.13 (t, J = 4.2 Hz, 4H).

MHz, Chloroform-d) δ 12.74 (s, 1H), 9.13 (dd, J = 7.8, 1.2 Hz, 1H),

C{ H} NMR (150 MHz, Chloroform-d) δ 161.3, 160.2, 148.1,

8.79 (dd, J = 4.2, 1.8 Hz, 1H), 8.17 (dd, J = 8.4, 1.2 Hz, 1H), 8.11 (d,

39.0, 136.6, 135.9, 128.3, 128.2, 127.7, 127.6, 121.7, 121.7, 118.8,

J = 7.8 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H),

17.8, 66.4, 56.5. HRMS (ESI-TOF): m/z calcd for C H NaN O S

.45 (dd, J = 8.4, 4.2 Hz, 1H), 7.07 (d, J = 7.8 Hz, 1H), 7.03 (s, 1H),

.73 (d, J = 50.4 Hz, 1H), 3.09 (s, 4H), 2.41 (s, 3H), 1.43 (s, 9H).

C{ H} NMR (150 MHz, Chloroform-d) δ 165.7, 154.9, 151.3,

[

M + Na] 362.0934, found 362.0927.

Ethyl-1-(5-methyl-2-(quinolin-8-ylcarbamoyl)phenyl)piperidine-

-carboxylate (4a). Compound 4a was prepared according to the GP

48.0, 143.0, 138.9, 136.5, 135.8, 132.3, 128.5, 127.7, 126.2, 125.4,

and puriﬁed by silica column chromatography in petroleum

21.7, 121.7, 120.4, 117.9, 79.9, 28.5, 21.7. HRMS (ESI-TOF): m/z

ether:ethyl acetate = 4:1. 4a was obtained as a white solid (97 mg,

calcd for C H N NaO [M + Na] 469.2210, found 469.2215.

26 30

8%). Melting point: 125−127 °C. H NMR (600 MHz, Chloroform-

-(Azepan-1-yl)-4-methyl-N-(quinolin-8-yl)benzamide (4f).

d) δ 12.8 (s, 1H), 9.16 (dd, J = 7.8, 1.2 Hz, 1H), 8.88 (dd, J = 4.2, 1.6

Hz, 1H), 8.14 (dd, J = 8.4, 1.8 Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.57

Compound 4f was prepared according to the GP and puriﬁed by

silica column chromatography in petroleum ether:ethyl ether: ethyl

acetate = 5:1:1. 4f was obtained as an oﬀ-white solid (54 mg, 50%).

(t, J = 7.8 Hz, 1H), 7.51 (dd, J = 7.8, 1.2 Hz, 1H), 7.44 (dd, J = 8.4,

4.2 Hz, 1H), 7.03 (s, 1H), 7.04 (d, J = 7.8 Hz, 1H), 4.05 (q, J = 7.2

Melting point: 130−132 °C. H NMR (600 MHz, Chloroform-d) δ

Hz, 2H), 3.40 (d, J = 12.0 Hz, 2H), 2.98−2.79 (m, 2H), 2.43−2.38

2.73 (s, 1H), 9.09 (dd, J = 7.8, 1.2 Hz, 1H), 8.82 (dd, J = 4.2, 1.8 Hz,

H), 8.16 (dd, J = 8.4, 1.8 Hz, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.58 (t, J

(

m, 1H), 2.40 (s, 3H), 2.32−2.22 (m, 2H), 2.05−1.93 (m, 2H), 1.15

13 1

t, J = 7.2 Hz, 3H). C{ H} NMR (150 MHz, Chloroform-d) δ

7.8 Hz, 1H), 7.51 (dd, J = 8.4, 1.2 Hz, 1H), 7.44 (dd, J = 8.4, 4.2

74.9, 165.9, 152.1, 148.3, 142.8, 139.1, 136.3, 136.1, 132.2, 128.4,

Hz, 1H), 7.10 (s, 1H), 6.97 (d, J = 7.8 Hz, 1H), 3.47−3.25 (m, 4H),

27.5, 126.1, 125.0, 121.6, 121.5, 120.4, 117.9, 60.4, 54.0, 41.0, 27.7,

.39 (s, 3H), 2.05−1.83 (m, 4H), 1.62 (m, 4H). C{ H} NMR (150

1.7, 14.3. HRMS (ESI-TOF): m/z calcd for C H N O [M + H]

MHz, Chloroform-d) δ 166.4, 153.7, 147.9, 142.5, 139.4, 136.3, 136.1,

18.2125, found 418.2128.

31.8, 128.4, 127.7, 125.7, 123.9, 122.0, 121.5, 121.4, 117.9, 57.0,

-Methyl-N-(quinolin-8-yl)-2-(1,4-dioxa-8-azaspiro[4.5]decan-8-

8.2, 27.2, 21.8. HRMS (ESI-TOF): m/z calcd for C H N O [M +

yl)benzamide (4b). Compound 4b was prepared according to the GP

and puriﬁed by silica column chromatography in petroleum

H] 360.2070, found 360.2079.

-(Diethylamino)-4-methyl-N-(quinolin-8-yl)benzamide (4h).

ether:ethyl acetate = 3:1. 4b was obtained as a white solid (82 mg,

Compound 4h was prepared according to the GP and puriﬁed by

8%). Melting point: 201−203 °C. H NMR (600 MHz, Chloroform-

silica column chromatography in petroleum ether:ethyl acetate = 6:1.

d) δ 13.08 (s, 1H), 9.16 (dd, J = 7.8, 1.2 Hz, 1H), 8.93 (dd, J = 4.2,

.8 Hz, 1H), 8.21−8.10 (m, 2H), 7.58 (t, J = 7.8 Hz, 1H), 7.52 (dd, J

8.4, 1.2 Hz, 1H), 7.47 (dd, J = 8.4, 4.2 Hz, 1H), 7.15 (s, 1H), 7.06

h was obtained as a light-yellow oil (45 mg, 45%). H NMR (600

MHz, chloroform-d) δ 14.67 (s, 1H), 9.07 (d, J = 7.8 Hz, 1H), 8.83

dd, J = 4.2, 1.2 Hz, 1H), 8.30 (d, J = 7.8 Hz, 1H), 8.15 (dd, J = 8.4,

.8 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.43

dd, J = 8.4, 4.2 Hz, 1H), 7.14 (s, 1H), 7.12 (d, J = 8.4 Hz, 1H), 3.25

(

d, J = 7.8 Hz, 1H), 3.96 (s, 4H), 3.21 (t, J = 5.4 Hz, 4H), 2.40 (s,

H), 2.13 (s, 4H). ¹C{ H} NMR (150 MHz, Chloroform-d) δ 165.9,

(

52.0, 148.1, 142.9, 139.2, 136.4, 136.3, 132.2, 128.4, 127.6, 126.1,

q, J = 7.2 Hz, 4H), 2.41 (s, 3H), 1.06 (t, J = 7.2 Hz, 6H). C{ H}

25.4, 121.7, 121.7, 121.2, 118.2, 107.2, 64.4, 52.6, 34.7, 21.7. HRMS

NMR (150 MHz, Chloroform-d) δ 165.3, 149.2, 148.0, 142.5, 140.0,

136.7, 136.1, 131.6, 128.8, 128.4, 127.7, 126.2, 124.3, 121.4, 121.3,

(ESI-TOF): m/z calcd for C H N O [M + H] 404.1969, found

04.1972.

17.8, 50.0, 21.6, 12.0. HRMS (ESI-TOF): m/z calcd for C H N O

21 24 3

-Methyl-2-(piperidin-1-yl)-N-(quinolin-8-yl)benzamide (4c).

[M + H] 334.1914, found 334.1928.

Compound 4c was prepared according to the GP and puriﬁed by

silica column chromatography in petroleum ether:ethyl acetate = 5:1.

-(Dipropylamino)-4-methyl-N-(quinolin-8-yl)benzamide (4i).

Compound 4i was prepared according to the GP and puriﬁed by

silica column chromatography in petroleum ether:ethyl acetate = 6:1.

4i was obtained as a white solid (47 mg, 43%). Melting point: 113−

c was obtained as a white solid (82 mg, 60%). Melting point: 190−

192 °C. H NMR (600 MHz, Chloroform-d) δ 9.14 (dd, J = 7.8, 1.2

Hz, 1H), 8.84 (dd, J = 4.2, 1.8 Hz, 1H), 8.17 (dd, J = 8.4, 1.8 Hz,

115 °C. H NMR (600 MHz, Chloroform-d) δ 14.55 (s, 1H), 9.08

H), 8.08 (d, J = 8.4 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.52 (dd, J =

.4, 1.2 Hz, 1H), 7.45 (dd, J = 8.4, 4.2 Hz, 1H), 7.05 (s, 1H), 7.03−

.97 (m, 1H), 3.07 (s, 4H), 2.40 (s, 3H), 1.91−1.77 (m, 4H), 1.50 (d,

(dd, J = 7.8, 1.2 Hz, 1H), 8.83 (dd, J = 4.2, 1.8 Hz, 1H), 8.29 (d, J =

8.4 Hz, 1H), 8.15 (dd, J = 8.4, 1.8 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H),

7.52−7.48 (m, 1H), 7.43 (dd, J = 8.4, 4.2 Hz, 1H), 7.15 (s, 1H), 7.11

(d, J = 8.4 Hz, 1H), 3.19−3.05 (m, 4H), 2.41 (s, 3H), 1.60−1.47 (m,

J = 5.4 Hz, 2H). C{ H} NMR (150 MHz, Chloroform-d) δ 166.3,

53.0, 147.9, 142.7, 139.2, 136.3, 136.2, 132.0, 128.4, 127.7, 126.0,

24.5, 121.6, 121.5, 120.3, 118.0, 55.5, 25.4, 24.2, 21.8. HRMS (ESI-

4H), 0.77 (t, J = 7.2 Hz, 6H). C{ H} NMR (150 MHz, Chloroform-

d) δ 165.3, 149.8, 147.9, 142.5, 139.9, 136.7, 136.1, 131.6, 128.4,

0588

J. Org. Chem. 2021, 86, 10580−10590

The Journal of Organic Chemistry

tions. Chem. Rev. 2017 , 117 , 9247. (b) Shin, K.; Kim, H.; Chang, S.

Article

28.3, 127.7, 126.0, 124.2, 121.4, 121.3, 117.9, 58.6, 21.7, 19.8, 12.1.

Transition-Metal-Catalyzed C −N Bond Forming Reactions Using

Organic Azides as the Nitrogen Source: A Journey for the Mild and

Versatile C −H Amination. Acc. Chem. Res. 2015, 48, 1040.

HRMS (ESI-TOF): m/z calcd for C H N O [M + H] 362.2227,

found 362.2224.

-Morpholinobenzoic Acid (5). Yellowish oil, Yield 55 mg (89%)

at a 0.3 mmol scale. H NMR (600 MHz, Chloroform-d) δ 8.28 (dd, J

7.8, 1.8 Hz, 1H), 7.65−7.59 (m, 1H), 7.44 (dd, J = 8.4, 1.2 Hz, 1H),

H Nitrogenation and Oxygenation by Ruthenium Catalysis. Chem.

Commun. 2014 , 50 , 29. (d) Louillat, M.-L.; Patureau, F. W. Oxidative

C −H amination reactions. Chem. Soc. Rev. 2014 , 43 , 901. (e) Jiao, J.;

Murakami, K.; Itami, K. Catalytic Methods for Aromatic C −H

Amination: An Ideal Strategy for Nitrogen- Based Functional

Molecules. ACS Catal. 2016 , 6 , 610. (f) Jeffrey, J. L.; Sarpong, R.

.41 (td, J = 7.8, 1.2 Hz, 1H), 3.94 (s, 4H), 3.07 (s, 4H). C{ H}

NMR (150 MHz, Chloroform-d) δ 166.8, 150.3, 134.2, 132.6, 128.0,

25.2, 122.6, 67.0, 53.6. HRMS (ESI-TOF): m/z calcd for

C H NO [M + H] 208.0968, found 208.0968.

ASSOCIATED CONTENT

■

Intramolecular C(sp )−H amination. Chem. Sci. 2013 , 4 , 4092.

sı Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.1c01229.

(g) Gephart, R. T., III; Warren, T. H. Copper-Catalyzed sp C −H

Amination. Organometallics 2012 , 31 , 7728. (h) Feng, Y.-L.; Shi, B.-F.

Recent Advances in Base Metal (Copper, Cobalt and Nickel)-

Catalyzed Directed C −H Amination. Chin. J. Org. Chem. 2021 , 41.

Veriﬁcation test, copies of all spectral, and full

characterization for all new compounds (PDF)

(2) For recent reviews, see: (a) Rao, W.-H.; Shi, B.-F. Recent

advances in copper-mediated chelation-assisted functionalization of

unactivated C −H bonds. Org. Chem. Front. 2016 , 3 , 1028. (b) Zhu,

R.-Y.; Farmer, M. E.; Chen, Y.-Q.; Yu, J.-Q. A Simple and Versatile

Amide Directing Group for C −H Functionalizations. Angew. Chem.,

Int. Ed. 2016, 55, 10578. (c) Chen, Z.; Wang, B.; Zhang, J.; Yu, W.;

Liu, Z.; Zhang, Y. Transition Metal-Catalyzed C −H Bond

Functionalizations by the Use of Diverse Directing Groups. Org.

Chem. Front. 2015 , 2 , 1107. (d) Rej, S.; Ano, Y.; Chatani, N.

Bidentate Directing Groups: An Efficient Tool in C −H Bond

Functionalization Chemistry for the Expedient Construction of C −C

AUTHOR INFORMATION

■

Corresponding Author

Wei-Hao Rao − College of Chemistry and Chemical

Engineering, Xinyang Normal University, Xinyang 464000,

China; Ministry-of-Education Key Laboratory for the

Synthesis and Application of Organic Functional Molecules,

Hubei University, Wuhan 430062, China; orcid.org/

000-0001-6197-0148 ; Email: whrao@xynu.edu.cn

Bonds. Chem. Rev. 2020, 120, 1788. (e) Gandeepan, P.; Muller, T.;

Zell, D.; Cera, G.; Warratz, S.; Ackermann, L. 3d Transition Metals

for C −H Activation. Chem. Rev. 2019, 119 , 2192. (f) He, J.; Wasa, M.;

Chan, K. S. L.; Shao, Q.; Yu, J.-Q. Palladium-Catalyzed Trans-

formations of Alkyl C −H Bonds. Chem. Rev. 2017 , 117 , 8754.

Authors

Qi Li − College of Chemistry and Chemical Engineering,

Xinyang Normal University, Xinyang 464000, China

Li-Li Jiang − College of Chemistry and Chemical Engineering,

Xinyang Normal University, Xinyang 464000, China

Xue-Wan Deng − College of Chemistry and Chemical

Engineering, Xinyang Normal University, Xinyang 464000,

China

(g) Daugulis, O.; Roane, J.; Tran, L. D. Bidentate, Monoanionic

Auxiliary-Directed Functionalization of Carbon −Hydrogen Bonds.

Acc. Chem. Res. 2015 , 48 , 1053. (h) Wu, Y.; Shi, B. Transition Metal-

Catalyzed C −H Activation via Imine-Based Transient Directing

Group Strategy. Chin. J. Org. Chem. 2020 , 40 , 3517. (i) Zhang, Q.;

Shi, B.-F. From Reactivity and Regioselectivity to Stereoselectivity: An

Odyssey of Designing PIP Amine and Related Directing Groups for

C −H Activation. Chin. J. Chem. 2019, 37, 647.

Pan Xu − College of Chemistry and Chemical Engineering,

Xinyang Normal University, Xinyang 464000, China

Fang-Yuan Chen − College of Chemistry and Chemical

Engineering, Xinyang Normal University, Xinyang 464000,

China

Ming Li − College of Chemistry and Chemical Engineering,

Xinyang Normal University, Xinyang 464000, China

Guo-Dong Zou − College of Chemistry and Chemical

Engineering, Xinyang Normal University, Xinyang 464000,

China

(3) (a) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. Cu(II)-

Catalyzed Functionalizations of Aryl C −H Bonds Using O as an

Oxidant. J. Am. Chem. Soc. 2006 , 128 , 6790. (b) Uemura, T.; Imoto,

S.; Chatani, N. Amination of the Ortho C −H Bonds by the

Cu(OAc) -mediated Reaction of 2-Phenylpyridines with Anilines.

Chem. Lett. 2006 , 35 , 842. (c) John, A.; Nicholas, K. M. Copper-

Catalyzed Amidation of 2-Phenylpyridine with Oxygen as the

Terminal Oxidant. J. Org. Chem. 2011, 76, 4158.

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.1c01229

4) (a) Peng, J.; Chen, M.; Xie, Z.; Luo, S.; Zhu, Q. Copper-

mediated C(sp )−H amination using TMSN as a nitrogen source:

redox-neutral access to primary anilines. Org. Chem. Front. 2014 , 1 ,

Notes

777. (b) Peng, J.; Xie, Z.; Chen, M.; Wang, J.; Zhu, Q. Copper-

The authors declare no competing ﬁnancial interest.

Catalyzed C(sp2)−H Amidation with Azides as Amino Sources. Org.

Lett. 2014 , 16 , 4702. (c) Xie, Z.; Peng, J.; Zhu, Q. Copper-Mediated

ACKNOWLEDGMENTS

C(sp )−H Amination in a Multiple C −N bond-Forming Strategy for

■

the Synthesis of N -heterocycles. Org. Chem. Front. 2016 , 3 , 82.

We are grateful for the ﬁnancial support from the National

Natural Science Foundation of China (Grant No. 21807091),

Ministry-of-Education Key Laboratory for the Synthesis and

Application of Organic Functional Molecules (Grant No.

KLSAOFM2010), and Nanhu Scholars Program for Young

Scholars of XYNU. We also gratefully acknowledge Dr. Qiu-Ju

Zhou for NMR assistance.

(5) (a) Tran, L. D.; Roane, J.; Daugulis, O. Directed Amination of

Non-Acidic Arene C −H Bonds by a Copper-Silver Catalytic System.

Angew. Chem., Int. Ed. 2013 , 52 , 6043. (b) Roane, J.; Daugulis, O. A

General Method for Aminoquinoline-Directed, Copper-Catalyzed sp

C −H Bond Amination. J. Am. Chem. Soc. 2016 , 138 , 4601.

6) Kwak, S. H.; Daugulis, O. N -Aminopyridinium Ylide-Directed,

Copper-Promoted Amination of sp C −H Bonds. J. Org. Chem. 2019,

4, 13022.

7) Singh, B. K.; Polley, A.; Jana, R. Copper(II)-Mediated

REFERENCES

■

1) For reviews, see: (a) Park, Y.; Kim, Y.; Chang, S. Transition

Metal-Catalyzed C −H Amination: Scope, Mechanism, and Applica-

Intermolecular C(sp )−H Amination of Benzamides with Electron-

Rich Anilines. J. Org. Chem. 2016, 81, 4295.

0589

J. Org. Chem. 2021, 86, 10580−10590

The Journal of Organic Chemistry

Article

8) Shang, M.; Sun, S.-Z.; Dai, H.-X.; Yu, J.-Q. Cu(II)-Mediated C −

B. Copper-Catalyzed Remote C −H Amination of Quinolines with N -

Fluorobenzenesulfonimide. Adv. Synth. Catal. 2017 , 359 , 1037.

(15) Berman, A. M.; Johnson, J. S. Copper-Catalyzed Electrophilic

Amiantion of Diorganozinc Reagents: 4-Phenylmorpholine. Org.

Synth. 2006, 83, 31.

(16) Karthikeyan, J.; Haridharan, R.; Cheng, C.-H. Rhodium(III)-

Catalyzed Oxidative C −H Coupling of N -Methoxybenzamides with

Aryl Boronic Acids: One-Pot Synthesis of Phenanthridinones. Angew.

Chem., Int. Ed. 2012, 51, 12343.

H Amidation and Amination of Arenes: Exceptional Compatibility

with Heterocycles. J. Am. Chem. Soc. 2014, 136, 3354.

Copper-Catalyzed Carboxamide-Directed Ortho Amination of Ani-

lines with Alkylamines at Room Temperature. Org. Lett. 2014, 16,

9) (a) Li, Q.; Zhang, S.-Y.; He, G.; Ai, Z.; Nack, W. A.; Chen, G.

1764. (b) Martínez, A. M.; Rodríguez, N.; Arrayás, R. G.; Carretero, J.

C. Copper-Catalyzed Ortho -C −H Amination of Protected Anilines

with Secondary Amines. Chem. Commun. 2014, 50, 2801.

(

10) Kumar, M.; Sharma, R.; Raziullah; Khan, A. A.; Ahmad, A.;

Dutta, H. S.; Koley, D. Cu(II)-Catalyzed Ortho C(sp )−H Diary-

lamination of Arylamines To Synthesize Triarylamines. Org. Lett.

(

020, 22, 2152.

11) For non-electrochemical versions, see: (a) Yan, Q.; Chen, Z.;

Yu, W.; Yin, H.; Liu, Z.; Zhang, Y. Nickel-Catalyzed Direct Amination

of Arenes with Alkylamines. Org. Lett. 2015 , 17 , 2482. (b) Yan, Q.;

Xiao, T.; Liu, Z.; Zhang, Y. Cobalt-Catalyzed Direct Amination of

Arenes with Alkylamines via Bidentate-Chelation Assistance. Adv.

Synth. Catal. 2016, 358, 2707. For electrochemical versions, see:

T.-S. Copper-Catalyzed Electrochemical C −H Amination of Arenes

with Secondary Amines. J. Am. Chem. Soc. 2018 , 140 , 11487. (d) Li,

Q.; Huang, J.; Chen, G.; Wang, S.-B. Copper-Catalyzed Ortho -

C(sp )−H Amination of Benzamides and Picolinamides with

Alkylamines Using Oxygen as a Green Oxidant. Org. Biomol. Chem.

020 , 18 , 4802. (e) Kathiravan, S.; Suriyanarayanan, S.; Nicholls, I. A.

Electrooxidative Amination of sp C −H Bonds: Coupling of Amines

with Aryl Amides via Copper Catalysis. Org. Lett. 2019, 21, 1968.

(f) Zhang, S.-K.; Samanta, R. C.; Sauermann, N.; Ackermann, L.

Nickel-Catalyzed Electrooxidative C −H Amination: Support for

Nickel(IV). Chem.-Eur. J. 2018 , 24 , 19166. (g) Gao, X.; Wang, P.;

Zeng, L.; Tang, S.; Lei, A. Cobalt(II)-Catalyzed Electrooxidative C −

H Amination of Arenes with Alkylamines. J. Am. Chem. Soc. 2018,

(

40, 4195.

12) (a) Xu, L.-L.; Wang, X.; Ma, B.; Yin, M.-X.; Lin, H.-X.; Dai, H.-

X.; Yu, J.-Q. Copper Mediated C −H Amination with Oximes: En

Route to Primary Anilines. Chem. Sci. 2018 , 9 , 5160. (b) Begam, H.

M.; Choudhury, R.; Behera, A.; Jana, R. Copper-Catalyzed Electro-

philic Ortho C(sp )−H Amination of Aryl Amines: Dramatic

Reactivity of Bicyclic System. Org. Lett. 2019, 21, 4651.

(13) Matsubara, T.; Asako, S.; Ilies, L.; Nakamura, E. Synthesis of

Anthranilic Acid Derivatives through Iron-Catalyzed Ortho Amina-

tion of Aromatic Carboxamides with N -Chloroamines. J. Am. Chem.

Soc. 2014, 136, 646.

(14) For selected reviews on electrophilic amination with hydroxyl-

amine derivatives, see: (a) Zhou, Z.; Kurti, L. Electrophilic

Amination: An Update. Synlett 2019 , 30 , 1525. (b) Hendrick, C. E.;

Wang, Q. Emerging Developments Using Nitrogen-Heteroatom

Bonds as Amination Reagents in the Synthesis of Aminoarenes. J.

Org. Chem. 2017 , 82 , 839. (c) Dong, X.; Liu, Q.; Dong, Y.; Liu, H.

Transition-Metal-Catalyzed Electrophilic Amination: Application of

O -Benzoylhydroxylamines in the Construction of the C −N Bond.

Chem.-Eur. J. 2017 , 23 , 2481. (d) Dask

by the Electrophilic Amination of Organomagnesium, −Zinc,

Copper, and -Lithium Reagents. ARKIVOC 2011, 230. For selected

̧ apan, T. Synthesis of Amines

examples of electrophilic amination with hydroxylamine derivatives,

see: (e) Kawano, T.; Hirano, K.; Satoh, T.; Miura, M. A New Entry of

Amination Reagents for Heteroaromatic C −H Bonds: Copper-

Catalyzed Direct Amination of Azoles with Chloroamines at Room

Temperature. J. Am. Chem. Soc. 2010 , 132 , 6900. (f) Zhou, Z.; Ma, Z.;

Behnke, N. E.; Gao, H.; Ku

Secondary Amination of (Hetero)Arylmetals. J. Am. Chem. Soc. 2017 ,

39 , 115. (g) He, J.; Shigenari, T.; Yu, J.-Q. Palladium(0)/PAr -

rti, L. Non-Deprotonative Primary and

Catalyzed Intermolecular Amination of C(sp ) −H Bonds: Synthesis

of β -Amino Acids. Angew. Chem., Int. Ed. 2015, 54, 6545. (h) Yoo, E.

J.; Ma, S.; Mei, T.-S.; Chan, K. S. L.; Yu, J.-Q. Pd-Catalyzed

Intermolecular C −H Amination with Alkylamines. J. Am. Chem. Soc.

011, 133, 7652. (i) Yin, Y.; Xie, J.; Huang, F.-Q.; Qi, L.-W.; Zhang,

0590