N-acylation of amides through internal nucleophilic catalysis

Article abstract of DOI:10.1177/1747519820925755

An efficient method for N-acylation of amides is described using a pyridine ring as the internal nucleophilic catalyst to give imides in moderate to excellent yields. The methodology provides a facile, air insensitive, and environmentally friendly route to form diversified imide scaffolds, which exist widely in natural products and biologically active materials.

Full text of DOI:10.1177/1747519820925755

925755CHL0010.1177/1747519820925755Journal of Chemical ResearchYao et al.
research-article2020
Research Paper
Journal of Chemical Research
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N-acylation of amides through internal
nucleophilic catalysis
https://doi.org/10.1177/1747519820925755
DOI: 10.1177/1747519820925755
journals.sagepub.com/home/chl
Meng Yao, Xia Chen, Yuling Lu, Zhenhua Guan,
Zengwei Luo and Yonghui Zhang
Abstract
An efficient method for N-acylation of amides is described using a pyridine ring as the internal nucleophilic catalyst to
give imides in moderate to excellent yields. The methodology provides a facile, air insensitive, and environmentally
friendly route to form diversified imide scaffolds, which exist widely in natural products and biologically active materials.
Keywords
imides, internal nucleophilic catalysis, Mumm rearrangement, N,N-diisopropylethylamine, pyridine
Date received: 28 February 2020; accepted: 20 April 2020
O
R1
R2
O
DIPEA, CH2Cl2
r.t.
H
N
R1
+
N
O
R2 Cl
N
3
h,
N
O
to 98%
up
H
N
yield
examples
35
R1
N
N
-H
N
R1
O
Mumm-
O
R2
O
O
rearrangement
R2
Introduction
Ph
N
O
O
OMe
Me
H
N
O
N
O
NH2
Imides are well represented as valuable intermediates in
synthetic organic chemistry, and these structural motifs also
occur in natural products and pharmaceuticals such as the
antibiotic fumaramidmycin,1,2 palauimide,3 thalidomide,4
the antifeedant ypaoamide,5 and the platelet-activating fac-
tor (PAF) antagonist CV-62096,7 (Figure 1). To date, vari-
ous methods for imides have been developed. Imides can
be prepared by the palladium-catalyzed three-component
reaction between terminal alkynes, isonitriles, and sodium
carboxylates.8 Yamaguchi reported a copper-catalyzed aer-
obic oxidative acylation of amides with alcohols for the
synthesis of imides.9 Also, Nicolaou reported the oxidation
of secondary amides to the corresponding imides using
Dess–Martin periodinane.10
In spite of the above-mentioned methods, imides are
usually prepared between amides and an excess of acti-
vated forms of carboxylic acids, such as acyl chlorides,
anhydrides, and esters, under strong basic or acidic condi-
tions (Scheme 1(a)).11–14 However, for some acid- or base-
sensitive or biologically related compounds, metal-free and
versatile conditions are in demand. Although there are sev-
eral examples described using mild conditions with a weak
base,15–19 for instance, the conversion of NHBoc to N(Boc)2
with 4-dimethylaminopyridine (DMAP),20 the develop-
ment of versatile and efficient methods for the preparation
of imides is still challenging.
n-Bu
NH
O
O
N
H
O
O
Me
O
O
thalidomide
fumaramidmycin
O
palauimide
4
OAc
HN
O
O
O
N
Cl
N
N
O
O
O
N
H
17
MeO
OMe
O
ypaoamide
CV-6209
Figure 1. Compounds containing an imide core.
Hubei Key Laboratory of Natural Medicinal Chemistry and Resource
Evaluation, School of Pharmacy, Tongji Medical College, Huazhong
University of Science and Technology, Wuhan, P.R. China
Corresponding authors:
Zengwei Luo, Hubei Key Laboratory of Natural Medicinal Chemistry
and Resource Evaluation, School of Pharmacy, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan 430030, P.R.
China.
Email: luozengwei@hust.edu.cn
Yonghui Zhang, Hubei Key Laboratory of Natural Medicinal Chemistry
and Resource Evaluation, School of Pharmacy, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan 430030, P.R.
China.
Email: zhangyh@mails.tjmu.edu.cn

2
Journal of Chemical Research 00(0)
Table 1. Optimization of the reaction conditions.a
(a)
O
O
R3
R2
O
O
H
N
R1
R1
N
strong base
or acid
R2
+
O
H
N
R3
X
Cl
Base
CH2Cl2
+
strong
O
O
N
N
O
X = halogen, OCOR, OR
N
CH3
CH3
(b)
1a
2a
3a
R
R
DIPEA
T3P,
N
O
N
O
XH
N
XH
R
Entry
Base (equiv.)
2a (equiv.)
Yieldb (%)
R
R
X
R
O
X = O, N
HO
1
2
3
4
5
6
7
8
DIPEA (1.0)
DIPEA (1.5)
DIPEA (2.0)
DIPEA (1.5)
DIPEA (1.5)
Et3N (1.5)
1.0
1.0
1.0
1.3
1.5
1.3
1.3
1.3
51
83
82
94
93
48
23
35
(c)
O
R1
R2
O
DIPEA, CH2Cl2
r.t.
H
N
R1
+
N
O
R2 Cl
N
3
h,
N
O
H
N
R1
N
N
-H
N
R1
Na2CO3 (1.5)
CH3COOK (1.5)
O
Mumm-
rearrangement
O
R2
O
O
R2
DIPEA: N,N-diisopropylethylamine.
aConditions: 1a (0.2mmol), CH2Cl2 (2.0mL), room temperature, 3h.
Scheme 1. Strategies relevant to imides synthesis: (a)
traditional work, (b) Unsworth’s work, and (c) this work.
bIsolated yields.
Significance for bold value in table 1 was illustrated as the highlighted
sentence.
Using an internal nucleophilic catalyst may be the solution
to this problem. Acylation is one type of basic organic trans-
formation to form amides or esters, which can be accelerated
using a nucleophilic catalyst. Pyridine can act as a nucleo-
phile for activated carboxylic acids and is often used as a cata-
lyst in acylation reactions. Recently, Unsworth demonstrated
a strategy for the synthesis of medium-sized rings readily
from linear precursors mediated by an internal nucleophilic
catalyst, a pyridine ring, which can capture the carboxylic
acid to provide a reactive intermediate (Scheme 1(b)).21–23
Inspired by this work, we have taken advantage of internal
catalysis to achieve mild N-acylation reactions of amides.
Herein, we used the amides possessing a pyridine ring as sub-
strates, the pyridine ring can form an active acylammonium
salt with an acyl chloride. Thus, the original intermolecular
reaction will be transformed into an intramolecular reaction.
The imide will be obtained following a Mumm rearrange-
ment of the intermediate isoimide (Scheme 1(c)).
N
S
O
O
O
O
N
N
N
O
O
O
3a
3b
3c
, 69%
, 94%
N
, 65%
O
O
O
N
N
N
N
O
O
O
3d
3e
3f
, 0%
, 68%
, 0%
Scheme 2. Acyl transfer catalyst optimization.
the internal nucleophilic catalyst were found to be 1.5equiv.
of DIPEA and 1.3equiv. of 2a in CH2Cl2 at room tempera-
ture for 3h, from which compound 3a was isolated in 94%
yield (entry 4).
After determining the optimized reaction conditions, we
then set out to investigate the substrate scope of the amides and
the acid chlorides. The results are summarized in Scheme 3.
Aliphatic and α,β-unsaturated amides, especially hin-
dered t-butyryl amide, reacted smoothly to produce the tar-
get imides 5a–5d in moderate to excellent yields. Amides
bearing either electron-donating or electron-withdrawing
groups on the phenyl ring successfully delivered the desired
products 5ea–5ej in good to excellent yields. Combined
with the above results, the transformation still ran smoothly
regardless of the presence of substituents at ortho, meta, or
para positions on the phenyl ring (5f–5j). This transforma-
tion was also applicable to heteroaryl amides (5k and 5l).
Next, the scope of the acyl chlorides was examined. Acetyl
chloride and 2-methoxyacetyl chloride reacted with cin-
namamide to deliver the products 5m and 5n in 90% and
82% yields, respectively. As in the case of benzamide and
isobutyramide, conjugated acyl chlorides and various func-
tional-group-substituted alkyl acyl chlorides also reacted
smoothly to provide the corresponding imides 5o–5u. It
was noteworthy that when a diamide was used as the sub-
strate, product 5v was obtained as the sole product.
Results and discussion
With N-(pyridin-2-ylmethyl)acetamide (1a) as the acyl
acceptor and benzoyl chloride (2a) as the acyl donor, an
initialstudywasperformedwithN,N-diisopropylethylamine
(DIPEA) as the base in CH2Cl2 at room temperature for 3h
(Table 1, entry 1). To our delight, the desired product 3a
was obtained in 51% yield. It was found that a higher yield
(83%) was achieved when using 1.5equiv. of DIPEA
(entries 2 and 3). Furthermore, the yield was improved to
94% when screening the amount of acyl chloride (entries 4
and 5). Three other bases were also tested (entries 6–8) but
all led to a reduction in the yield of 3a.
Next, other aromatic substrates as internal nucleophilic
catalysts were examined (Scheme 2). Thiophene and furan
were less efficient leading to 3b and 3c in moderate yields.
The 2-methylpyridine was found to be optimal when alter-
ing the carbon chain number between the pyridine ring and
the amide (3d and 3e). Moreover, replacing the pyridine
ring with a phenyl ring did not give any product 3f. Thus,
the optimized reaction conditions with a pyridine ring as

Yao et al.
3
(HRMS) were obtained on a Thermo Fisher LC-LTQ-
Orbitrap XL spectrometer. For more information about
chemical spectra, please see the supplemental material.
General procedure for the synthesis of imides 5. To a
mixture of amide 4 (0.2mmol) and DIPEA (0.3mmol) in
CH2Cl2 (2mL) was added acyl chloride 2 (0.26mmol) drop-
wise at 0°C. The reaction mixture was stirred at room tem-
perature for 3h. After completion of the reaction, the mixture
was poured into water (20mL) and extracted with CH2Cl2
(3×20mL). The combined organic layers were dried with
anhydrous Na2SO4. After removal of the solvents in vacuo,
the obtained crude product was further purified by column
chromatography on silica gel, eluting with a mixture of petro-
leum and ethyl acetate (5:1) to give the desired products.
N-Acetyl-N-(pyridin-2-ylmethyl)benzamide (3a): color-
less oil; yield: 47.8mg, (94%). 1H NMR (400MHz, CDCl3):
δ 8.51 (d, J=4.7Hz, 1H), 7.70 (d, J=8.1Hz, 2H), 7.62 (t,
J=7.1Hz, 1H), 7.52 (t, J=7.4Hz, 1H), 7.42 (t, J=7.6Hz,
2H), 7.22 (d, J=7.8Hz, 1H), 7.17–7.11 (m, 1H), 5.09 (s,
2H), 2.26 (s, 3H); 13C NMR (100MHz, CDCl3): δ 174.3,
173.5, 156.5, 149.2, 136.6, 135.7, 132.2, 128.6, 128.5,
122.1, 121.4, 50.8, 26.2; HRMS (ESI+): m/z [M+Na]+
calcd for C15H14N2O2Na: 277.0947; found: 277.0944.
O
R2
R1
O
H
N
DIPEA (1.5 equiv)
O
N
O
R2 Cl CH2Cl2, r.t.
N
+
N
R1
5
4
2
O
O
O
O
Ph
N
N
O
N
N
N
N
N
N
O
O
O
5c,
5d
90%
, 89%
5a 75%
5b 76%
,
,
O
O
O
R
N
O
5ea, R = H, 88%
5eb, R = 4-CH3, 90% 5eg, R = 4-CF3, 82%
5ec, R = 4-tBu, 85% 5eh, R = 4-CN, 78%
5ef, R = 4-Br, 91%
N
O
N
N
N
O
Br
Ph
N
5ed, R = 4-OCH3, 80% 5ei, R = 4-SO2CH3, 80%
5ee, R = 4-Cl, 90%
5ej, R = 4-NO2, 91%
5f
80%
,
81%
5g,
O
O
O
O
N
O
N
O
N
O
N
S
N
N
N
N
O
Br
OCH3
5k
, 89%
5h
,
90%
5j
5i,
79%
,
85%
CF3
O
O
O
O
O
O
N
N
N
N
N
N
N
N
O
O
O
O
, 82%
5n
5o
86%
,
5m
, 90%
5l
87%
,
O
O
O
O
O
O
O
O
O
N
O
N
O
N
N
N
N
N
N
O
5p
, 82%
5r
5q
, 93%
5s
98%
90%
,
,
O
O
O
N
Cl
N
O
N
O
N-Acetyl-N-(thiophen-2-ylmethyl)benzamide
(3b):
N
O
N
N
H
N
1
O
colorless oil; yield: 33.7mg, (65%). H NMR (400MHz,
CDCl3): δ 7.60–7.53 (m, 3H), 7.45 (t, J=7.6Hz, 2H), 7.21
(dd, J=5.0, 1.4Hz, 1H), 6.93–6.87 (m, 2H), 5.15 (s, 2H),
2.10 (s, 3H); 13C NMR (100MHz, CDCl3): δ 173.9, 173.0,
139.3, 135.7, 132.6, 128.9, 128.5, 127.3, 126.5, 125.8,
44.0, 26.5; HRMS (ESI+): m/z [M+Na]+ calcd for
C14H13NO2SNa: 282.0559; found: 282.0569.
O
5t, 85%
5u, 96%
5v, 96%
Scheme 3. Substrate scope of the amides and acyl chlorides.
Reaction conditions: 4 (0.2mmol), 2 (0.26mmol), DIPEA
(0.3mmol), CH2Cl2 (2.0mL), room temperature, 3h. Isolated
yields are given.
N-Acetyl-N-(furan-2-ylmethyl)benzamide (3c): colorless
1
oil; yield: 33.5mg, (69%). H NMR (400MHz, CDCl3): δ
Conclusion
7.59 (d, J=8.0Hz, 2H), 7.54 (t, J=7.4Hz, 1H), 7.44 (t,
J=7.6Hz, 2H), 7.29 (s, 1H), 6.27 (s, 1H), 6.20 (d, J=3.1Hz,
1H), 4.96 (s, 2H), 2.17 (s, 3H); 13C NMR (100MHz, CDCl3):
δ 174.0, 172.8, 150.4, 142.1, 135.5, 132.5, 128.8, 128.4,
110.4, 108.4, 42.3, 26.1; HRMS (ESI+): m/z [M+Na]+
calcd for C14H13NO3Na: 266.0788; found: 266.0782.
In conclusion, we have developed a mild and robust
N-acylation tactic for the preparation of imides from simple
amides with acyl chlorides via internal nucleophilic cataly-
sis. The method employs a mild readily available DIPEA as
the base and thus provides an inexpensive, environmentally
friendly, and easy to operate route toward diverse imide
derivatives with good substrate scope. Regarding the wide-
spread distribution of imide fragments, the utility of this
method in synthetic chemistry is being explored in our
laboratory.
N-Acetyl-N-(2-(pyridin-2-yl)ethyl)benzamide
(3d):
1
colorless oil; yield: 36.5mg, (68%). H NMR (400MHz,
CDCl3): δ 8.43 (d, J=4.2Hz, 1H), 7.57 (td, J=7.65,1.32Hz,
1H), 7.51–7.47 (m, 3H), 7.40 (t, J=7.6Hz, 2H), 7.15–7.07
(m, 2H), 4.19 (t, J=6.9Hz, 2H), 3.11 (t, J=6.9Hz, 2H),
2.15 (s, 3H); 13C NMR (100MHz, CDCl3): δ 174.4, 173.3,
158.5, 149.1, 136.6, 135.4, 132.3, 128.7, 128.5, 123.8,
121.6, 46.3, 37.1, 25.9; HRMS (ESI+): m/z [M+Na]+
calcd for C16H16N2O2Na: 291.1104; found: 291.1121.
Experimental analysis
Reagents and solvents were purchased from commercial
suppliers unless otherwise specified. All reactions were car-
ried out under an air atmosphere. Anhydrous solvents were
purified and dried following standard procedures.
Purification was generally done by flash column chroma-
tography on brand silica gel (200–300 mesh size). Thin-
layer chromatography (TLC) analysis was performed on
brand precoated, glass-backed silica gel plates. Nuclear
magnetic resonance (NMR) spectra were recorded on a 400-
MHz Bruker spectrometer (400MHz for 1H NMR, 100MHz
for 13C NMR). Chemical shifts (1H and 13C) are given in
ppm relative to the residual solvent peak (CDCl3, 7.26ppm,
77.0ppm, respectively). High-resolution mass spectra
N-Pivaloyl-N-(pyridin-2-ylmethyl)benzamide
(5a):
1
colorless oil; yield: 44.4mg, (75%). H NMR (400MHz,
CDCl3): δ 8.54 (d, J=4.7Hz, 1H), 7.80 (d, J=7.1Hz, 2H),
7.62 (t, J=6.9Hz, 1H), 7.51 (t, J=6.7Hz, 1H), 7.41 (t,
J=7.4Hz, 2H), 7.22–7.12 (m, 2H), 4.92 (s, 2H), 1.31 (s,
9H); 13C NMR (100MHz, CDCl3): δ 187.4, 174.8, 156.5,
149.2, 136.6, 134.6, 132.3, 129.0, 128.6, 122.2, 121.6,
52.6, 43.4, 28.5; HRMS (ESI+): m/z [M+Na]+ calcd for
C18H20N2O2Na: 319.1417; found: 319.1424.
N-(Cyclopropanecarbonyl)-N-(pyridin-2-ylmethyl)ben-
zamide (5b): colorless oil; yield: 42.6mg, (76%). 1H NMR
(400MHz, CDCl3): δ 8.53 (d, J=4.4Hz, 1H), 7.80–7.75

4
Journal of Chemical Research 00(0)
(m, 2H), 7.64 (td, J=7.7, 1.7Hz, 1H), 7.52 (t, J=7.4Hz,
N-Benzoyl-4-methoxy-N-(pyridin-2-ylmethyl)benza-
1
1H), 7.43 (t, J=7.5Hz, 2H), 7.28 (d, J=7.85, 1H), 7.15 (dd, mide (5ed): colorless oil; yield: 55.4mg, (80%). H NMR
J=7.2, 5.2Hz, 1H), 5.21 (s, 2H), 1.59 (ddd, J=12.4, 7.8, (400MHz, CDCl3): δ 8.59 (d, J=4.9Hz, 1H), 7.72 (t,
4.6Hz, 1H), 1.07–1.00 (m, 2H), 0.65 (m, 2H); 13C NMR J=7.6Hz, 1H), 7.63 (dd, J=8.4, 2.5Hz, 4H), 7.46 (d,
(100MHz, CDCl3): δ 177.9, 173.9, 156.9, 149.3, 136.6, J=7.8Hz, 1H), 7.33 (t, J=7.2Hz, 1H), 7.23 (q, J=7.7Hz,
136.2, 132.2, 129.0, 128.5, 122.1, 121.4, 50.7, 18.3, 11.7; 3H), 6.73 (d, J=8.6Hz, 2H), 5.40 (s, 2H), 3.79 (s, 3H); 13
C
HRMS (ESI+): m/z [M+Na]+ calcd for C17H16N2O2Na: NMR (100MHz, CDCl3): δ 174.1, 173.7, 162.4, 156.7,
303.1104; found: 303.1115.
149.3, 136.5, 131.5, 131.4, 128.9, 128.6, 128.1, 122.1,
N-Acryloyl-N-(pyridin-2-ylmethyl)benzamide
colorless oil; yield: 47.9mg, (90%). H NMR (400MHz, calcd for C21H18N2O3Na: 369.1210; found: 369.1218.
(5c): 121.7, 113.4, 55.3, 51.6; HRMS (ESI+): m/z [M+Na]+
1
CDCl3): δ 8.52 (d, J=4.7Hz, 1H), 7.72 (d, J=8.2Hz, 2H),
N-Benzoyl-4-chloro-N-(pyridin-2-ylmethyl)benzamide
7.64 (t, J=7.7Hz, 1H), 7.53 (t, J=7.5Hz, 1H), 7.41 (t, (5ee): colorless oil; yield: 63.0mg, (90%). 1H NMR
J=7.6Hz, 2H), 7.29 (d, J=7.8Hz, 1H), 7.18–7.12 (m, 1H), (400MHz, CDCl3): δ 8.51 (d, J=4.9Hz, 1H), 7.67 (t,
6.31–6.17 (m, 2H), 5.51 (dd, J=9.1, 2.7Hz, 1H), 5.21 (s, J=7.7Hz, 1H), 7.56 (d, J=7.6Hz, 2H), 7.52 (d, J=8.3Hz,
2H); 13C NMR (100MHz, CDCl3): δ 173.7, 169.2, 156.4, 2H), 7.37 (d, J=7.9Hz, 1H), 7.30 (t, J=7.4Hz, 1H), 7.22–
149.3, 136.6, 135.8, 132.5, 130.8, 129.1, 128.8, 128.6, 7.11 (m, 5H), 5.33 (s, 2H); 13C NMR (100MHz, CDCl3): δ
122.2, 121.5, 50.6; HRMS (ESI+): m/z [M+Na]+ calcd for 174.0, 173.3, 156.3, 149.4, 137.8, 136.6, 136.3, 135.0,
C16H14N2O2Na: 289.0947; found: 289.0951.
132.0, 130.4, 129.1, 128.4, 128.3, 122.3, 121.8, 51.4;
N-(3-Phenylpropioloyl)-N-(pyridin-2-ylmethyl)benza- HRMS (ESI+): m/z [M+Na]+ calcd for C20H15ClN2O2Na:
1
mide (5d): colorless oil; yield: 60.5mg, (89%). H NMR 373.0714; found: 373.0712.
(400MHz, CDCl3): δ 8.55 (d, J=4.9Hz, 1H), 7.88 (d,
N-Benzoyl-4-bromo-N-(pyridin-2-ylmethyl)benzamide
J=7.5Hz, 2H), 7.67 (t, J=7.7Hz, 1H), 7.53 (t, J=7.4Hz, (5ef): colorless oil; yield: 71.7mg, (91%). 1H NMR (400MHz,
1H), 7.45 (t, J=7.5Hz, 2H), 7.35 (t, J=7.8Hz, 2H), 7.24 CDCl3): δ 8.51 (d, J=4.4Hz, 1H), 7.67 (td, J=7.7, 1.8Hz,
(m, 2H), 7.21–7.13 (m, 1H), 7.09 (d, J=7.7Hz, 2H), 5.34 1H), 7.58–7.53(m, 2H), 7.47–7.42(m, 2H), 7.37(d, J=7.8Hz,
(s, 2H); 13C NMR (100MHz, CDCl3): δ 173.4, 156.1, 1H), 7.30 (m, 3H), 7.23–7.14 (m, 3H), 5.33 (s, 2H); 13C NMR
155.0, 149.5, 136.6, 136.0, 132.7, 132.6, 130.6, 129.7, (100MHz, CDCl3): δ 174.0, 173.4, 156.2, 149.4, 136.5,
128.5, 128.3, 122.3, 121.5, 119.5, 95.9, 82.7, 49.9; HRMS 136.2, 135.4, 132.0, 131.3, 130.5, 129.1, 128.3, 126.4, 122.3,
(ESI+): m/z [M+Na]+ calcd for C22H16N2O2Na: 363.1104; 121.7, 51.4; HRMS (ESI+): m/z [M+Na]+ calcd for
found: 363.1113.
C20H15BrN2O2Na: 417.0209; found: 417.0208.
N-Benzoyl-N-(pyridin-2-ylmethyl)benzamide
(5ea):
N-Benzoyl-N-(pyridin-2-ylmethyl)-4-(trifluoromethyl)
1
1
colorless oil; yield: 55.6mg, (88%). H NMR (400MHz, benzamide (5eg): colorless oil; yield: 63.0mg, (82%). H
CDCl3): δ 8.52 (d, J=4.7Hz, 1H), 7.66 (td, J=7.7, 1.4Hz, NMR (400MHz, CDCl3): δ 8.52 (d, J=4.9Hz, 1H), 7.69
1H), 7.54 (d, J=7.3Hz, 4H), 7.39 (d, J=7.8Hz, 1H), 7.25 (d, J=7.8Hz, 3H), 7.56 (d, J=7.5Hz, 2H), 7.43 (d,
(t, J=7.20, 3H), 7.14 (t, J=7.5Hz, 5H), 5.34 (s, 2H); 13C J=7.7Hz, 2H), 7.38 (d, J=7.6Hz, 1H), 7.33–7.25 (m, 1H),
NMR (100MHz, CDCl3): δ 174.2, 156.6, 149.3, 136.6, 7.19 (t, J=6.9Hz, 3H), 5.35 (s, 2H); 13C NMR (100MHz,
136.5, 131.7, 129.1, 128.1, 122.3, 121.8, 51.4; HRMS CDCl3): δ 174.0, 173.0, 156.0, 149.4, 139.9, 136.6, 136.0,
(ESI+): m/z [M+Na]+ calcd for C20H16N2O2Na: 339.1104; 132.8 (q, J=32.0Hz), 132.09, 129.2, 129.1, 128.3, 125.3
found: 311.1111.
(q, J=4.0Hz), 123.4 (d, J=271.0Hz), 122.4, 121.8, 51.2;
N-Benzoyl-4-methyl-N-(pyridin-2-ylmethyl)benzamide HRMS (ESI+): m/z [M+Na]+ calcd for C21H15F3N2O2Na:
(5eb): colorless oil; yield: 59.3mg, (90%). 1H NMR 407.0978; found: 407.0970.
(400MHz, CDCl3): δ 8.53 (d, J=4.9Hz, 1H), 7.67 (t,
N-Benzoyl-4-cyano-N-(pyridin-2-ylmethyl)benzamide
J=7.7Hz, 1H), 7.56 (d, J=7.4Hz, 2H), 7.47 (d, J=7.9Hz, (5eh): colorless oil; yield: 53.2mg, (78%). 1H NMR
2H), 7.40 (d, J=7.8Hz, 1H), 7.25 (d, J=7.0Hz, 1H), 7.17 (400MHz, CDCl3): δ 8.52 (d, J=4.7Hz, 1H), 7.72–7.65
(t, J=7.9Hz, 3H), 6.96 (d, J=7.9Hz, 2H), 5.34 (s, 2H), (m, 3H), 7.58–7.53 (m, 2H), 7.46 (d, J=8.3Hz, 2H), 7.37
2.23 (s, 3H); 13C NMR (100MHz, CDCl3): δ 174.3, 174.2, (d, J=7.8Hz, 1H), 7.32 (t, J=7.4Hz, 1H), 7.23–7.17 (m,
156.7, 149.3, 142.5, 136.6, 136.5, 133.6, 131.6, 129.3, 3H), 5.35 (s, 2H); 13C NMR (100MHz, CDCl3): δ 173.7,
129.0, 128.8, 128.0, 122.2, 121.8, 51.6, 21.4; HRMS 172.5, 155.7, 149.3, 140.6, 136.8, 135.8, 132.3, 131.8,
(ESI+): m/z [M+Na]+ calcd for C21H18N2O2Na: 353.1260; 129.3, 129.1, 128.5, 122.5, 121.8, 117.8, 114.6, 51.1;
found: 353.1262.
N-Benzoyl-4-(tert-butyl)-N-(pyridin-2-ylmethyl)benza- 364.1056; found: 364.1060.
HRMS (ESI+): m/z [M+Na]+ calcd for C21H15N3O2Na:
1
mide (5ec): colorless oil; yield: 63.3mg, (85%). H NMR
N-Benzoyl-4-(methylsulfonyl)-N-(pyridin-2-ylmethyl)ben-
1
(400MHz, CDCl3): δ 8.54 (d, J=4.4Hz, 1H), 7.67 (t, zamide (5ei): colorless oil; yield: 63.1mg, (80%). H NMR
J=7.7Hz, 1H), 7.53 (d, J=7.5Hz, 2H), 7.49 (d, J=8.2Hz, (400MHz, CDCl3): δ 8.53 (d, J=4.7Hz, 1H), 7.79–7.67 (m,
2H), 7.40 (d, J=7.8Hz, 1H), 7.22 (t, J=7.2Hz, 1H), 7.17– 5H), 7.57 (d, J=7.3Hz, 2H), 7.38 (d, J=7.8Hz, 1H), 7.31 (t,
7.12 (m, 5H), 5.35 (s, 2H), 1.19 (s, 9H); 13C NMR (100MHz, J=7.4Hz, 1H), 7.20 (t, J=7.8Hz, 3H), 5.36 (s, 2H), 2.93 (s,
CDCl3): δ 174.4, 174.2, 156.7, 155.3, 149.4, 136.6, 133.5, 3H); 13C NMR (100MHz, CDCl3): δ 173.8, 172.5, 155.7,
131.4, 129.1, 129.0, 128.0, 125.0, 122.2, 121.8, 51.4, 34.9, 149.3, 142.4, 141.5, 136.8, 135.9, 132.3, 129.7, 129.2, 128.4,
30.9; HRMS (ESI+): m/z [M+Na]+ calcd for 127.2, 122.5, 121.8, 51.1, 44.2; HRMS (ESI+): m/z[M+Na]+
C24H24N2O2Na: 395.1730; found: 395.1725.
calcd for C21H18N2O4SNa: 417.0879; found: 417.0881.

Yao et al.
5
N-Benzoyl-4-nitro-N-(pyridin-2-ylmethyl)benzamide 134.3, 132.0, 131.9, 129.6, 129.0, 128.3, 127.5, 122.3,
(5ej): colorless oil; yield: 65.7mg, (91%). 1H NMR 122.1, 121.7, 51.3; HRMS (ESI+): m/z [M+Na]+ calcd for
(400MHz, CDCl3): δ 8.52 (d, J=4.5Hz, 1H), 8.02 (d, C20H15BrN2O2 417.0209; found: 417.0214.
J=8.6Hz, 2H), 7.74 (d, J=8.6Hz, 2H), 7.69 (t, J=7.7Hz,
1H), 7.58 (d, J=7.8Hz, 2H), 7.37 (d, J=7.8Hz, 1H), 7.31 mide (5k): colorless oil; yield: 57.3mg, (89%). H NMR
(t, J=7.4Hz, 1H), 7.20 (t, J=7.7Hz, 3H), 5.36 (s, 2H); 13
(400MHz, CDCl3): δ 8.52 (d, J=4.7Hz, 1H), 7.71–7.61 (m,
N-Benzoyl-N-(pyridin-2-ylmethyl)thiophene-2-carboxa-
1
C
NMR (100MHz, CDCl3): δ 173.7, 172.3, 155.7, 149.4, 3H), 7.44–7.36 (m, 3H), 7.32 (t, J=7.3Hz, 1H), 7.24 (t,
148.9, 142.3, 136.7, 135.8, 132.4, 129.8, 129.2, 128.5, J=7.32, 2H), 7.20–7.14 (m, 1H), 6.81 (t, J=4.4Hz, 1H),
123.2, 122.5, 121.8, 51.2; HRMS (ESI+): m/z [M+Na]+ 5.35(s, 2H), 13C NMR (100MHz, CDCl3): δ 173.5, 167.5,
calcd for C20H15N3O4Na: 384.0955; found: 384.0956.
156.5, 149.1, 139.5, 136.8, 136.2, 133.3, 133.0, 131.8,
N-Benzoyl-N-(pyridin-2-ylmethyl)-[1,1′-biphenyl]-2- 129.0, 128.3, 127.2, 122.3, 121.8, 51.8; HRMS (ESI+): m/z
carboxamide (5f): colorless oil; yield: 40.5mg, (80%). H [M+Na]+ calcd for C18H14N2O2SNa: 345.0668; found:
NMR (400MHz, CDCl3): δ 8.47 (d, J=4.5Hz, 1H), 7.56 345.0678.
1
(td, J=7.7, 1.7Hz, 1H), 7.43–7.40 (m, 3H), 7.39–7.33 (m,
N-Benzoyl-N-(pyridin-2-ylmethyl)furan-2-carboxamide
3H), 7.27–7.22 (m, 4H), 7.21 (d, J=11.7Hz, 1H), 7.18– (5l): colorless oil; yield: 53.3mg, (87%). 1H NMR
7.16 (m, 1H), 7.15–7.12 (m, 1H), 7.12–7.07 (m, 3H), 4.87 (400MHz, CDCl3): δ 8.51 (d, J=4.7Hz, 1H), 7.66 (dd,
(s, 2H); 13C NMR (100MHz, CDCl3): δ 174.4, 172.9, J=15.9, 7.7Hz, 3H), 7.40 (d, J=7.7Hz, 1H), 7.33 (t,
156.4, 149.3, 139.7, 139.4, 136.6, 136.0, 135.8, 131.6, J=6.1Hz, 1H), 7.29–7.19 (m, 3H), 7.17–7.11 (m, 1H), 6.95
130.3, 129.8, 129.8, 128.7, 128.6, 128.5, 127.9, 127.2, (s, 1H), 6.22 (s, 1H), 5.32 (s, 2H); 13C NMR (100MHz,
122.2, 121.7, 51.0; HRMS (ESI+): m/z [M+Na]+ calcd for CDCl3): δ 173.3, 162.9, 156.6, 149.4, 147.9, 145.3, 136.6,
C26H20N2O2Na: 415.1417; found: 415.1429.
136.0, 131.8, 128.7, 128.1, 122.2, 121.4, 118.8, 112.3, 51.3;
N-Benzoyl-2-bromo-N-(pyridin-2-ylmethyl)benzamide HRMS (ESI+): m/z [M+Na]+ calcd for C18H14N2O3Na:
(5g): colorless oil; yield: 63.9mg, (81%). 1H NMR 329.0897; found: 329.0902.
(400MHz, CDCl3): δ 8.55 (d, J=4.8Hz, 1H), 7.67 (t,
N-Acetyl-N-(pyridin-2-ylmethyl)cinnamamide
(5m):
1
J=7.8Hz, 1H), 7.57 (d, J=7.6Hz, 2H), 7.46 (d, J=7.6Hz, colorless oil; yield: 50.4mg, (90%). H NMR (400MHz,
1H), 7.39 (d, J=7.9Hz, 1H), 7.28 (t, J=8.45, 2H), 7.23– CDCl3): δ 8.56 (d, J=4.9Hz, 1H), 7.76 (d, J=15.5Hz, 1H),
7.16 (m, 3H), 7.10 (t, J=7.5Hz, 1H), 7.01 (t, J=7.8Hz, 7.67 (d, J=6.36Hz, 1H), 7.52 (s, 2H), 7.37 (s, 3H), 7.28 (d,
1H), 5.35 (s, 2H); 13C NMR (100MHz, CDCl3): δ 174.0, J=13.6Hz, 2H), 7.20 (s, 1H), 5.14 (s, 2H), 2.53 (s, 3H); 13C
171.1, 156.2, 149.4, 137.8, 136.5, 136.4, 133.3, 131.6, NMR (100MHz, CDCl3): δ 173.8, 169.4, 156.7, 149.4,
131.3, 130.3, 128.6, 128.1, 126.8, 122.3, 121.9, 120.8, 145.2, 136.9, 134.7, 130.4, 128.8, 128.3, 122.5, 121.7,
50.5; HRMS (ESI+): m/z [M+Na]+ calcd for 120.5, 49.5, 26.3; HRMS (ESI+): m/z [M+Na]+ calcd for
C20H15BrN2O2Na: 417.0209; found: 417.0205.
C17H16N2O2Na: 303.1104; found: 303.1115.
N-Benzoyl-3-methyl-N-(pyridin-2-ylmethyl)benzamide
N-(2-Methoxyacetyl)-N-(pyridin-2-ylmethyl)cinnama-
1
(5h): colorless oil; yield: 59.4mg, (90%). 1H NMR mide (5n): colorless oil; yield: 50.9mg, (82%). H NMR
(400MHz, CDCl3): δ 8.53 (d, J=4.7Hz, 1H), 7.67 (t, (400MHz, CDCl3): δ 8.57 (d, J=4.7Hz, 1H), 7.76 (d,
J=7.6Hz, 1H), 7.54 (d, J=7.7Hz, 2H), 7.40 (d, J=7.8Hz, J=15.5Hz, 1H), 7.67 (td, J=1.9, 7.6Hz, 1H), 7.51 (dd,
1H), 7.35 (d, J=4.5Hz, 1H), 7.33 (s, 1H), 7.24 (d, J=7.3Hz, J=6.6, 2.9Hz, 2H), 7.37 (dd, J=5.1, 1.8Hz, 3H), 7.32 (d,
1H), 7.16 (t, J=7.6Hz, 3H), 7.04 (d, J=4.9Hz, 2H), 5.35 J=7.9Hz, 1H), 7.26 (d, J=15.5Hz, 2H), 7.21 (dd, J=7.1,
(s, 2H), 2.21 (s, 3H); 13C NMR (100MHz, CDCl3): δ 174.4, 5.3Hz, 1H), 5.18 (s, 2H), 4.66 (s, 2H), 3.49 (s, 3H); 13C
174.3, 156.7, 149.4, 137.9, 136.6, 136.6, 136.3, 132.4, NMR (100MHz, CDCl3): δ 174.0, 169.1, 156.3, 149.4,
131.6, 129.7, 129.0, 128.1, 128.0, 126.3, 122.3, 121.8, 146.3, 137.0, 134.4, 130.6, 128.9, 128.4, 122.7, 122.2,
51.5, 21.1; HRMS (ESI+): m/z [M+Na]+ calcd for 119.3, 74.6, 59.3, 48.8; HRMS (ESI+): m/z [M+Na]+
C21H18N2O2Na: 353.1260; found: 353.1257.
calcd for C18H18N2O3Na: 333.1210; found: 333.1214.
N-Benzoyl-3-methoxy-N-(pyridin-2-ylmethyl)benzamide
N-(Pyridin-2-ylmethyl)-N-(3,3,3-trifluoropropanoyl)
1
(5i): colorless oil; yield: 54.7mg, (79%). 1H NMR (400MHz, benzamide (5o): colorless oil; yield: 55.4mg, (86%). H
CDCl3): δ 8.54 (d, J=4.6Hz, 1H), 7.67 (t, J=7.6Hz, 1H), NMR (400MHz, CDCl3): δ 8.52 (d, J=4.6Hz, 1H), 7.71–
7.56 (d, J=7.7Hz, 2H), 7.40 (d, J=7.9Hz, 1H), 7.30–7.24 7.67 (m, 2H), 7.64 (td, J=7.7, 1.6Hz, 1H), 7.54 (t,
(m, 1H), 7.21–7.13 (m, 4H), 7.07 (dd, J=14.7, 6.7Hz, 2H), J=7.5Hz, 1H), 7.43 (t, J=7.6Hz, 2H), 7.18 (t, J=6.4Hz,
6.79 (d, J=8.1Hz, 1H), 5.35 (s, 2H), 3.70 (s, 3H); 13C NMR 2H), 5.05 (s, 2H), 3.74 (q, J=9.9Hz, 2H); 13C NMR
(100MHz, CDCl3): δ 174.2, 174.1, 159.2, 156.6, 149.3, (100MHz, CDCl3): δ 174.1, 166.9 (t, J=3.0Hz), 155.3,
137.7, 136.7, 136.5, 131.7, 129.2, 129.1, 128.1, 122.3, 121.8, 149.2, 136.8, 134.4, 132.5, 128.8, 128.4, 123.7 (d,
121.6, 118.4, 113.7, 55.4, 51.4; HRMS (ESI+): m/z[M+Na]+ J=276.0Hz), 122.5, 121.6, 51.3, 41.9 (q, J=30.0Hz);
calcd for C21H18N2O3Na: 369.1210; found: 269.1214.
N-Benzoyl-3-bromo-N-(pyridin-2-ylmethyl)benzamide 345.0821; found: 345.0825.
(5j): colorless oil; yield: 67.0mg, (85%). 1H NMR
Propyl Benzoyl(pyridin-2-ylmethyl)carbamate (5p):
(400MHz, CDCl3): δ 8.53 (d, J=4.5Hz, 1H), 7.69 (m, 2H), colorless oil; yield: 48.8mg, (82%). H NMR (400MHz,
7.55 (d, J=7.5Hz, 2H), 7.49 (d, J=7.4Hz, 1H), 7.36 (t, CDCl3): δ 8.56 (d, J=4.2Hz, 1H), 7.70–7.62 (m, 3H), 7.48
J=8.3Hz, 2H), 7.29 (t, J=7.29, 1H), 7.23–7.15 (m, 3H), (t, J=7.3Hz, 1H), 7.41 (t, J=7.5Hz, 2H), 7.30 (d, J=7.8Hz,
7.02 (t, J=7.8Hz, 1H), 5.34 (s, 2H); 13C NMR (100MHz, 1H), 7.20–7.13 (m, 1H), 5.18 (s, 2H), 3.92 (t, J=6.6Hz,
CDCl3): δ 174.0, 172.7, 156.2, 149.4, 138.4, 136.6, 136.3, 2H), 1.27 (h, J=7.1Hz, 2H), 0.58 (t, J=7.4Hz, 3H); 13C
HRMS (ESI+): m/z [M+Na]+ calcd for C16H13F3N2O2Na:
1

6
Journal of Chemical Research 00(0)
NMR (100MHz, CDCl3): δ 173.0, 156.9, 155.1, 149.4, 133.2, 131.5, 128.5, 128.4, 128.2, 128.2, 127.7, 126.0, 122.1,
136.9, 136.6, 131.3, 128.1, 127.8, 122.2, 121.0, 68.7, 50.4, 121.6, 69.2, 49.8, 19.0; HRMS (ESI+): m/z [M+Na]+ calcd
21.5, 10.0; HRMS (ESI+): m/z [M+Na]+ calcd for for C29H25N3O4Na: 502.1737; found: 502.1746.
C17H18N2O3Na: 321.1210; found: 321.1225.
(E)-N-Isobutyryl-N-(pyridin-2-ylmethyl)but-2-enamide Declaration of conflicting interests
(5q): colorless oil; yield: 48.3mg, (98%). 1H NMR
The author(s) declared no potential conflicts of interest with respect
(400MHz, CDCl3): δ 8.52(d, J=4.8Hz, 1H), 7.63 (t,
J=7.6Hz, 1H), 7.17 (d, J=7.3Hz, 2H), 7.07–6.98 (m, 1H),
6.48 (d, J=14.9, 1H), 5.04 (s, 2H), 3.32 (p, J=6.1, 5.6Hz,
1H), 1.89 (d, J=6.9Hz, 3H), 1.15 (d, J=6.6Hz, 6H); 13C
NMR (100MHz, CDCl3): δ 181.5, 169.5, 156.9, 149.3,
144.9, 136.8, 125.2, 122.3, 121.2, 49.2, 34.8, 19.5, 18.3;
HRMS (ESI+): m/z [M+Na]+ calcd for C14H18N2O2Na:
269.1260; found: 269.1256.
to the research, authorship, and/or publication of this paper.
Funding
The author(s) disclosed receipt of the following financial support for
the research, authorship, and/or publication of this paper: This work
was financially supported by the National Natural Science Foundation
of China (No. 81102334, 31370372, 31170323), the Program for
New Century Excellent Talents in University, State Education
Methyl 3-Oxo-3-(N-(pyridin-2-ylmethyl)isobutyramido) Ministry of China (NCET-2008-0224), and the Fundamental
1
Research Funds for the Central Universities (2017KFYXJJ152).
propanoate (5r): colorless oil; yield: 51.7mg, (93%). H
NMR (400MHz, CDCl3): δ 8.52 (d, J=4.8Hz, 1H), 7.67 (t,
J=7.6Hz, 1H), 7.29 (d, J=7.8Hz, 1H), 7.19 (t, J=5.0Hz,
1H), 5.12 (s, 2H), 3.93 (s, 2H), 3.73 (s, 3H), 3.05 (p, J=6.6Hz,
1H), 1.10 (d, J=6.6Hz, 6H); 13C NMR (100MHz, CDCl3): δ
181.1, 169.2, 168.0, 156.3, 149.3, 137.1, 122.5, 121.2, 52.3,
48.7, 46.0, 34.2, 19.2; HRMS (ESI+): m/z [M+Na]+ calcd
for C14H18N2O4Na: 301.1159; found: 301.1158.
Supplemental material
Supplemental material for this paper is available online.
References
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N-(2-Methoxyacetyl)-N-(pyridin-2-ylmethyl)isobutyra-
1
mide (5s): colorless oil; yield: 45.0mg, (90%). H NMR
(400MHz, CDCl3): δ 8.50 (d, J=4.7Hz, 1H), 7.64 (td,
J=7.7, 1.7Hz, 1H), 7.23–7.15 (m, 2H), 5.08 (s, 2H), 4.56
(s, 2H), 3.45 (s, 3H), 3.13 (hept, J=6.7Hz, 1H), 1.12 (d,
J=6.7Hz, 6H); 13C NMR (100MHz, CDCl3): δ 181.0,
174.1, 156.2, 149.3, 136.9, 122.5, 121.5, 74.7, 59.2, 48.2,
34.2, 19.3; HRMS (ESI+): m/z [M+Na]+ calcd for
C13H18N2O3Na: 273.1210; found: 273.1218.
N-Isobutyryl-N-(pyridin-2-ylmethyl)cyclopropanecar-
1
boxamide (5t): colorless oil; yield: 41.8mg, (85%). H
NMR (400MHz, CDCl3): δ 8.53 (d, J=3.8Hz, 1H), 7.66
(td, J=7.7, 1.7Hz, 1H), 7.18 (dd, J=7.6, 4.0Hz, 2H), 5.16
(s, 2H), 3.41 (p, J=6.7Hz, 1H), 2.21–2.15 (m, 1H), 1.17 (d,
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J=6.7Hz, 6H), 1.10–1.06 (m, 2H), 0.92–0.87 (m, 2H); 13
C
NMR (100MHz, CDCl3): δ 181.5, 177.8, 157.1, 149.2,
137.0, 122.4, 121.1, 49.2, 35.1, 19.6, 15.8, 10.5; HRMS
(ESI+): m/z [M+Na]+ calcd for C14H18N2O2Na: 269.1260;
found: 269.1259.
4-Chloro-N-isobutyryl-N-(pyridin-2-ylmethyl)butana-
1
mide (5u): colorless oil; yield: 54.2mg, (96%). H NMR
(400MHz, CDCl3): δ 8.52 (d, J=33.8Hz, 1H), 7.65 (t,
J=7.6Hz, 1H), 7.17 (d, J=7.3Hz, 2H), 5.06 (s, 2H), 3.60
(t, J=6.2Hz, 2H), 3.27 (p, J=6.6Hz, 1H), 2.98 (t, J=6.8Hz,
2H), 2.13 (p, J=6.56Hz, 2H), 1.15 (d, J=6.6Hz, 6H); 13
C
NMR (100MHz, CDCl3): δ 181.3, 175.7, 156.6, 149.3,
136.9, 122.5, 121.2, 48.8, 44.2, 35.1, 34.9, 27.7, 19.4;
HRMS (ESI+): m/z [M+Na]+ calcd for C14H19ClN2O2Na:
307.0998; found: 307.0997.
Benzyl(2-(Benzoyl(pyridin-2-ylmethyl)carbamoyl)-6-methyl-
phenyl)carbamate (5v): colorless oil; yield: 92.0mg (96%).
1H NMR (400MHz, CDCl3): δ 8.28 (d, J=4.9Hz, 1H), 7.72
(dd, J=8.2, 1.3Hz, 2H), 7.43 (td, J=7.7, 1.6Hz, 1H), 7.34
(d, J=7.4Hz, 1H), 7.29–7.21 (m, 5H), 7.16–7.07 (m, 4H),
7.04–6.96 (m, 2H), 6.86 (d, J=6.6Hz, 2H), 5.06 (s, 2H), 4.91
(s, 2H), 2.24 (s, 3H); 13C NMR (100MHz, CDCl3): δ 171.2,
166.2, 155.8, 154.2, 148.7, 137.0, 135.7, 134.8, 134.5, 133.3,
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