Room temperature clickable coupling electron deficient amines with sterically hindered carboxylic acids for the construction of amides

Article abstract of DOI:10.1016/j.tet.2020.131724

A method for the synthesis of difficult-to-access amides was developed through the coupling of sterically hindered carboxylic acids and electron deficient amines via SO₂F₂-mediated dehydration. The method feathers with broad substrate scope, mild conditions, excellent functional group compatibility and high yields.

Full text of DOI:10.1016/j.tet.2020.131724

Journal Pre-proof
Room temperature clickable coupling electron deficient amines with sterically
hindered carboxylic acids for the construction of amides
Jing Liu, Shi-Meng Wang, Hua-Li Qin
PII:
S0040-4020(20)30944-3
https://doi.org/10.1016/j.tet.2020.131724
TET 131724
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 1 September 2020
Revised Date: 12 October 2020
Accepted Date: 24 October 2020
Please cite this article as: Liu J, Wang S-M, Qin H-L, Room temperature clickable coupling electron
deficient amines with sterically hindered carboxylic acids for the construction of amides, Tetrahedron,
https://doi.org/10.1016/j.tet.2020.131724.
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Room temperature clickable coupling
electron deficient amines with sterically
hindered carboxylic acids for the
construction of amides
Leave this area blank for abstract info.
,
Jing Liua, Shi-Meng Wangb and Hua-Li Qina
a School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, 205 Luoshi Road, Wuhan 430070, P. R. China.
b School of Life Science, Wuchang University of Technology, Wuhan, 430223, P. R. China.

1
Tetrahedron
journal homepage: www.elsevier.com
Room temperature clickable coupling electron deficient amines with sterically
hindered carboxylic acids for the construction of amides
Jing Liua, Shi-Meng Wangb and Hua-Li Qina,
a School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, 205 Luoshi Road, Wuhan 430070, P. R. China.
b School of Life Science, Wuchang University of Technology, Wuhan, 430223, P. R. China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A method for the synthesis of difficult-to-access amides was developed through the coupling of
sterically hindered carboxylic acids and electron deficient amines via SO2F2-mediated
dehydration. The method feathers with broad substrate scope, mild conditions, excellent
functional group compatibility and high yields.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Amide synthesis
Electron deficient amines
Sterically hindered carboxylic acids
Room temperature clickable coupling
Sulfuryl fluoride
1. Introduction
chloride or acid anhydride species (Scheme 1, a); or through the
pre- or in situ carboxylic acid activation strategies using
stoichiometric “coupling” reagents, such as carbodiimides,
boronic acid derivatives, phosphonium salts, uronium (or
guanidinium) salts,11 have become the most prevailing processes
(Scheme 1, b). Nevertheless, because of the steric hindrance
effects of the carboxylic acid starting materials and poor
nucleophilicity of some electron-deficient amines, especially the
anilines, some simple amides may resist formation through
coupling of the corresponding acids with amines, for which,
scientists are required to use more toxic, expensive reagents to
As one of the most important functional groups in organic
molecules,1 amide bond is found in a large number of natural
products2 and it is also prevalent in almost a quarter of all
pharmaceuticals,3 for example (Figure 1), atorvastatin,4 nilotinib,5
valsartan,6 articaine,7 lidocaine,8 and acetaminophen.9 Direct
condensation of a carboxylic acid and an amine is the most
straightforward method for preparing amides. To avoid the harsh
thermal conditions (T > 180 °C)10 of direct condensation, the
activations of the carboxylic acids either through activated acid
N
COOH
OH
N
HN
OH
N
N
N
N
NH
N
F
O
O
N
N
NH
OH
NH
O
O
CF3
Nilotinib
(Tasigna@Novartis)
Atorvastatin
(Lipitor@Altamed Pharma)
Valsartan
(Act Valsartan@Actavis Pharma Company)
O
S
O
NH
NH
N
HO
NHCOCH3
O
O
NH
Articaine
Lidocaine
Acetaminophen
(Articadent@Dentsply Pharmaceutical) (Accucaine@Asclemed Usa, Inc.) (Ofirmev@Mallinckrodt Hospital Products
Inc.)
Scheme 1. Strategies for amide bond formation.
Figure 1. Representative drugs containing amide motifs.
———
Corresponding author. Tel.: +86 27 87749300; fax: +86 27 87749300; e-mail: qinhuali@whut.edu.cn

2
Tetrahedron
overcome the synthetic issues.12 Among these reported
Scheme 2. Substrate Scope for the Amide-Forming
methods, amide condensations of sterically hindered carboxylic
acids with electron-deficient amines have been rarely achieved.13
Therefore, considering atom-economical and cost-effective
principles, the development of new method for construction of
amides from the corresponding sterically hindered carboxylic
acids and electron deficient amines is highly desirable and of
great significance.
Reactiona,b
On the other hand, sulfuryl fluoride (SO2F2),14 as one of the
SuFEx click chemistry reagents,15 has been successfully applied
as an electrophile to react with the hydroxy groups of phenols (or
alcohols) to generate fluorosulfates,15a and participates in many
other transformations.16 Recently, we discovered the first SO2F2-
mediated amidation of carboxylic acids for the construction of
amides and peptide linkages (Scheme 1, c).17 Recently, Hein and
Sammis group studied the mechanism of this coupling reaction,18
revealed that SO2F2-mediated acid activation proceeds via the
anhydride, which was then converted to the corresponding acyl
fluoride. However, neither of these two papers studied whether
this method can be feasible for coupling of steric hindrance
carboxylic acids with electron-deficient amines to synthesize
those difficult-to access amides. Therefore, we intended to adopt
this simple, practical and efficient method for constructing more
rare amides with sterically hindered carboxylic acids and electron
deficient amines.19
a
Reaction conditions: A mixture of acid (1, 1.0 mmol), amine (2, 3.0 mmol)
and DIPEA (3.0 mmol, 3.0 equiv.) in MeCN (0.3 M) was stirred at room
temperature under a SO2F2 atmosphere (balloon) for 5 h. bIsolated yield.
2. Results and discussion
Initially, 2,6-dimethylbenzoic acid (1a) and 4-chloroaniline
(2a) were selected as model substrates to test the feasibility of
amidation in the presence of N,N-diisopropylethyl-amine
(DIPEA) in MeCN under a SO2F2 atmosphere (balloon) at room
temperature. The desired amidation product 3aa was obtained in
74% yield (Table 1, entry 1). Encouraged by this preliminary
result, we next tested other bases and solvents in order to achieve
better yields (Table 1, entries 1-4). Et3N did not give improved
yield, and DIPEA was found to promote the amidation the most
effectively. The investigation of solvent effect revealed that in
acetonitrile the clickable amidation performed the best. Because
the reactant equivalent also plays a critical role in organic
reactions, we next examined the influence of different reactant
equivalents. To our delight, when the reaction was conducted
with 3 equivalent of 4-chloroaniline, amide product 3aa was
obtained in 83% yield (Table 1, entry 5). Increasing the
temperature from 25 oC to 50 oC resulted in an obviously
decreased yield, which probably due to the side reactions caused
from aniline and SO2F2 at elevated temperature (Table 1, entry 6
vs entry 5). Our subsequent investigations focused on using two
kinds of temperature to maximize the formation of sulfonyl
fluoride intermediate, but no improved yields were obtained
(Table 1, entries 7-9).
Table 1. Screening the optimized reaction conditionsa
With optimized reaction conditions in hand, we moved on to
investigate the substrate scope of sterically hindered carboxylic
acids with different groups (1) in reactions to amines with
different electron withdrawing groups (2). As shown in Scheme
2, from the viewpoint of acids at first, a wide range of substituted
sterically hindered carboxylic acids 1 was smoothly transformed
into the corresponding amides in excellent yields. Aromatic
carboxylic acids with 2,6-electron-donating groups, such as Me
(1a), OMe (1b), or with 2,6-electron-withdrawing groups, such
as halogen atoms (1c-1d) were well tolerated. Those with phenyl
(1e) and p-methylphenyl groups (1f) can also undergo amidation
reactions. It is worth noting that the aliphatic carboxylic acid
pivalic acid (1g) afforded the desired amide products with similar
efficiency and great yields. In addition, sterically hindered
pyridine carboxylic acids were also smoothly transformed into
their corresponding amides in excellent yields (3hb-3jb). From
the point of view of the amines, whether they functionalized with
halogen group (2a-2b and 2e), or the cyano group (2c), the
amidations proceeded with good efficiency. Not surprisingly,
even 3,4-dichloroaniline (2d) also reacted smoothly with
sterically hindered carboxylic acid to afford the corresponding
amide products in moderate to high yields.
Entry
1
Base
DIPEA
Et3N
Aniline
2 eq.
2 eq.
2 eq.
2 eq.
3 eq.
3 eq.
3 eq.
3 eq.
3 eq.
Solvent
MeCN
MeCN
NMP
T1 (oC)
25
T2 (oC)
Yield (%)c
74
-
-
2
25
64
3
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
25
-
9
4
toluene
MeCN
MeCN
MeCN
MeCN
MeCN
25
-
48
5
25
-
83
6
50
-
63
7b
8b
9b
25
25
40
80
< 5%
< 1%
< 5%
25
25
a Reaction conditions: A mixture of 2,6-dimethylbenzoic acid (1a, 0.5 mmol),
4-chloroaniline (2a) and base (1.5 mmol, 3.0 equiv.) in solvent (0.3 M) was
b
stirred at T1 under a SO2F2 atmosphere (balloon) for 5 h.
Reaction
conditions: A mixture of 2,6-dimethylbenzoic acid (1a, 0.5 mmol) and
DIPEA (1.5 mmol, 3.0 equiv.) in MeCN (0.3 M) was stirred at T1 under a
SO2F2 atmosphere (balloon) for 2 h. Then SO2F2 gas was pumped out of the
system before the addition of 4-chloroaniline (2a, 1.0 mmol) and the resulting
mixture was further stirred at T2 for another 3 h. c The yield was determined
by HPLC using 3aa as the external standard (tR = 3.727 min, λmax = 251.2 nm,
water/methanol = 20 : 80 (v / v)).

3
3. Conclusions
4.2.2 N-(4-bromophenyl)-2,6-dimethylbenzamide (3ab).
In conclusion, we have developed a practical method for the
synthesis of a class of difficult-to-access amides through
coupling electron deficient amines and sterically hindered
carboxylic acids. This SO2F2-mediated, mild and robust method
feathers with a high efficiency, wide substrate scope, and
excellent functional group compatibility. Further application of
this method in chemical biology and drug discovery will be
explored.
White solid; yield: 237.75 mg (78%). 1H NMR (500 MHz,
DMSO-d6) δ 10.52 (s, 1H), 7.73-7.72 (m, 2H), 7.53-7.52 (m,
2H), 7.11 (d, J = 7.6 Hz, 2H), 7.08 (d, J = 7.7 Hz, 1H), 2.27 (s,
6H). 13C NMR (126 MHz, DMSO-d6) δ 168.1, 138.4, 138.2,
133.7, 131.6, 128.5, 127.3, 121.5, 115.2, 18.8. Mp 200-202 °C.
HRMS ESI (m/z): [M+H]+ calcd for C15H15BrNO: 304.0332,
found: 304.0335.
4.2.3 N-(4-cyanophenyl)-2,6-dimethylbenzamide (3ac).
White solid; yield: 133.56 mg (53%). 1H NMR (500 MHz,
DMSO-d6) δ 10.85 (s, 1H), 7.94-7.92 (m, 2H), 7.82-7.81 (m,
2H), 7.26 (t, J = 7.6 Hz, 1H), 7.13 (d, J = 7.7 Hz, 2H), 2.26 (s,
6H). 13C NMR (126 MHz, DMSO-d6) δ 168.7, 143.2, 137.8,
133.7, 133.3, 128.8, 127.4, 119.5, 119.0, 105.4, 18.8. Mp 202-
204 °C. HRMS ESI (m/z): [M+H]+ calcd for C16H15N2O:
333.9543, found: 333.9545.
4. Experimental
4.1 General information
All reactions were carried out under an air atmosphere.
Reagents used in the reactions were all purchased from
commercial sources and used without further purification. Unless
otherwise specified, NMR spectra were recorded in CDCl3 or
DMSO-d6 on a 500 MHz (for 1H), 126 MHz (for 13C)
spectrometer. All chemical shifts were reported in ppm relative to
TMS (1H NMR, 0 ppm) as internal standards. The HPLC
experiments were carried out on a Waters e2695 instrument
(column: J&K, RP-C18, 5 μm, 4.6 × 150 mm), and the yields of
the products were determined by using the corresponding pure
compounds as the external standards. Melting points of the
products were measured on a micro melting point apparatus
(SGW X-4) and uncorrected. HRMS experiments were
performed on a TOF-Q ESI or CI/EI instrument. The coupling
constants were reported in Hertz (Hz). The following
abbreviations were used to explain the multiplicities: s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet.
4.2.4 N-(3,4-dichlorophenyl)-2,6-dimethylbenzamide (3ad).
White solid; yield: 190.92 mg (65%). 1H NMR (500 MHz,
DMSO-d6) δ 10.71 (s, 1H), 8.15 (d, J = 2.3 Hz, 1H), 7.65 (dd, J =
8.8 Hz, J = 2.4 Hz, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.25 (t, J = 7.6
Hz, 1H), 7.12 (d, J = 7.8 Hz, 2H), 2.27 (s, 6H). 13C NMR (126
MHz, DMSO-d6) δ 168.3, 139.1, 137.8, 133.8, 131.1, 130.8,
128.7, 127.4, 125.1, 120.6, 119.5, 18.8. Mp 172-174 °C. HRMS
ESI (m/z): [M+H]+ calcd for C15H14Cl2NO: 294.0447, found:
294.0444.
4.2.5 N-(4-chlorophenyl)-2,6-dimethoxybenzamide (3ba).
White solid; yield: 212.38 mg (73%). 1H NMR (500 MHz,
DMSO-d6) δ 10.38 (s, 1H), 7.78 (d, J = 8.8 Hz, 2H), 7.38 (d, J =
8.7 Hz, 2H), 7.35 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 8.5 Hz, 2H),
3.76 (s, 6H). 13C NMR (126 MHz, DMSO-d6) δ 163.5, 156.7,
138.6, 130.5, 128.6, 126.6, 120.5, 116.6, 104.3, 55.8. Mp 203-
205 °C. HRMS ESI (m/z): [M+H]+ calcd for C15H15ClNO3:
292.0735, found: 292.0732.
4.2 Procedures
Carboxylic acid (1, 1.0 mmol, 1.0 equiv.), amine (2, 3.0
mmol, 3.0 equiv.), DIPEA (3.0 mmol, 3.0 equiv.) and MeCN
(reaction mixture was diluted to 0.3 M) were added to an oven-
dried 25 mL reaction flask equipped with a stirring bar and
covered with a rubber stopper. Sulfuryl fluoride gas was
introduced into the stirred reaction mixture by slowly bubbling
from a balloon. The reaction mixture was stirred at room
temperature for 5 h. After the reaction was complete, 1 M
aqueous HCl solution (20 mL) was added to remove the excess
amine and the reaction mixture was extracted with ethyl acetate
(3 × 20 mL). (For products 3hb, 3ib and 3jb, the reaction
mixture was directly concentrated under vacuum without
washing with aqueous HCl solution.) The extracts were dried
over anhydrous Na2SO4, and concentrated under reduced
pressure. The residue was purified by column chromatography on
silica gel using a mixture of petroleum ether and ethyl acetate as
eluents to give the desired product.
4.2.6 N-(4-bromophenyl)-2,6-dimethoxybenzamide (3bb).
White solid; yield: 232.72 mg (69%). 1H NMR (500 MHz,
DMSO-d6) δ 10.36 (s, 1H), 7.71 (d, J = 8.8 Hz, 2H), 7.50 (d, J =
8.8 Hz, 2H), 7.36 (t, J = 8.4 Hz, 1H), 6.73 (d, J = 8.4 Hz, 2H),
3.76 (s, 6H). 13C NMR (126 MHz, DMSO-d6) δ 163.5, 156.7,
139.0, 131.5, 130.5, 120.9, 116.6, 114.6, 104.3, 55.8. Mp 176-
178 °C. HRMS ESI (m/z): [M+H]+ calcd for C15H15BrNO3:
336.0230, found: 336.0233.
4.2.7 N-(4-fluorophenyl)-2,6-dimethoxybenzamide (3be).
4.2.1 N-(4-chlorophenyl)-2,6-dimethylbenzamide (3aa).
White solid; yield: 210.21 mg (76%). 1H NMR (500 MHz,
DMSO-d6) δ 10.27 (s, 1H), 7.75 (dd, J = 8.9, J = 5.2 Hz, 2H),
7.35 (t, J = 8.4 Hz, 1H), 7.15 (t, J = 8.7 Hz, 2H), 6.73 (d, J = 8.4
Hz, 2H), 3.76 (s, 6H). 13C NMR (126 MHz, DMSO-d6) δ 163.3,
157.9 (d, J = 239.8), 156.8, 136.2 (d, J = 2.7), 130.5, 120.6 (d, J
= 7.3), 116.8, 115.2 (d, J = 22.7), 104.3, 55.8. Mp 179-181 °C.
HRMS ESI (m/z): [M+H]+ calcd for C15H15FNO3: 276.1030,
found: 276.1035.
White solid; yield: 200.01 mg (77%). 1H NMR (500 MHz,
DMSO-d6) δ 10.54 (s, 1H), 7.82-7.79 (m, 2H), 7.42-7.39 (m,
2H), 7.23 (t, J = 7.5 Hz, 1H), 7.11 (d, J = 7.6 Hz, 2H), 2.29 (s,
6H). 13C NMR (126 MHz, DMSO-d6) δ 168.0, 138.2, 138.0,
133.7, 128.7, 128.5, 127.3, 127.2, 121.1, 18.8. Mp 200-202 °C.
HRMS ESI (m/z): [M+H]+ calcd for C15H15ClNO: 260.0837,
found: 260.0840.

4
Tetrahedron
4.2.8 2,6-dichloro-N-(4-chlorophenyl)benzamide (3ca).20
White solid; yield: 260.40 mg (76%). 1H NMR (500 MHz,
DMSO-d6) δ 10.54 (s, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.60-7.58
(m, 2H), 7.53 (d, J = 9.0 Hz, 1H), 7.50-7.48 (m, 2H), 7.45-7.36
(m, 5H), 7.30 (t, J = 7.0 Hz, 1H). 13C NMR (126 MHz, DMSO-
d6) δ 168.2, 139.8, 139.4, 139.1, 136.4, 130.9, 130.6, 130.2,
130.1, 128.3, 128.3, 127.8, 127.4, 127.3, 125.0, 120.6, 119.5. Mp
107-109 °C. HRMS ESI (m/z): [M+H]+ calcd for C19H14Cl2N:
342.0447, found:342.0448.
White solid; yield: 170.31 mg (57%). 1H NMR (500 MHz,
DMSO-d6) δ 10.88 (s, 1H), 7.73-7.71 (m, 2H), 7.59-7.58 (m,
2H), 7.51 (dd, J = 8.8 Hz, J = 7.2 Hz, 1H), 7.44-7.42 (m, 2H).
4.2.9 2,6-dichloro-N-(3,4-dichlorophenyl)benzamide (3cd).
White solid; yield: 146.87 mg (44%). 1H NMR (500 MHz,
DMSO-d6) δ 11.10 (s, 1H), 8.06 (d, J = 2.3 Hz, 1H), 7.64-7.59
(m, 3H), 7.27 (t, J = 7.9 Hz, 2H). 13C NMR (126 MHz, DMSO-
d6) δ 158.6, 138.4, 132.6, 131.3, 131.0, 125.9, 120.6, 119.5,
114.8, 112.3 (d, J = 4.5 Hz), 112.1 (d, J = 3.6 Hz). Mp 209-211
°C. HRMS ESI (m/z): [M+H]+ calcd for C13H8Cl4NO: 333.9355,
found: 333.9356.
4.2.16
N-(4-chlorophenyl)-4'-methyl-[1,1'-biphenyl]-2-
carboxamide (3fa).23
White solid; yield: 226.33 mg (70%). 1H NMR (500 MHz,
DMSO-d6) δ 10.38 (s, 1H), 7.59-7.54 (m, 4H), 7.48-7.44 (m,
2H), 7.33 (dd, J = 9.0 Hz, J = 3.6 Hz, 4H), 7.17 (d, J = 8.0 Hz,
2H), 2.28 (s, 3H).
4.2.10 N-(4-bromophenyl)-2,6-difluorobenzamide (3db).21
White solid; yield: 136.84 mg (44%). 1H NMR (500 MHz,
DMSO-d6) δ 10.93 (s, 1H), 7.68-7.66 (m, 2H), 7.63-7.58 (m,
1H), 7.57-7.55 (m, 2H), 7.25 (t, J = 8.1 Hz, 2H).
4.2.17
N-(4-bromophenyl)-4'-methyl-[1,1'-biphenyl]-2-
carboxamide (3fb).23
White solid; yield: 169.00 mg (46%). 1H NMR (500 MHz,
DMSO-d6) δ 10.36 (s, 1H), 7.56-7.51 (m, 4H), 7.47-7.44 (m,
4H), 7.32 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 7.9 Hz, 2H), 2.28 (s,
3H).
4.2.11 N-(3,4-dichlorophenyl)-2,6-difluorobenzamide (3dd).
White solid; yield: 172.46 mg (57%). 1H NMR (500 MHz,
DMSO-d6) δ 11.11 (s, 1H), 8.06 (d, J = 2.1 Hz, 1H), 7.65-7.59
(m, 3H), 7.27 (t, J = 8.1 Hz, 2H). 13C NMR (126 MHz, DMSO-
d6) δ 158.7 (dd, J = 248.9 Hz, J = 7.3 Hz), 158.6, 138.4, 132.6,
131.3, 131.0, 125.8, 120.6, 119.5, 112.3 (d, J = 3.6 Hz), 112.1 (d,
J = 4.5 Hz). Mp 152-154 °C. HRMS ESI (m/z): [M+H]+ calcd for
C13H8Cl2F2NO: 301.9946, found: 301.9944.
4.2.18
carboxamide (3fc).
N-(4-cyanophenyl)-4'-methyl-[1,1'-biphenyl]-2-
White solid; yield: 176.99 mg (57%). 1H NMR (500 MHz,
DMSO-d6) δ 10.71 (s, 1H), 7.75 (s, 4H), 7.60-7.56 (m, 2H), 7.48
(dd, J = 13.0 Hz, J = 7.5 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.17
(d, J = 8.0 Hz, 2H), 2.27 (s, 3H). 13C NMR (126 MHz, DMSO-
d6) δ 168.6, 143.3, 139.3, 136.9, 136.7, 136.4, 133.2, 130.2,
130.0, 129.0, 128.2, 127.9, 127.1, 119.5, 119.1, 105.3, 20.7. Mp
160-161 °C. HRMS ESI (m/z): [M+H]+ calcd for C21H17N2O:
313.1335, found: 313.1336.
4.2.12
N-(4-chlorophenyl)-[1,1'-biphenyl]-2-carboxamide
(3ea).22
White solid; yield: 209.25 mg (68%). 1H NMR (500 MHz,
DMSO-d6) δ 10.37 (s, 1H), 7.59-7.56 (m, 4H), 7.51-7.47 (m,
2H), 7.45-7.43 (m, 2H), 7.38-7.35 (m, 2H), 7.34-7.30 (m, 3H).
4.2.19
N-(3,4-dichlorophenyl)-4'-methyl-[1,1'-biphenyl]-2-
carboxamide (3fd).23
White solid; yield: 280.18 mg (79%). 1H NMR (500 MHz,
DMSO-d6) δ 10.53 (s, 1H), 7.92-7.91 (m, 1H), 7.59-7.56 (m,
2H), 7.54 (d, J = 8.9 Hz, 1H), 7.49-7.45 (m, 3H), 7.30 (d, J = 7.9
Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 2.29 (s, 3H).
4.2.13
N-(4-bromophenyl)-[1,1'-biphenyl]-2-carboxamide
(3eb).22
White solid; yield: 251.93 mg (72%). 1H NMR (500 MHz,
DMSO-d6) δ 10.37 (s, 1H), 7.60-7.57 (m, 2H), 7.53-7.49 (m,
3H), 7.49-7.43 (m, 5H), 7.37 (t, J = 7.4 Hz, 2H), 7.30 (t, J = 7.2
Hz, 1H).
4.2.20 N-(4-chlorophenyl)pivalamide (3ga).12d
White solid; yield: 108.60 mg (51%). 1H NMR (500 MHz,
DMSO-d6) δ 9.30 (s, 1H), 7.69-7.67 (m, 2H), 7.34-7.32 (m, 2H),
1.21 (s, 9H).
4.2.14 N-(4-cyanophenyl)-[1,1'-biphenyl]-2-carboxamide (3ec).
White solid; yield: 201.49 mg (68%). 1H NMR (500 MHz,
DMSO-d6) δ 10.69 (s, 1H), 7.73 (s, 4H), 7.61 (dd, J = 13.6 Hz, J
= 7.3 Hz, 2H), 7.51 (dd, J = 13.6 Hz, J = 7.6 Hz, 2H), 7.43 (d, J
= 7.4 Hz, 2H), 7.36 (t, J = 7.5 Hz, 2H), 7.29 (t, J = 7.2 Hz, 1H).
13C NMR (126 MHz, DMSO-d6) δ 168.5, 143.2, 139.8, 139.4,
136.4, 133.2, 130.3, 130.1, 128.4, 128.3, 127.9, 127.4, 127.4,
119.5, 119.1, 105.3. Mp 182-184 °C. HRMS ESI (m/z): [M+H]+
calcd for C20H15N2O: 299.1179, found: 299.1178.
4.2.21 N-(4-bromophenyl)pivalamide (3gb).12e
White solid; yield: 207.46 mg (81%). 1H NMR (500 MHz,
DMSO-d6) δ 9.29 (s, 1H), 7.63-7.62 (m, 2H), 7.46-7.45 (m, 2H),
1.21 (s, 9H).
4.2.22 N-(4-bromophenyl)-6-methylpicolinamide (3hb).24
4.2.15
N-(3,4-dichlorophenyl)-[1,1'-biphenyl]-2-carboxamide
(3ed).

5
White solid; yield: 173.56 mg (60%). 1H NMR (500 MHz,
DMSO-d6) δ 10.54 (s, 1H), 7.95-7.92 (m, 2H), 7.89-7.86 (m,
2H), 7.56-7.50 (m, 2H), 2.62 (s, 3H).
54, 3451–3479. (p) Wilson, T. A.; Tokarski, R. J.; Sullivan, P.;
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4.2.23 6-bromo-N-(4-bromophenyl)picolinamide (3ib).
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White solid; yield: 299.87 mg (85%). 1H NMR (500 MHz,
DMSO-d6) δ 10.54 (s, 1H), 8.13 (dd, J = 7.6, J = 1.0 Hz, 1H),
7.99 (t, J = 7.9 Hz, 1H), 7.91 (dd, J = 7.9, J = 0.9 Hz, 1H), 7.87-
7.83 (m, 2H), 7.57-7.53 (m, 2H). 13C NMR (126 MHz, DMSO-
d6) δ 161.6, 151.3, 141.1, 140.2, 137.5, 131.5, 131.4, 122.7,
122.2, 116.1. Mp 124-126 °C. HRMS ESI (m/z): [M+H]+ calcd
for C12H9Br2N2O: 354.9076, found: 354.9072.
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1
White solid; yield: 254.96 mg (72%). H NMR (500 MHz,
DMSO-d6) δ 10.62 (s, 1H), 8.36-8.34 (m, 2H), 8.24-8.22 (m,
1H), 8.15-8.08 (m, 1H), 7.92-7.90 (m, 2H), 7.59-7.48 (m, 5H).
13C NMR (126 MHz, DMSO-d6) δ 162.8, 155.3, 149.7, 139.2,
137.6, 137.5, 131.5, 129.7, 128.8, 127.3, 123.4, 122.7, 121.1,
115.9. Mp 147-149 °C. HRMS ESI (m/z): [M+H]+ calcd for
C18H14BrN2O: 353.0284, found: 353.0287.
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Acknowledgments
We are grateful to the National Natural Science Foundation of
China (Grant No. 21772150, Grant No. 22071190), the Wuhan
applied fundamental research plan of Wuhan Science and
Technology Bureau (grant NO. 2017060201010216), the 111
Project (No. B18038), and Wuhan University of Technology for
the financial support.
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Highlights
1. A simple and practical method for the synthesis of difficult-to-access amides through
the coupling of sterically hindered carboxylic acids and electron deficient amines.
2. This method has the features of high efficiency, wide substrate scope, and excellent
functional group compatibility.

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: