Imidazolium chloride: An efficient catalyst for transamidation of primary amines

Article abstract of DOI:10.3390/molecules23092234

A highly efficient and convenient protocol of imidazolium chloride (30 mol %) catalyzed amidation of amines with moderate to excellent yields was reported. The protocol shows broad substrate scope for aromatic, aliphatic, and heterocyclic primary amines.

Full text of DOI:10.3390/molecules23092234

molecules
Article
Imidazolium Chloride: An Efficient Catalyst for
Transamidation of Primary Amines
Qingqiang Tian, Zongjie Gan, Xuetong Wang, Dan Li, Wen Luo, Huajun Wang, Zeshu Dai
and Jianyong Yuan *
College of Pharmacy, Chongqing Medical University, Chongqing 400016, China; Tqingqiang@163.com (Q.T.);
gzj@cqmu.edu.cn (Z.G.); wxy998298@163.com (X.W.); ld28115@163.com (D.L.); lwen1129@163.com (W.L.);
jonh_wong@163.com (H.W.); daizs11@163.com (Z.D.)
* Correspondence: Yuanjianyong@cqmu.edu.cn; Tel./Fax: +86-23-6848-5161
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 15 August 2018; Accepted: 28 August 2018; Published: 2 September 2018
Abstract: A highly efficient and convenient protocol of imidazolium chloride (30 mol %) catalyzed
amidation of amines with moderate to excellent yields was reported. The protocol shows broad
substrate scope for aromatic, aliphatic, and heterocyclic primary amines.
Keywords: imidazolium chloride; catalyst; primary amines; transamidation
1. Introduction
Formamide and acetamide are common organic fragments in organic compounds. An amide bond
is considered to be one of the most important linkages from a medicinal point of view [
amide is also an important structural core of many FDA approved drugs, such as formoterol [
itopride [ ], trametinib [ ], apremilast [ ], paracetamol [ ], and procainamide [10] (Figure 1). Therefore,
1–
4]. In addition,
5],
6
7
8
9
finding new methods of amidation would definitely be of major benefit for the drug discovery process.
Generally, the classical method of preparing acetamide involves the reaction of an amine with a
carboxylic acid derivative [11–13]. Alternatively, transamidation has been proved to be an attractive
tool and represents one of the most convenient and straightforward methods for the preparation of
acetamide [14].
Figure 1. Amide bonds in some drug molecules.
Molecules 2018, 23, 2234; doi:10.3390/molecules23092234
www.mdpi.com/journal/molecules

Molecules 2018, 23, 2234
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Stahl [15
–
19], Williams [20
,
21], Myers [22], Beller [23], and other groups [24
–
28] have
developed many transamidation synthetic methods employing metallic catalysts such as copper [29],
Fe (NO3)3 [30], Pd (OAc)2 [31], ZnCl2 [32], ZnO [33], and Ni(quin)2 [34] as promoters. On the
other hand, metal-free methods utilizing catalytic hydroxylamine hydrochloride [35], L-proline [36],
.
and H2SO4 SiO2 [37] have also been reported. Recently, Hudson et al. [38] have developed an
alternative and elegant protocol for the N-formylation of amino acid ester hydrochloride with
N,N-Dimethylformamide (DMF) employing imidazole as the catalyst. However, further research
showed that this synthesis method was not compatible with aromatic amine or aliphatic amine
substrates. In view of this, herein, we wish to report a general imidazolium chloride catalyzed
transamidation of aromatic or aliphatic amines with satisfactory results (Scheme 1).
Previous work
Metal catalytic methods
O
R
N
O
1
R
1
Catalyst
HN
R
N
R
R
2
R
2
...
Catalyst: Copper, Fe(NO3)3, Pb(OAc)2 , ZnCl2, ZnO, Ni(quin)2
.
Metal-free methods
O
R
N
O
1
R
1
Catalyst
HN
R
N
R
R
...
2
R
2
.
.
Catalyst: H2SO4 SiO2, NH2 HCl, L-Proline
This work
H
N
H
N
H N R
1
3
R
NH
O
1
(cat)
HCl
(cat)
N
N
Trace
R
O
R
N
No metal
yield up to 97%
32 examples
R = H, CH , Phenyl
3
R = aryl, aromatic heterocyclic, alkyl, cycloalkyl
1
Scheme 1. Methods for transamidation.
2. Results and Discussion
In preliminary reactions, p-toluidine was treated with DMA in the presence of various protic acids
◦
or bases such as HAc, PTSA, or Et3N at 150 C for 6 h, however, with resulting low yields of acetamide
(Table 1, entries 4–11). Interestingly, when a reaction was carried out with imidazolium chloride
(Table 1, entry 12) at room temperature, traces of product formation was observed. Encouraged by
this result, the reaction was carried with 3 equiv. imidazolium chloride under moderate conditions.
◦
◦
Upon varying the temperature between 30 C and 150 C, the transamidation product increased.
No target product was detected at 30 ◦C (Table 1, entry 17), and 59% yield of product was obtained at
60 ◦C (Table 1, entry 18), while a satisfactory yield (96%) was observed at 150 ◦C (Table 1, entry 13),
indicating that the reaction was highly sensitive to temperature. Subsequently, the reaction was also
found to be efficient with 0.3 equiv. imidazolium chloride, affording a yield of the product with 96%
within 2 h (Table 1, entries 15). Further optimization showed that reducing the amount of imidazolium
chloride decreased the yield of compound (Table 1, entry 16) and no significant effect on reactivity was
observed when the loading was raised from 0.3 to 0.5 equiv. (Table 1, entries 13 and 14). Additionally,
the reaction failed to proceed in the absence of imidazolium chloride, suggesting the imidazolium
chloride complex may be responsible for the activation of DMA (Table 1, entry 22).

Molecules 2018, 23, 2234
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Table 1. Optimization studies for transamidation a.
O
NH
2
NH
conditions
N
O
◦
Yield b (%)
Entry
Base (equiv.)
Solvent (mL)
Temp ( C)
Time (h)
1
2
3
4
5
6
7
8
9
CuCl2
Zr(SO4)2
CH3COOH(2)
HCl(2)
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
150
150
150
150
150
150
150
150
150
150
150
rt
150
150
150
150
30
12
12
6
6
6
6
6
6
6
6
6
6
2
2
2
6
2
Trace
Trace
8
46
52
50
Trace
12
H2SO4(2)
p-toluenesulfonic acid
Pyridine(3)
KOtBu(2)
NaOH(2)
2,6-lutidine(3)
TEA(3)
18
10
11
Trace
Trace
Trace
96
95
96
65
Trace
59
68
85
12
13
14
15
16
17
18
19
20
21
22
Imidazolium chloride(3)
Imidazolium chloride(3)
Imidazolium chloride(0.5)
Imidazolium chloride(0.3)
Imidazolium chloride(0.1)
Imidazolium chloride(3)
Imidazolium chloride(3)
Imidazolium chloride(3)
Imidazolium chloride(3)
Imidazole(3)
60
90
135
150
150
2
2
2
12
Trace
NOC
-
12
a
Reaction conditions: amine (0.3 g, 2.8 mmol, 1 equiv.), solvent (5.0 mL), temperature 60–150 ◦C, all reagent and
substrate addition was done at room temperature (25 ◦C), b isolated yield; c no reaction.
Having established the optimal reaction conditions (Table 1, entry 15), we next set out to examine
the scope and limitations of this reaction, as shown in Table 2. N,N-Dimethylacetamide (DMA) was
chosen as the acetyl donor and a variety of primary amines were studied. To our delight, the aromatic
primary amines bearing electron-donating and -withdrawing groups were tolerated well under the
reaction conditions, affording the desired products in moderate to good yields (Table 2, entries 1–14).
It was noteworthy that the electronic properties of the substituent groups on the phenyl ring played an
important role in the reaction. Aromatic primary amine containing electron-donating groups provided
the desired N-acetamide product in better yields than those of electron-withdrawing groups (Table 2,
entries 2, 3, and 11 vs. entries 12, 13, and 14). The halogen substituted aniline (m/p/o) showed more
reactivity in comparison with that of p-nitroaniline and gave corresponding products in relatively
high yields (Table 2, entries 4–6 and 7–9 vs. entry 12). Benzlyamines with electron-rich and -deficient
substituents were reacted smoothly and produced corresponding transamidation products in good
to excellent yields as well (Table 2, entries 15 and 16). In addition, the heterocyclic amines and the
aliphatic amines were also compatible and afforded the corresponding products in moderate to good
yields (Table 2, entries 17–23).

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Table 2. Synthesis of benzamides via transamidation a.
DMA
NH
NH
2
Imidazolium chloride
R
R
O
150℃, 2-6h
1
Yield b (%)
Entry
Substrate
Time
Product
NH
NH2
1
2
3
2 h
92
O
1a
NH
NH
2
2 h
3 h
97
90
O
1b
NH
NH2
O
1c
NH
NH
2
O
4
2 h
75
Cl
1d
Cl
NH2
Cl
NH
Cl
5
6
2 h
4 h
82
84
O
1e
NH
NH
2
O
Cl
Cl
1f
NH
NH
2
O
7
6 h
83
1g
Br
Br
NH
NH2
Br
O
8
9
6 h
5 h
6 h
80
89
90
Br
1h
NH2
NH
O
Br
Br
1i
NH
NH
2
10
O
Br
Br
1j
NH
NH
2
11
12
13
4 h
4 h
5 h
O
89
63
57
HO
HO
1k
NH
NH
2
O
O2N
O N
2
1l
NH
NH
2
O
OHC
OHC
1m
O
O
O
NH
NH2
14
15
16
4 h
3 h
3 h
68
93
94
1n
NH
NH2
O
1o
NH
NH2
O
1p
S
S
NH
NH
2
N
17
5 h
60
N
O
1q

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Table 2. Cont.
Time
Yield b (%)
Entry
Substrate
Product
S
S
NH
N
1r
NH
2
18
19
5 h
72
N
O
Cl
S
Cl
S
NH
N
NH2
5 h
75
95
94
95
N
O
1s
NH
NH
2
O
20
21
22
3 h
MeO
MeO
1t
NH
NH2
3 h
3 h
O
1u
NH
NH
2
O
1v
NH
NH2
N
O
N
23
3 h
89
Br
Br
1w
a
Conditions unless otherwise stated: amine (1.0 equiv.), DMA (1.5 mL), Imidazolium chloride (0.3 equiv.) in a
sealed tube at 150 ◦C for 2–8 h. isolated yield.
b
In order to explore the scope of transamidation, a variety of aromatic, aliphatic, or benzylic
amines were conducted to react with DMF (Table 3) and N,N-Dimethylbenzamide (Table 4). In general,
the transamidation of formide with aromatic amines and benzylic amines (electron-deficient, -neutral,
-rich) gave corresponding transamidation products in moderate to good yields (2a
–2e). Similarly,
transamidation of benzamide with N,N-Dimethylbenzamide also gave 3a 3d in excellent yields.
–
It should be noted that the acylation products can be obtained with good quality and purity by a
simple filtration procedure in most cases.
Table 3. N-benzamides of amines 2a–2e a.
DMF
NH
NH2
Imidazolium chloride
R
R
O
150℃ ,2-6h
2
Yield b (%)
Entry
Substrate
Time
Product
NH
H
NH2
1
4 h
89
O
2a
NH
H
NH
2
O
2
3
4 h
4 h
85
89
Cl
Cl
Cl
2b
NH
Cl
H
NH2
O
2c
NH2
NH
H
O
4
5
4 h
3 h
71
92
2d
NO2
NO2
NH
H
NH2
O
2e
a
Conditions unless otherwise stated: amine (1.0 equiv.), DMF (1.5 mL), Imidazolium chloride (0.3 equiv.) in a sealed
tube at 150 ◦C for 2–8 h. isolated yield.
b

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Table 4. N-benzoylation of amines 3a–3d a.
O
O
150 ℃
R
NH2
NH
N
R
3
Yield b (%)
Entry
Substrate
Time
Product
NH
NH
2
1
4 h
89
O
3a
NH
NH2
2
3
4
3 h
3 h
3 h
94
97
93
O
3b
NH2
NH
O
MeO
MeO
3c
NH
NH
2
O
3d
a Conditions unless otherwise stated: amine (1.0 equiv.), N,N-Dimethylbenzamide (2.0 equiv.), Imidazolium chloride
b
(0.3 equiv.) in a sealed tube at 150 ◦C for 2–4 h. isolated yield.
To demonstrate the practical utility, the amidation of 4-aminophenol with DMA was carried out
on a 50 g scale under the same conditions to give 4-acetamidophenol in 91% satisfactory yield after
silica gel chromatography.
Based on our experimental results and previous studies [38], a plausible mechanism is proposed
in Scheme 2. Firstly, DMA was activated by H+ to afford intermediate A, which was attacked by
imidazole, resulting in the formation of intermediate B; HNMe2 was removed, leading to the formation
of the key intermediate C. Next, nucleophilic addition of the primary amine generates a tetrahedral
intermediate D which undergoes an elimination of imidazole to afford the target compound.
HN
N
H
O
H
N
O
O
N
N
N
R
+
HCl
N
N
H
N
NH
NH2
R
R
product
D
C
N
+
H
NH
H
NH
O
OH
O
N
N
N
N
N
N
B
A
Scheme 2. Plausible mechanism for N-acetylation using imidazolium chloride catalyst.
3. Materials and Methods
3.1. General Information
All reactions were carried out under normal conditions and no any stringent conditions were used.
All reagents were obtained from Aladdin Reagent Co., Ltd. (Shanghai, China), Lagewell Technology
Co., Ltd. (Shenzhen, China), Meyer Reagent Co., Ltd. (Shanghai, China), Macklin Reagent Co., Ltd.

Molecules 2018, 23, 2234
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(Shanghai, China), Chongqing Chuandong Chemical Co., Ltd. (Chongqing, China). etc. without
further purification unless otherwise noted. Reactions were monitored by TLC analysis using Merck
Silica Gel 60 F-254 thin layer plates. The plates were visualized first with short wavelength UV light
1
followed by iodine stain. H and 13C NMR spectra were recorded in CDCl3 and DMSO-d6 on a Bruker
Ascend-III 600 MHz spectrometer using TMS as an internal standard. The residual solvent signals were
used as references and the chemical shifts converted to the TMS scale (CDCl3:
δ H = 7.25–7.30 ppm,
δ C = 77.23 ppm; DMSO-d6: δ H = 2.51 ppm, δ C = 39.51 ppm).
3.2. General Procedures for the Synthesis of N-Acetamides 1a–1w
To a mixture of aromatic or aliphatic or heterocyclic amine (3.0 mmol, 1.0 equiv.), Imidazolium
chloride (1.0 mmol, 0.3 equiv.), N,N-Dimethyl acetamide (2.0 mL) was added. The mixture was
refluxed at 150 ◦C and the progress of the reaction was monitored by TLC visualized with UV short
wavelength followed by iodine stain. After completion, the mixture was diluted with cold water
(10 mL) then extracted with EtOAc (10 mL). The EtOAc layer was washed with 1 M hydrochloric
acid (3.0
×
15 mL). Adsorption of pigment with activated carbon, filtration of filtrate. The filtrate was
dried over anhydrous Na2SO4 and concentrated under vacuum to obtain crude N-acetamide amine,
the N-acetamide amine product was isolated by column chromatography eluting with petroleum
ether:ethyl acetate (10:1) mixtures.
3.3. General Procedures for the Synthesis of N-Formamides 2a–2e
To a mixture of aromatic or aliphatic or heterocyclic amine (3.0 mmol, 1.0 equiv.), Imidazolium
chloride (1.0 mmol, 0.3 equiv.), N,N-Dimethyl formamide (2.0 mL) was added. The mixture was
refluxed at 150 ◦C and the progress of the reaction was monitored by TLC visualized with UV short
wavelength followed by iodine stain. After completion, the mixture was diluted with cold water
(10 mL) then extracted with EtOAc (10 mL). The EtOAc layer was washed with 1 M hydrochloric
acid (3.0
×
15 mL). Adsorption of pigment with activated carbon, filtration of filtrate. The filtrate
was dried over anhydrous Na2SO4 and concentrated under vacuum to obtain crude N-formyl amine,
the N-formyl amine product was isolated by column chromatography eluting with petroleum ether:
ethyl acetate (10:1) mixtures.
3.4. General Procedures for the Synthesis of N-Benzoylation 3a–3d
To a mixture of aromatic or aliphatic or heterocyclic amine (3.0 mmol, 1.0 equiv), Imidazolium
chloride (1.0 mmol, 0.3 equiv.), N,N-Dimethylbenzamide (2.0 equiv.) was added. The mixture was
refluxed at 150 ◦C and the progress of the reaction was monitored by TLC visualized with UV short
wavelength followed by iodine stain. After completion, the mixture was diluted with cold water
(10 mL). The crystallized solid were filtered and washed with water and heptane, dried under vacuum
to give the product.
N-Phenylacetamide (1a): The product was obtained as off-white solid in 92% yield (0.37 g); MP:
112–115 ◦C; 1H NMR (600 MHz, CDCl3)
δ
7.82 (s, 1H), 7.54–7.47 (m, 2H), 7.29 (dd, J = 8.5, 7.4 Hz, 2H),
7.12–7.07 (m, 1H), 2.15 (s, 3H); 13C NMR (151 MHz, CDCl3)
δ
168.74, 137.90, 128.94, 124.29, 119.97, 24.43.
N-p-Tolylacetamide (1b): The product was obtained as pale yellow solid in 97% yield (0.43 g); MP:
◦
1
150–153 C; H NMR (600 MHz, DMSO-d6)
δ 9.83 (s, 1H), 7.46 (dd, J = 8.7, 2.4 Hz, 2H), 7.08 (d,
J = 8.3 Hz, 2H), 2.24 (s, 3H), 2.02 (s, 3H); 13C NMR (151 MHz, DMSO-d6)
δ 168.93, 136.84, 132.67, 129.52,
119.56, 24.16, 20.81.
N-m-Tolyl-acetamide (1c): The product was obtained as dark brown solid in 90% yield (0.40 g); MP:
◦
66–68 C; 1H NMR (600 MHz, DMSO-d6)
δ 9.91 (s, 1H), 7.43 (d, J = 2.0 Hz, 1H), 7.40–7.35 (m, 1H), 7.18

Molecules 2018, 23, 2234
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(t, J = 7.8 Hz, 1H), 6.89–6.84 (m, 1H), 2.27 (s, 3H), 2.05 (s, 3H); 13C NMR (151 MHz, DMSO-d6)
δ
168.82,
139.47, 138.30, 128.94, 124.24, 119.96, 116.63, 24.32, 21.60.
N-(2-Chloro-phenyl)-acetamide (1d): The product was obtained as off-white solid in 75% yield (0.38 g);
MP: 87–88 ◦C; 1H NMR (600 MHz, CDCl3)
δ 8.35 (d, J = 8.4 Hz, 1H), 7.64 (s, 1H), 7.36 (d, J = 8.0 Hz,
1H), 7.27 (t, J = 7.8 Hz, 1H), 7.03 (t, J = 7.7 Hz, 1H), 2.24 (s, 3H); 13C NMR (151 MHz, CDCl3)
δ 168.26,
134.61, 128.96, 127.73, 124.62, 122.55, 121.66, 24.88.
N-(3-Chlorophenyl)acetamide (1e): The product was obtained as pale yellowish-brown solid in 82% yield
(0.42 g); MP: 74–77 ◦C; 1H NMR (600 MHz, DMSO-d6)
δ 10.13 (s, 1H), 7.94–7.68 (m, 1H), 7.57–7.35 (m,
1H), 7.36–7.27 (m, 1H), 7.14–7.02 (m, 1H), 2.06 (d, J = 0.8 Hz, 3H); 13C NMR (151 MHz, DMSO-d6)
δ
169.17, 141.01, 133.50, 130.80, 123.17, 118.80, 117.67, 24.39.
N-(4-Chlorophenyl)acetamide (1f): The product was obtained as pale brown solid in 84% yield (0.43 g);
◦
1
MP: 175–177 C; H NMR (600 MHz, DMSO-d6)
δ 10.07 (s, 1H), 7.71–7.48 (m, 2H), 7.48–7.23 (m,
2H), 2.04 (d, J = 1.3 Hz, 3H); 13C NMR (151 MHz, DMSO-d6)
δ 169.00, 138.48, 138.46, 129.01, 127.06,
120.93, 24.31.
N-(3-Bromo-phenyl)-acetamide (1g): The product was obtained as pale brown solid in 83% yield (0.53 g);
◦
MP: 85–87 C; 1H NMR (600 MHz, DMSO-d6)
δ 10.11 (s, 1H), 7.95 (d, J = 1.9 Hz, 1H), 7.47–7.44 (m, 1H),
7.26 (t, J = 8.0 Hz, 1H), 7.24–7.19 (m, 1H), 2.05 (s, 3H); 13C NMR (151 MHz, DMSO-d6)
δ 169.24, 141.11,
131.17, 126.12, 121.98, 121.65, 118.09, 24.38.
N-(2-Bromo-phenyl)-acetamide (1h):The product was obtained as pale brown solid in 80% yield (0.51 g);
◦
MP: 97–99 C; 1H NMR (600 MHz, CDCl3)
δ 8.33 (d, J = 8.3 Hz, 1H), 7.61 (s, 1H), 7.53 (dd, J = 8.0,
1.4 Hz, 1H), 7.31 (ddd, J = 8.5, 7.4, 1.5 Hz, 1H), 7.01–6.92 (m, 1H), 2.24 (s, 3H); 13C NMR (151 MHz,
CDCl3) δ 168.17, 135.59, 132.19, 128.39, 125.16, 121.87, 113.10, 24.83.
N-(4-Bromophenyl)-acetamide (1i): The product was obtained as pale yellowish-brown solid in 89%
yield (0.57 g); MP: 166–169 ◦C; 1H NMR (600 MHz, DMSO-d6)
δ 10.07 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H),
7.47 (d, J = 8.8 Hz, 2H), 2.05 (s, 3H); 13C NMR (151 MHz, DMSO-d6)
δ 169.12, 138.83, 131.91, 121.36,
115.10, 24.31.
N-(4-Bromo-2-methyl-phenyl)-acetamide (1j): The product was obtained as off-white solid in 90% yield
◦
(0.61 g); MP:160–162 C; 1H NMR (600 MHz, CDCl3)
δ 7.68 (d, J = 8.3 Hz, 1H), 7.32 (d, J = 8.8 Hz,
2H), 6.97 (s, 1H), 2.21 (d, J = 17.0 Hz, 6H); 13C NMR (151 MHz, CDCl3)
δ 168.26, 134.64, 133.88, 131.14,
129.72, 124.70, 118.08, 24.27, 17.58.
N-(4-Hydroxyphenyl)-acetamide (1k)The product was obtained as white solid in 89% yield (0.40 g);
MP: 170–172 ◦C; 1H NMR (600 MHz, DMSO-d6)
δ 9.65 (s, 1H), 9.14 (s, 1H), 7.34 (d, J = 8.8 Hz, 2H),
6.68 (d, J = 8.8 Hz, 2H), 1.98 (s, 3H); 13C NMR (151 MHz, DMSO-d6)
δ 168.09, 153.43, 131.32, 121.27,
115.38, 24.09.
N-(4-Nitro-phenyl)-acetamide (1l): The product was obtained as yellow solid in 63% yield (0.34 g); MP:
209–211 ◦C; 1H NMR (600 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.21 (dd, J = 9.1, 1.7 Hz, 2H), 7.95–7.65 (m,
2H), 2.12 (s, 3H); 13C NMR (151 MHz, DMSO-d6) δ 169.95, 145.66, 142.50, 125.42, 119.01, 24.56.
N-(4-Formyl-phenyl)-acetamide (1m): The product was obtained as white solid in 57% yield (0.28 g); MP:
◦
155–157 C; 1H NMR (600 MHz, CDCl3)
δ
9.92 (s, 1H), 8.07 (s, 1H), 7.95–7.78 (m, 2H), 7.73 (d, J = 8.3 Hz,
2H), 2.24 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 191.27, 168.97, 143.65, 132.12, 131.19, 119.20, 24.72.

Molecules 2018, 23, 2234
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N-(4-Acetyl-phenyl)-acetamide (1n): The product was obtained as white solid in 68% yield (0.36 g); MP:
166–168 ◦C; 1H NMR (600 MHz, DMSO-d6)
δ 10.28 (s, 1H), 8.03–7.83 (m, 2H), 7.80–7.60 (m, 2H), 2.52
(s, 3H), 2.09 (s, 3H); 13C NMR (151 MHz, DMSO-d6)
δ
197.15, 169.48, 143.90, 131.97, 129.93, 118.57,
26.84, 24.53.
◦
N-Benzylacetamide (1o): The product was obtained as off-white solid in 93% yield (0.42 g); MP: 60–63 C;
1H NMR (600 MHz, DMSO-d6)
δ 8.48–8.24 (m, 1H), 7.40–7.28 (m, 2H), 7.28–7.17 (m, 3H), 4.26 (dd,
J = 9.6, 4.1 Hz, 2H), 1.92–1.83 (m, 3H); 13C NMR (151 MHz, DMSO-d6)
δ 169.95, 139.88, 128.73, 127.69,
127.21, 42.50, 22.92.
(R)-N-methyl-N-phenylacetamide (1p): The product was obtained as yellow solid in 94% yield (0.46 g);
◦
MP: 98–101 C; 1H NMR (600 MHz, DMSO-d6)
δ 8.29 (d, J = 8.1 Hz, 1H), 7.33–7.23 (m, 4H), 7.25–7.13 (m,
1H), 4.90 (dd, J = 7.9, 6.8 Hz, 1H), 1.84 (s, 3H), 1.32 (d, J = 7.1 Hz, 3H); 13C NMR (151 MHz, DMSO-d6)
δ 168.97, 145.18, 128.69, 127.04, 126.38, 48.26, 23.06, 22.9. [α]2D5 = 124 (c = 0.5, CHCl3).
N-(4-Methyl-benzothiazol-2-yl)-acetamide (1q): The product was obtained as white solid in 60% yield
◦
1
(0.37 g); MP: 250–252 C; H NMR (600 MHz, DMSO-d6)
δ 12.44 (s, 1H), 7.77 (d, J = 7.8 Hz, 1H),
7.39–6.96 (m, 2H), 2.57 (s, 3H), 2.19 (s, 3H); 13C NMR (151 MHz, DMSO-d6)
δ 169.84, 157.36, 147.97,
131.44, 130.25, 127.08, 123.95, 119.48, 23.08, 18.36.
N-(6-Methyl-benzothiazol-2-yl)-acetamide (1r): The product was obtained as white solid in 72% yield
(0.44 g); MP: 216–218 ◦C; 1H NMR (600 MHz, DMSO-d6)
δ 12.28 (s, 1H), 7.87–7.66 (m, 1H), 7.62 (d,
J = 8.2 Hz, 1H), 7.24 (dd, J = 8.3, 1.7 Hz, 1H), 2.41 (s, 3H), 2.20 (s, 3H); 13C NMR (151 MHz, DMSO-d6)
δ
169.78, 157.39, 146.84, 133.46, 131.95, 127.87, 121.67, 120.57, 23.13, 21.38.
N-(6-Chloro-benzothiazol-2-yl)-acetamide (1s): The product was obtained as white solid in 75% yield
(0.51 g); MP: 225–227 ◦C; 1H NMR (600 MHz, DMSO-d6)
δ 12.45 (s, 1H), 8.11 (d, J = 2.5 Hz, 1H), 7.73
(dd, J = 8.7, 1.5 Hz, 1H), 7.46 (s, 1H), 2.23 (s, 3H); 13C NMR (151 MHz, DMSO-d6)
δ 170.14, 159.05,
147.75, 133.49, 128.03, 126.89, 122.13, 121.71, 23.09.
N-[2-(4-Methoxy-phenyl)-ethyl]-acetamide (1t): The product was obtained as white solid in 95% yield
(0.55 g); MP: 86–87 ◦C; 1H NMR (600 MHz, DMSO-d6)
δ 7.89 (s, 1H), 7.12 (d, J = 8.6 Hz, 2H), 6.96–6.71
(m, 2H), 3.72 (s, 3H), 3.29–3.07 (m, 2H), 2.63 (t, J = 7.5 Hz, 2H), 1.78 (s, 3H); 13C NMR (151 MHz,
DMSO-d6) δ 169.97, 158.07, 131.75, 130.00, 114.17, 55.39, 40.95, 34.66, 22.97.
N-Cyclohexylacetamide (1u): The product was obtained as off-white solid in 94% yield (0.40 g); MP:
100–103 ◦C; 1H NMR (600 MHz, CDCl3) 5.57 (s, 1H), 4.00–3.53 (m, 1H), 1.96 (s, 5H), 1.80–1.64 (m, 2H),
1.68–1.53 (m, 1H), 1.48–1.28 (m, 2H),1.23–1.00 (m, 3H); 13C NMR (151 MHz, CDCl3)
33.15, 25.52, 24.88, 23.49.
δ 169.12, 48.15,
N-(4-Methyl-cyclohexyl)-acetamide (1v): The product was obtained as white solid in 95% yield (0.44 g);
◦
MP: 139–140 C; 1H NMR (600 MHz, DMSO-d6)
δ 7.67 (d, J = 7.9 Hz, 1H), 3.42 (dtd, J = 11.7, 7.7, 3.9 Hz,
1H), 1.81–1.67 (m, 5H), 1.68–1.59 (m, 2H), 1.32–1.19 (m, 1H), 1.19–1.02 (m, 2H), 1.03–0.89 (m, 2H), 0.85
(d, J = 6.6 Hz, 3H); 13C NMR (151 MHz, DMSO-d6) δ 168.86, 47.99, 34.05, 32.75, 31.94, 23.06, 22.60.
N-(6-Bromo-pyridin-2-yl)-acetamide (1w): The product was obtained as off-white solid in 89% yield
(0.57 g); MP: 158–159 ◦C; 1H NMR (600 MHz, CDCl3)
δ 8.16 (d, J = 8.2 Hz, 1H), 8.09 (s, 1H), 7.56 (t,
J = 7.9 Hz, 1H), 7.21 (dd, J = 7.7, 0.8 Hz, 1H), 2.21 (s, 3H); 13C NMR (151 MHz, CDCl3)
δ 168.65, 151.28,
140.69, 139.12, 123.52, 112.27, 24.67.

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N-Phenyl-formamide (2a): The product was obtained as off-white solid in 89% yield (0.34 g); MP:
48–50 ◦C; 1H NMR (600 MHz, CDCl3) Mixture of rotamers is observed. Ratio: 5/5. Major rotamer:
δ
8.47 (s, 1H), 8.35 (d, J = 2.0 Hz, 1H), 7.58 (dd, J = 8.6, 1.0 Hz, 1H), 7.39–7.30 (m, 2H), 7.17–7.09 (m,
2H); Minor rotamer:
δ 9.19 (d, J = 9.0 Hz, 1H), 8.72 (d, J = 11.4 Hz, 1H), 7.58 (dd, J = 8.6, 1.0 Hz, 1H),
7.39–7.30 (m, 2H,), 7.22–7.17 (m, 1H), 7.17–7.09 (m, 1H); 13C NMR (151 MHz, CDCl3)
136.88, 125.25, 120.00, 118.69, 77.08.
δ 162.90, 159.39,
N-(4-Chloro-phenyl)-for◦mamide (2b): The product was obtained as yellow brown solid in 85% yield
1
(0.40 g); MP: 104–106 C; H NMR (600 MHz, DMSO-d6), Mixture of rotamers is observed. Ratio:
5.9/4.1; Major rotamer:
rotamer:
8.82 (d, J = 11.6 Hz, 1H), 7.38 (s, 1H), 7.39–7.23 (m, 2H) 7.21 (m, 2H); 13C NMR (151 MHz,
DMSO-d6) 162.89, 160.18, 160.11, 160.09, 137.45, 137.43, 129.67, 129.21, 129.20, 127.69, 121.19, 121.11,
δ 8.31 (d, J = 1.2 Hz, 1H), 8.23 (s, 1H), 7.65 (m, 2H), 7.39–7.23 (m, 2H); Minor
δ
δ
119.47, 119.38.
N-(3-Chloro-phenyl)-formamide (2c): The product was obtained as cream white solid in 89% yield (0.42 g);
◦
MP: 49–50 C; 1H NMR (600 MHz, DMSO-d6)
δ 10.36 (t, J = 4.1 Hz, 1H), 8.62 (t, J = 2.0 Hz, 1H), 8.47–8.20
(m, 2H), 2.21–1.98 (m, 3H); 13C NMR (151 MHz, DMSO-d6)
δ 169.85, 144.63, 144.60, 139.25, 137.24,
128.18, 128.09, 120.09, 24.25.
N-(3-Nitro-phenyl)-formamide (2d): The product was obtained as yellow solid in 71% yield (0.35 g); MP:
138–139 ◦C; 1H NMR (600 MHz, DMSO-d6), Mixture of rotamers is observed. Ratio: 7.1/2.9 Major
rotamer:
8.96 (d, J = 10.4 Hz,1H), 7.97 (d, J = 1.2 Hz, 1H), 7.89–7.88 (m, 1H), 7.87 (dd, J = 8.0 and 1.6 Hz, 1H),
7.66–7.63 (m, 1H); 13C NMR (151 MHz, DMSO-d6)
160.85, 148.39, 139.40, 130.88, 125.58, 118.80, 113.77.
δ 8.63 (s, 1H), 8.38 (t, J = 2.0 Hz, 1H), 7.96–7.89 (m, 2H), 7.89–7.88 (m, 2H); (Minor rotamer: δ
δ
N-Benzyl-formamide (2e): The product was obtained as white solid in 92% yield (0.37 g); MP: 61–62 ◦C;
1H NMR (600 MHz, DMSO-d6) 8.53 (s, 1H), 8.23–8.08 (m, 1H), 7.40–7.19 (m, 5H), 4.34 (s, 2H); 13
NMR (151 MHz, DMSO-d6) δ 161.64, 139.28, 128.82, 127.73, 127.39, 41.12.
δ
C
◦
N-p-Tolyl-benzamide (3a): The product was obtained as gray solid in 89% yield (0.57 g); MP: 156–158 C;
1H NMR (600 MHz, CDCl3)
δ 7.85 (dt, J = 7.1, 1.4 Hz, 3H), 7.55–7.42 (m, 5H), 7.16 (d, J = 8.2 Hz, 2H),
2.34 (s, 3H); 13C NMR (151 MHz, CDCl3)
120.35, 120.23, 20.93.
δ 165.64, 135.27, 135.05, 134.24, 131.74, 129.58, 128.75 , 127.00,
(R)-N-(1-Phenyl-ethyl)-benzamide (3b): The product was obtained as white solid in 94% yield (0.64 g);
◦
MP: 137–138 C; 1H NMR (600 MHz, CDCl3)
δ
7.80–7.74 (m, 2H), 7.52–7.47 (m, 1H), 7.45–7.34 (m, 5H),
166.54,
7.31–7.27 (m, 1H), 5.34 (q, J = 6.9 Hz, 1H), 1.61 (d, J = 6.9 Hz, 3H); 13C NMR (151 MHz, CDCl3)
δ
143.06, 134.54, 131.51, 128.77, 128.58, 127.50, 126.90, 126.26, 49.13, 21.71. [α]2D5 = +19.9 (c = 1.0, CHCl3).
N-[2-(4-Methoxy-phenyl)-ethyl]-benzamide (3c): The product was obtained as white solid in 97% yield
(0.74 g); MP: 120–121 ◦C; 1H NMR (600 MHz, CDCl3)
δ 7.75–7.62 (m, 2H), 7.52–7.44 (m, 1H), 7.40 (dd,
J = 8.4, 7.0 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 3.80 (s, 3H), 3.68 (td, J = 6.9, 5.8 Hz,
2H), 2.87 (t, J = 6.9 Hz, 2H); 13C NMR (151 MHz, CDCl3)
δ 167.43, 158.31, 134.62, 131.39, 130.85, 129.75,
128.55, 126.79, 114.12, 55.28, 41.19, 34.75.
N-Cyclohexyl-benzamide (3d
)
:
The product was obtained as white solid in 93% yield (0.57 g); MP:
7.87–7.64 (m, 2H), 7.54–7.34 (m, 3H), 5.99 (s, 1H), 3.98 (dt,
146–147 ◦C; 1H NMR (600 MHz, CDCl3)
δ
J = 6.8, 2.8 Hz, 1H), 2.03 (dt, J = 12.5, 3.9 Hz, 2H), 1.91–1.55 (m, 4H), 1.53–1.33 (m, 2H), 1.33–1.09 (m,
3H); 13C NMR (151 MHz, CDCl3) δ 166.60,135.06, 131.25, 128.52, 126.80, 48.56, 33.21, 25.58, 24.91.

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Experimental procedures and analytical data of all compounds (1H NMR and 13C NMR), copy of
the 1H NMR, 13C NMR and data are available in the Supplementary Materials.
4. Conclusions
In conclusion, a simple method for the transamidation process of primary amines taking
imidazolium chloride as the only promoter is reported. This method has wide substrate scope and
provides moderate to good yields. Moreover, considering the advantages of imidazolium chloride,
including being inexpensive, readily available, and environmentally-friendly, this simple procedure is
a valuable addition to the arsenal of amide syntheses.
Supplementary Materials: The following are available online, general procedure for Transamidation of primary
amines reaction and 1H NMR and 13C NMR spectra of all products.
Author Contributions: Q.T. and J.Y. conceived and designed the experiments; Q.T. performed the experiments;
W.L. and X.W. analyzed the data; H.W., Z.D. and D.L. contributed reagents/materials/analysis tools; Z.G. wrote
the paper.
Funding: Supported by the Fundamental Research Funds for the Chongqing Science and Technology Commission
(No. cstc2018jscx-msyb0048) and the Fundamental and Advanced Research Projects of Chongqing City
(No. cstc2017jcyjAX0228).
Acknowledgments: Chongqing University Pharmaceutical Engineering Research Center for support.
Conflicts of Interest: The authors declare no conflicts of interest.
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Sample Availability: Samples of the compounds are not available from the authors.
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2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).