Beckmann rearrangement of ketoxime catalyzed by N-methyl-imidazolium hydrosulfate

Article abstract of DOI:10.3390/molecules23071764

Beckmann rearrangement of ketoxime catalyzed by acidic ionic liquid-N-methyl-imidazolium hydrosulfate was studied. Rearrangement of benzophenone oxime gave the desirable product with 45% yield at 90 ?C. When co-catalyst P₂O₅ was added, the yield could be improved to 91%. The catalyst could be reused three cycles with the same efficiency. Finally, reactions of other ketoximes were also investigated.

Full text of DOI:10.3390/molecules23071764

molecules
Article
Beckmann Rearrangement of Ketoxime Catalyzed by
N-methyl-imidazolium Hydrosulfate
Hongyu Hu †, Xuting Cai †, Zhuying Xu, Xiaoyang Yan * and Shengxian Zhao *
Xingzhi College, Zhejiang Normal University, Jinhua 321004, China; huhongyu22@126.com (H.H.);
CxuT1998@163.com (X.C.); hu841124@126.com (Z.X.)
* Correspondence: eastmorningsun@163.com (X.Y.); shengxian.zhao@apeloa.com (S.Z.);
Tel./Fax: +86-579-8229-1129 (X.Y. & S.Z.)
† These authors contributed equally to this work.
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 7 June 2018; Accepted: 14 July 2018; Published: 18 July 2018
Abstract: Beckmann rearrangement of ketoxime catalyzed by acidic ionic liquid-N-methyl-
imidazolium hydrosulfate was studied. Rearrangement of benzophenone oxime gave the desirable
product with 45% yield at 90 ◦C. When co-catalyst P2O5 was added, the yield could be improved to
91%. The catalyst could be reused three cycles with the same efficiency. Finally, reactions of other
ketoximes were also investigated.
Keywords: Beckmann rearrangement; ketoxime; acidic ionic liquid; catalysis
1. Introduction
Over the past years, amide derivatives have received much attention owing to their broad range
of applications in many fields such as the pharmaceutical industry, chemical biology, the agrochemical
industry, engineering plastics, and so on [
synthesis of amide compounds including nucleophilic acyl substitution reactions with amines [
Staudinger ligation [ ], Schmidt reaction [ ] and Beckmann rearrangement [10]. However, generations
1–
6
]. Various approaches have been developed for the
7],
8
9
of large amounts of undesired by-products and corrosive phenomenon associated with common acid
(H2SO4 and SOCl2) based on liquid phase protocols provide a challenging task for chemists to develop
alternative methods [11,12]. A variety of alternative routes [13–16] based on organic and inorganic
solid acids were developed. However, traditional methods often suffer from some drawbacks such as
poor selectivity, harsh conditions, are not atom economic, or are not environmentally friendly.
From the point of view of atom conversion efficiency, Beckmann rearrangement is a perfect way
for construction of amides, in general sulfuric acid is most commonly used rearrangement catalyst
in commercial production of amides. However, it brings equipment corrosion and environmental
pollution problems. Recently, ionic liquids [17] have emerged as potential green alternatives to
organic solvents due to their unique properties of low volatility, high polarity, good thermal stability,
and excellent solubility [18–20]. Further, there are more potential capabilities as effective catalysts
and reagents [13], as chemical transformations have also been explored. In order to develop a
green pathway of amide synthesis, we report here a Beckmann rearrangement reaction catalyzed by
N-methyl-imidazolium hydrosulfate ([HMIm]HSO4) [21] under solvent free conditions (Scheme 1).
Molecules 2018, 23, 1764; doi:10.3390/molecules23071764
www.mdpi.com/journal/molecules

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HO
R1
O
O
N
a
b
R1
R1
R2
N
R2
R2
H
1a-1k
2a-2o
3a-3o
Scheme 1. Synthesis of amides. Reagents and conditions: (
(b) acidic ionic liquid, P2O5, N2, 90 C, 6 h.
a) NH2OH.HCl, NaOH, EtOH, H2O, reflux;
◦
2. Results
Beckmann rearrangement of benzophenone oxime catalyzed by [HMIm]HSO4 was carried out
at 120 ◦C over 6 h without any solvent, the desired product, benzanilide, was obtained in moderate
yield (45%). The co-catalysts such as P2O5, FeCl3, ZnCl2, CuCl2.2H2O, and AlCl3 were investigated in
this reaction system, the yield was improved significantly to 91% with P2O5. However, it has been
shown in the literature that the conversion is around 20% only when P2O5 is used as the sole catalyst of
Beckmann rearrangement [15]. When CuCl2.2H2O was added, the yield was reduced to 14%, and the
reverse reaction of benzophenone oxime was observed, benzophenone was regenerated. The results
are presented in Table 1.
Table 1. Effect of co-catalyst on Beckmann rearrangement in ionic liquid systems.
Entry
Co-Catalyst
Yield (%)
a
1
2
3
4
5
6
45
91
47
P2O5
FeCl3
AlCl3
50
ZnCl2
53
14 b
CuCl2·2H2O
Reaction conditions: Benzophenone oxime (9.5 mmol), [HMIm]HSO4 (11.4 mmol), and co-catalyst (8%), 90 ◦C, 6 h;
without co-catalyst; b benzophenone(%) was obtained.
a
The effect of the amount of co-catalyst P2O5 on reaction was investigated. The reaction yield was
improved when more co-catalyst was added, and the best yield was around 90% when the amount of
P2O5 was higher than 8 mol %. The results are presented in Figure 1.
Figure 1. Effect of the amount of co-catalyst P2O5 on Beckmann rearrangement of benzop◦henone
oxime. Reaction conditions: Benzophenone oxime (9.5 mmol), [HMIm]HSO4 (11.4 mmol), 90 C, 6 h.

Molecules 2018, 23, 1764
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The influence of the reaction temperature on the yield was investigated subsequently. It was
found that 90 ◦C is the best reaction temperature. The results are presented in Figure 2.
Figure 2. Influence of the reaction temperature on Beckmann rearrangement of benzophenone oxime.
Reaction conditions: Benzophenone oxime (9.5 mmol), [HMIm]HSO4 (11.4 mmol), 6 h, co-catalyst
(P2O5 8%).
The recycling performance of ionic liquid has the most benefits from the point of view of
environmental protection. During the reaction workup, the white product was precipitated out
when ice water was added, after filtration, the mother liquid was evaporated in a vacuum, and ionic
liquid was recovered and could be reused for three times. The results are presented in Table 2.
Table 2. Effect of ionic liquid recycling on Beckmann rearrangement.
Reaction Turn
P2O5/%
Conversion/%
Yield/%
1
2
3
8
1
0.5
91
91
90
91
90
88
Reaction conditions: Benzophenone oxime (9.5 mmol), [HMIm]HSO4 (11.4 mmol), 90 ◦C, 6 h; Conversion was
determined by Gas Chromatography (GC) using internal standard method.
In order to explore the scope and limitations of this reaction, we extended the procedure to various
aryl-substituted and alkyl-substituted ketoximes. In general, the reaction proceeded easily under the
best conditions and the amide products were isolated in excellent yields and high purity. The results
are presented in Table 3.
Table 3. Formation of amides (3a–3o) from ketoxime (2a–2o) in the presence of ionic liquid and
co-catalyst P2O5.
Compd.
3a
R1
R2
Yield %
CH3
OCH3
91
CH3
3b
3c
CH3
90
90
CH3

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Table 3. Cont.
CH3
CH3
CH3
3d
3e
F
89
88
Br
NO2
3f
3g
3h
3i
86
91
89
85
84
90
Cl
Cl
3j
F
F
OCH3
OCH3
OCH3
3k
52
28
3l(3l’)
3m
OCH3
(
)
(
)
89
CF3
3n
3o
82
85
Caprolactam
Reaction conditions: Benzophenone oxime (9.5 mmol), [HMIm]HSO4 (11.4 mmol), catalyst (P2O5 8%), 90 ◦C, 6 h.
3. Experimental Section
All melting points were determined using a YRT-3 Digital Melting Point Apparatus
(Tianjin, China). All melting points were uncorrected. All new compounds were characterized
by HRMS-EI(M+), 1H and 13C-NMR spectra were recorded in CDCl3 or DMSO-d6 on a Bruker AV
600 MHz or Bruker AV 400 MHz instrument. HRMS spectra were obtained on an Agilent 6230
mass spectrometer.
3.1. Synthesis of N-methyl-imidazolium Hydrosulfate ([HMIm]HSO4)
◦
N-Methylimidazole (8.2 g, 0.10 mol) was cooled down to 0 C and concentrated sulfuric acid
(10.0 g) was added dropwise. After addition, the solution was stirred 24 h at room temperature,
a transparent viscous liquid (17.6 g) was obtained. Yield: 99%; IR (cm−1): 3345, 3150, 2870, 1447, 1337,
1221, 1048, 1082, 887.

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3.2. General Procedures for Synthesis of Oxime Substrates 2a–2o
Ketone (0.027 mol) and hydroxylamine hydrochloride (3.0 g, 0.043 mol) were dissolved in EtOH
(10 mL) and H2O (20 mL). To the mixture was added NaOH (5.5 g, 0.137 mol). The reaction mixture
was heated under reflux and the reaction was monitored by thin layer chromatography (TLC). After
completion of the reaction, the reaction mixture was cooled down to room temperature, to the reaction
mixture were added concentrated hydrochloric acid (15 mL) and water (100 mL). The solid was filtered
off and recrystallized from EtOH, affording the products 2a–2o.
2a: White solid, Yield: 91%. m.p.: 87.6–88.7 ◦C; 1H-NMR (400 MHz, CDCl3)
δ
7.60 (d, J = 8.9 Hz, 2H),
160.5, 155.6, 129.0,
6.93 (d, J = 8.9 Hz, 2H), 3.85 (s, 3H), 2.30 (s, 3H); 13C-NMR (100 MHz, CDCl3)
δ
127.4, 113.9, 55.3, 13.3.
2b: White solid, Yield: 93%. m.p.: 88.0–89.0 ◦C; 1H-NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.2 Hz, 2H),
7.22 (d, J = 8.0 Hz, 2H), 2.39(s, 3H), 2.31 (s, 3H); 13C-NMR (100 MHz, CDCl3)
δ 156.0, 139.3, 133.7, 129.3,
126.0, 21.3, 12.3.
◦
1
2c: White solid, Yield: 90%. m.p.: 51.7–53.0 C; H-NMR (600 MHz, CDCl3)
δ 7.68–7.64 (m, 2H),
7.44–7.40 (m, 3H), 2.35(s, 3H); 13C-NMR (150 MHz, CDCl3) δ 156.1, 136.5, 129.3, 128.5, 126.1, 12.3.
◦
2d: White solid, Yield: 70%. m.p.: 74.0–76.0 C;1H-NMR (600 MHz, DMSO-d6)
(m, 2H), 7.22–7.19 (m, 2H), 2.14 (s, 3H); 13C-NMR (150 MHz, DMSO-d6) 162.4 (d, 1JCF = 245.5 Hz),
152.1, 133.5 (d, 4JCF = 3.0 Hz), 127.6 (d, 3JCF = 8.3 Hz), 115.2 (d, 2JCF = 21.5 Hz), 11.9.
δ 11.21 (s, 1H), 7.76–7.59
δ
2e: White solid, Yield: 91%. m.p.: 141.0–142.0 ◦C; 1H-NMR (600 MHz, DMSO-d6)
11.40 (s, 1H), 7.80
δ
(t, J = 1.8 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.34 (dd, J = 11.1, 4.6 Hz, 1H), 2.14 (s,
3H); 13C-NMR (150 MHz,DMSO-d6) δ 151.9, 139.3, 131.3, 130.6, 128.1, 124.6, 121.8, 11.4.
◦
1
2f: Yellow solid, Yield: 90%. m.p.: 172.0–173.0 C; H-NMR (400 MHz, DMSO-d6)
δ
11.78 (s, 1H),
8.28—8.18 (m, 2H), 7.96–7.88 (m, 2H), 2.21 (s, 3H); 13C-NMR (100 MHz, DMSO-d6)
δ 157.1, 152.5, 148.3,
131.9, 131.8, 16.6.
2g: White solid, Yield: 95.6%. m.p.: 129.6–131.0 ◦C; 1H-NMR (600 MHz, DMSO-d6)
δ 10.49 (s, 1H),
7.42–7.27 (m, 5H), 3.04–2.85 (m, 1H), 1.75–1.66 (m, 2H), 1.64–1.50 (m, 6H); 13C-NMR (150 MHz,
DMSO-d6) δ 158.6, 135.8, 128.3, 128.2, 128.1, 45.2, 30.3, 24.9.
◦
2h: White solid, Yield: 60%. m.p.: 92.0–93.0 C; 1H-NMR (600 MHz, DMSO-d6)
δ 11.40 (s, 1H), 7.48–7.44
(m, 2H), 7.43–7.40 (m, 1H), 7.387.37 (m, 5H), 7.30–7.25 (m, 2H); 13C-NMR (150 MHz, DMSO-d6)
δ 155.2,
136.8, 133.5, 128.88, 128.86, 128.40, 128.36, 128.2, 127.0.
2i: White solid, Yield: 87.5%. m.p.: 134.0–136.0 ◦C; 1H-NMR (600 MHz, CDCl3)
δ
7.48 (d, J = 8.6 Hz,
2H), 7.43–7.37 (m, 4H), 7.36–7.31 (m, 2H); 13C-NMR (150 MHz, CDCl3)
130.4, 129.1, 128.8, 128.7.
δ 156.1, 135.9, 135.5, 134.3, 130.8,
2j: White solid, Yield: 88.5%. m.p.: 131.0–132.0 ◦C; 1H-NMR (600 MHz, DMSO-d6)
7.43–7.38 (m, 2H), 7.38–7.32 (m, 2H), 7.28 (dd, J = 12.3, 5.4 Hz, 2H), 7.19 (dd, J = 12.3, 5.4 Hz, 2H);
13C-NMR (150 MHz, DMSO-d6) 162.6 (d, 1JCF = 244.6 Hz), 161.9 (d, 1JCF = 244.6 Hz), 153.4, 133.2,
131.3 (d, 3JCF = 8.2 Hz), 129.5, 129.1 (d, 3JCF = 8.2 Hz), 115.4 (d, 2JCF = 22.6 Hz), 115.2 (d, 2JCF = 22.3 Hz).
δ 11.45 (s, 1H),
δ
2k: White solid, Yield: 87.5%. m.p.: 129.0–130.0 ◦C; 1H-NMR (400 MHz, DMSO-d6)
11.1 (s, 1H), 7.31
δ
(d, J = 8.8 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.7 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 3.79 (s, 3H),
3.76 (s, 3H); 13C-NMR (100 MHz, DMSO-d6)
δ
159.8, 159.1, 154.4, 130.7, 129.7, 128.6, 125.6, 113.7, 113.4,
55.2, 55.1.
1
2l: Light yellow solid, Yield: 87.9%. m.p.:155.0–160.0 ◦C; (isomer 1): H-NMR (600 MHz, DMSO-d6)
δ
11.27(s, 1H), 7.38–7.34 (m, 4H), 7.29–7.24 (m, 3H), 7.00 (d, J = 8.7 Hz, 2H), 3.79 (s, 3H); (isomer 2):
1H-NMR (600 MHz, DMSO-d6)
δ
11.09 (s, 1H), 7.46–7.43 (m, 2H), 7.42–7.38 (m, 3H), 7.30 (d, J = 8.8 Hz,

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2H), 6.92 (d, J = 8.8 Hz, 2H), 3.75 (s, 3H); (isomer 1): 13C-NMR (100 MHz, DMSO-d6)
δ
159.85, 154.85,
137.32, 130.74, 129.22, 128.32, 128.29, 128.12, 113.80, 55.20; (isomer 2): 13C-NMR (100 MHz, DMSO-d6)
δ
159.20, 154.80, 133.82, 128.87, 128.76, 128.29, 127.32, 125.37, 113.46, 55.15.
2m: Yield: 94.0%. m.p.: 84–86 ◦C; 1H-NMR (600 MHz, DMSO-d6)
δ 8.81 (brs, 1H), 7.30–7.18 (m, 5H),
2.83 (t, J = 8.2 Hz, 2H), 2.51 (t, J = 8.2 Hz, 2H), 1.91 (s, 3H); 13C-NMR (150 MHz, DMSO-d6)
δ 157.9,
141.0, 128.4, 128.3, 126.1, 37.7, 32.6,13.8.
2n: Yield: 90.0%. m.p.: 79–81 ◦C; 1H-NMR (600 MHz, DMSO-d6)
13C-NMR (150 MHz, DMSO-d6) 145.2 (q, 2JCF = 30.0), 130.6, 129.0, 128.9, 127.2, 121.6 (q, 1JCF3 = 271.5).
δ 12.74 (s, 1H), 7.73–7.16 (m, 5H);
δ
2o: Yield: 85.5%. m.p.: 89–91 ◦C; 1H-NMR (600 MHz, DMSO-d6)
2.48 (dd, J = 6.8, 5.3, 2H), 2.48 (m,
δ
2H), 1.76–1.45 (m, 6H); 13C-NMR (150 MHz, DMSO-d6) δ 157.1, 31.6, 26.6, 25.4, 25.2, 23.8.
3.3. General Procedures for the Synthesis of Amides 3a–3o
To a solution of the oxime substrates 2a
–
2o (9.50 mmol) in (HMIm)HSO4 (2.05 g, 11.4 mmol), the
◦
co-catalyst P2O5 (0.15 g, 1.0 mmol) was added. Then the solution was heated to 90 C and the reaction
was monitored by TLC. After completion of the reaction, the mixture was extracted with ethyl acetate
(50 mL) twice, and the combined organic phase was washed with the aqueous solution of sodium
bicarbonate and brine, dried over anhydrous Na2SO4 and concentrated in vacuo to afford a residue,
which was purified by column (ethyl acetate: petroleum ether = 1:4) to afford the products 3a–3o.
◦
1
3a [22]: White solid, Yield: 91%. m.p.: 127.0–128.0 C; H-NMR (600 MHz, DMSO-d6)
1H), 7.51–7.46 (m, 2H), 7.20 (d, J = 7.9 Hz, 1H), 6.89–6.84 (m, 2H), 3.71 (s, 3H), 2.01 (s, 3H); 13C-NMR
(150 MHz, DMSO-d6) 168.2, 155.5, 133.0, 121.0, 114.2, 55.6, 24.3; HRMS(+): calcd. for C9H11NO2
[M + H]+ 166.0863, found 166.0859; calcd. for C9H11NO2Na [M + Na]+ 188.0682, found 188.0682.
δ 9.80 (brs,
δ
3b [22]: White solid, Yield: 90%. m.p.: 149.0–150.0 ◦C; 1H-NMR (600 MHz, DMSO-d6)
9.84 (s, 1H),
7.46 (d, J = 8.3 Hz, 2H), 7.09 (d, J = 8.3 Hz, 2H), 2.24 (s, 3H), 2.02 (s, 3H); 13C-NMR (150 MHz, DMSO-d6)
δ
δ
173.2, 142.1, 137.0, 134.1, 124.2, 29.2, 25.6; HRMS(+): calcd. for C9H11NO [M + H]+ 150.0913, found
150.0912; calcd. for C9H11NONa [M + Na]+ 172.0733, found 172.0741.
3c [23]: White solid, Yield: 90%. m.p.: 108.5–110.0 ◦C; 1H-NMR (600 MHz, DMSO-d6)
δ 9.93 (brs, 1H),
7.58 (dd, J = 1.0, 8.5 Hz, 2H), 7.29 (dd, J = 7.5, 8.4 Hz, 2H), 7.08–6.91 (m, 1H), 2.05 (s, 3H); 13C-NMR
(150 MHz, DMSO-d6) δ
168.7, 139.8, 129.1, 123.4, 119.4, 24.5; HRMS(+): calcd. for C8H9NO [M + H]+
136.0757, found 136.0755; calcd. for C8H9NONa [M + Na]+ 158.0576, found 158.0572.
3d [24]: Light yellow solid, Yield: 89%. m.p.: 153–155 ◦C; 1H-NMR (600 MHz, DMSO-d6)
δ
9.99 (brs,
168.6,
1H), 7.87–7.47 (m, 2H), 7.12 (t, J = 8.99 Hz, 2H), 2.04 (s, 3H); 13C-NMR (150 MHz, DMSO-d6)
δ
158.3.8 (d, 1JCF = 237.0 Hz), 136.2 (d, 4JCF = 1.5 Hz), 121.1 (d,3JCF = 7.5 Hz), 115.2 (d, 2JCF = 22.5 Hz),
24.3; HRMS(+): calcd. for C8H8FNO [M + H]+ 154.0663, found 154.0665; calcd. for C8H8FNONa
[M + Na]+ 176.0482, found 176.0481.
◦
1
3e [25]: White solid, Yield: 88%. m.p.: 87.0–89.0 C; H-NMR (600 MHz, DMSO-d6)
1H), 7.95 (s, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.27–7.23 (m, 1H), 7.22–7.19 (m, 1H), 2.05 (s, 3H); 13C-NMR
(150 MHz, CDCl3) 169.1, 141.3, 131.1, 126.0, 122.0, 121.7, 118.1, 24.5; HRMS(+): calcd. for C8H8BrNO
[M + H]+ 213.9862, found 213.9860; calcd. for C8H8BrNONa [M + Na]+ 235.9681, found 235.9681.
δ 10.11 (brs,
δ
3f [25]: Yellow solid, Yield: 86%. m.p.: 214.0–215.0 ◦C; 1H-NMR (600 MHz, DMSO-d6)
10.57 (s, 1H),
169.8,
δ
8.21 (d, J = 9.2 Hz, 2H), 7.82 (d, J = 9.4 Hz, 2H), 2.12 (s, 3H); 13C-NMR (150 MHz, DMSO-d6)
δ
145.9, 142.3, 125.4, 119.0, 24.7; HRMS(+): calcd. for C8H8N2O3 [M + H]+ 181.0608, found181.0610;
Calcd. for C8H8N2O3Na [M + Na]+ 203.0433, found 203.0437.
3g: White solid, Yield: 91%. m.p.: 160.0–161.0 ◦C; 1H-NMR (600 MHz, DMSO-d6)
1H), 7.88–7.80 (m, 2H), 7.54–7.49 (m, 1H), 7.48–7.42 (m, 2H), 4.46–3.96 (m, 1H), 1.96–1.81 (m, 2H),
δ 8.29 (d, J = 7.0 Hz,

Molecules 2018, 23, 1764
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1.74–1.64 (m, 2H), 1.60–1.43 (m, 4H); 13C-NMR (150 MHz, DMSO-d6)
δ
166.4, 135.3, 131.4, 128.6,
127.7, 51.4, 32.6, 24.1; HRMS(+): calcd. for C12H15NO [M + H]+ 190.1226, found 190.1228; calcd. for
C12H15NO Na [M + Na]+ 212.1046, found 212.1044.
3h [23]: White solid, Yield: 89%. m.p.: 162.6–163.0 ◦C; 1H-NMR (400 MHz, DMSO-d6)
7.99–7.92 (m, 2H), 7.78 (d, J = 7.6 Hz, 2H), 7.63–7.58 (m, 1H), 7.57–7.51 (m, 2H), 7.36 (t, J = 7.9 Hz, 2H),
δ 10.25 (s, 1H),
7.15–7.07 (m, 1H); 13C-NMR (100 MHz, DMSO-d6)
δ 166.0, 139.6, 135.5, 132.0, 129.1, 128.9, 128.1, 124.1,
120.8; HRMS(+): calcd. for C13H11NO [M + H]+ 198.0913, found 198.0913; calcd. for C13H11NONa
[M + Na]+ 220.0733, found 220.0733.
◦
1
3i [25]: White solid, Yield: 85%. m.p.: 210.0–212.0 C; H-NMR (600 MHz, DMSO-d6)
1H), 8.02–7.96 (m, 2H), 7.86–7.79 (m, 2H), 7.66–7.59 (m, 2H), 7.45–7.39 (m, 2H); 13C-NMR (150 MHz,
DMSO-d6) 165.0, 138.4, 137.0, 133.8, 130.1, 129.0, 127.9, 122.4; HRMS(+): calcd. for C13H9Cl2NO
[M + H]+ 266.0134, found 266.0129; calcd. for C13H9Cl2NONa [M + Na]+ 287.9953, found 287.9951.
δ 10.45 (s,
δ
3j [26]: Light yellow solid, Yield: 84%. m.p.: 183–185.0 ◦C; 1H-NMR (600 MHz, DMSO-d6)
10.31 (s,
1H), 8.04–8.02 (m, 2H), 7.82–7.72 (m, 2H), 7.37 (t, J = 8.8 Hz, 2H), 7.19 (t, J = 8.8 Hz, 2H); 13C-NMR
δ
(150 MHz, DMSO-d6)
δ
164.3, 164.1 (d, 1JCF = 249.5 Hz), 158.3 (d, 1JCF = 240.3 Hz), 135.4, 131.2, 130.4 (d,
3JCF = 9.0 Hz), 122.2 (d, 3JCF = 7.8 Hz), 115.3 (d, 2JCF = 22.4 Hz), 115.2 (d, 2JCF = 22.8 Hz); HRMS(+):
calcd. for C13H9F2NO [M + H]+ 234.0725, found 234.0727; calcd. for C13H9F2NONa [M + Na]+
256.0544, found 256.0546.
3k [26]: Light yellow solid, Yield: 90%. m.p.: 204.0–205.0 ◦C; 1H-NMR (600 MHz, CDCl3)
J = 8.8 Hz, 2H), 7.65 (s, 1H), 7.52 (d, J = 9.0 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 9.0 Hz, 2H),
δ 7.83 (d,
3.87 (s, 3H), 3.81 (s, 3H); 13C-NMR (150 MHz, DMSO-d6)
δ 164.5, 161.7, 155.4, 132.4, 129.4, 127.1, 121.9,
113.7, 113.5, 55.4, 55.2; HRMS(+): calcd. for C15H15NO3 [M + H]+ 258.1125, found 258.1127; calcd. for
C15H15NO3Na [M + Na]+ 280.0944, found 280.0946.
3l [25] (N-(4-Methoxyphenyl)benzamide): Light yellow solid, Yield: 52%. M.p.: 156.5–159.5 ◦C; 1H-NMR
(600 MHz, DMSO-d6)
δ
10.07 (s, 1H), 7.95 (d, J = 9.2 Hz, 2H), 7.74 (d, J = 7.6 Hz, 2H), 7.51 (t, J = 7.6 Hz,
164.94,
1H), 7.33 (t, J = 7.9 Hz, 2H), 7.05 (d, J = 9.2 Hz, 2H), 3.84 (s, 3H); 13C-NMR (100 MHz, DMSO-d6)
δ
161.91, 139.36, 131.40, 129.61, 128.58, 123.45, 120.37, 113.62, 55.45; HRMS(+): calcd. for C14H13NO2
[M + H]+ 228.1019, found 228.1020; calcd. for C14H13NO2Na [M + Na]+ 250.0838, found 250.0838;
(4-Methoxy-N-phenylbenzamide): Light yellow solid, Yield: 28% 1H-NMR (600 MHz, DMSO-d6)
δ
10.12
(s, 1H), 7.94 (d, J = 7.2 Hz, 2H), 7.67 (d, J = 9.0 Hz, 2H), 7.57 (t, J = 7.2 Hz, 1H), 7.09 (t, J = 8.8 Hz, 2H),
6.93 (d, J = 9.0 Hz, 2H), 3.74 (s, 3H); 13C-NMR (100 MHz, DMSO-d6)
δ 165.14, 155.58, 135.07, 132.24,
128.37, 127.56, 127.00, 122.02, 113.76, 55.20. HRMS(+): calcd. for C14H13NO2 [M + H]+ 228.1019, found
228.1020; calcd. for C14H13NO2Na [M + Na]+ 250.0838, found 250.0838.
3m [27]: Yield: 89%. m.p.: 113–114 ◦C; 1H-NMR (600 MHz, DMSO-d6)
δ
7.34–7.30 (m, 2H), 7.26–7.21
173.4,
(m, 3H), 3.85–3.77 (m, 2H), 2.84–2.74 (m, 2H), 2.29 (s, 3H); 13C-NMR (150 MHz, DMSO-d6)
δ
139.0, 129.3, 129.0, 126.9, 46.4, 34.8, 26.6. HRMS(+): calcd. for C10H13NO [M + H]+ 164.1070, found
164.1071; calcd. for C10H13NONa [M + Na]+ 186.0889, found 186.0884.
◦
1
3n [28]: Yield: 82%. m.p.: 84–87 C; H-NMR (600 MHz, DMSO-d6)
δ
11.26 (brs, 1H), 7.70 (dd,
155.0 (q,
J = 0.83, 8.53 Hz, 2H), 7.43–7.38 (m, 2H), 7.24–7.20 (m, 1H), 13C-NMR (150 MHz, DMSO-d6)
δ
2JCF = 36.0), 136.8, 129.4, 126.0, 121.5, 116.3 (q, 1JCF3 = 286.5). HRMS(+): calcd. for C8H6F3NO [M + H]+
190.0474, found 190.0472; calcd. for C8H6F3NONa [M + Na]+ 212.0294, found 212.0296.
3o [29]: Yield: 85%. m.p.: 68–71 ◦C; 1H-NMR (600 MHz, DMSO-d6)
10.09 Hz, 2H), 2.38–2.13 (m, 2H), 1.66 (q, J = 5.87 Hz, 2H), 1.56–1.46 (m, 4H); 13C-NMR (150 MHz,
DMSO-d6)
177.4, 41.9, 36.9, 30.5, 30.3, 23.4, HRMS(+): calcd. for C6H11NO [M + H]+ 114.0913, found
114.0910; calcd. for C6H11NONa [M + Na]+ 136.0733, found136.0734.
δ 7.41 (brs, 1H), 3.05 (dd, J = 5.87,
δ

Molecules 2018, 23, 1764
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4. Conclusions
In conclusion, we successfully demonstrated an efficient approach for the synthesis of amide
derivatives via Beckmann rearrangement of ketoxime by using Brønsted acidic ionic liquid
N-methyl-imidazolium hydrosulfate as an environmental friendly catalyst and solvent. The best
reaction condition is: reaction temperature 90 ◦C, reaction time 6 h, solvent N-methyl-imidazolium
hydrosulfate 10 grams, co-catalyst P2O5 8 mol %. Ionic liquid can be reused three times. The procedure
can be extended to various symmetrical and unsymmetrical aryl-substituted and alkyl-substituted
ketoxime substrates. The aryl group migration products are sole products for unsymmetrical aryl alkyl
substituted amides.
Author Contributions: H.H., X.Y., and S.Z. conceived and designed the experiments; X.C. and Z.X. performed
the experiments; H.H. analyzed the data; and H.H. wrote the paper.
Funding: The project was supported by the Zhejiang province ecology first-class discipline and Zhejiang Provincial
Department of Education general research projects (Y201636410).
Conflicts of Interest: The authors declare no conflict of interest.
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2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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