3-benzoylisoxazolines by 1,3-dipolar cycloaddition: Chloramine-T-catalyzed condensation of α-nitroketones with dipolarophiles

Article abstract of DOI:10.3390/molecules26123491

In this study, 3-benzoylisoxazolines were synthesized by reacting alkenes with various α-nitroketones using chloramine-T as the base. The scope of α-nitroketones and alkenes is extensive, including different alkenes and alkynes to form various isoxazoline

Full text of DOI:10.3390/molecules26123491

molecules
Article
3-Benzoylisoxazolines by 1,3-Dipolar Cycloaddition:
Chloramine-T-Catalyzed Condensation of α-Nitroketones
with Dipolarophiles
Xinhui Pan 1,2,*,†, Xiaobing Xin 2,3,†, Ying Mao 4,†, Xin Li 2, Yanan Zhao 2 , Yidi Liu 2, Ke Zhang 2, Xiaoda Yang 1,2
and Jinhui Wang 2,
*
1
2
Stake Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology,
School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; xyang@bjmu.edu.cn
Key Laboratory of Xinjiang Phytomedicine Resource and Utilisation, Ministry of Education,
School of Pharmaceutical Sciences, Shihezi University, Shihezi 832002, China; 18699300391@163.com (X.X.);
lixin@stu.shzu.edu.cn (X.L.); zynhyl@stu.shzu.edu.cn (Y.Z.); lyd@stu.shzu.edu.cn (Y.L.);
xjzk1984@163.com (K.Z.)
Department of Pharmacology, Houbo College of Xinjiang Medical University, Karamay 834000, China
School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China;
maoying1984@163.com
3
4
*
†
Correspondence: panxhshzu@shzu.edu.cn (X.P.); wangjinhui@hrbmu.edu.cn (J.W.)
These authors contributed equally.
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: In this study, 3-benzoylisoxazolines were synthesized by reacting alkenes with various
α-
Citation: Pan, X.; Xin, X.; Mao, Y.; Li,
X.; Zhao, Y.; Liu, Y.; Zhang, K.; Yang,
X.; Wang, J. 3-Benzoylisoxazolines by
1,3-Dipolar Cycloaddition:
nitroketones using chloramine-T as the base. The scope of -nitroketones and alkenes is extensive,
including different alkenes and alkynes to form various isoxazolines and isoxazoles. The use of
chloramine-T, as the low-cost, easily handled, moderate base for 1,3-dipolar cycloaddition is attractive.
α
Chloramine-T-Catalyzed
Keywords: isoxazolines; α-nitroketones; alkenes; chloramine-T; 1,3-dipolar cycloaddition
Condensation of α-Nitroketones with
Dipolarophiles. Molecules 2021, 26,
3491. https://doi.org/10.3390/
molecules26123491
1. Introduction
Isoxazoline derivatives have been demonstrated to exhibit a variety of biological
and pharmacological activities, such as antithrombotic effects, insect growth regulation,
Academic Editors: Eugene Babaev,
Wim Dehaen, Richard A. Bunce and
Philippe Belmont
immunopotentiation and anticancer activities (Figure 1) [
lines are also useful intermediates. For instance, they can be converted into different critical
synthetic units, such as -hydroxy ketones [ ], -amino alcohols [ ], -unsaturated ke-
tones [ ] and -hydroxy nitriles [ ]. Carreira et al. and Lee et al. [10 12] used isoxazolines
in the total synthesis of natural products (Figure 2).
1–5]. In organic synthesis, isoxazo-
Received: 2 March 2021
Accepted: 3 June 2021
Published: 8 June 2021
β
6
γ
7 α,β
8
β
9
–
Previous studies described various methods for synthesizing isoxazolines, namely,
the 1,3-dipolar cycloaddition of dipolarophiles [13] (alkynes, alkenes) with nitrile oxides
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with regard to jurisdictional claims in
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iations.
from aldoximes [14] or
pared by dehydration with an acid (such as sulfuric acid [15], p-toluenesulfonic acid [16
α
-nitroketones. In the case of
α
-nitroketones, nitrile oxides are pre-
17
,
]
or polyphosphoric acid-silica (PPA/SiO2) [18]) or a base (such as N-methylimidazole [19],
1,4-diazabicyclo [2.2.2] octane [20] and copper (II) acetate/N-methylpiperidine [21]) as the
catalytic systems.
Moderate to good reaction efficiency can be obtained by utilizing these acidic or
basic catalytic systems. The majority of the reactions undergo 1,3-dipolar cycloadditions
Copyright:
© 2021 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 (https://
creativecommons.org/licenses/by/
4.0/).
with different
1,3-dipolar cycloadditions that start from nitroalkanes bearing a carbonyl group do not
proceed smoothly and thus, generate the desired products in low yields. Tsubaki et al. [22
α-nitroketones to obtain various isoxazoles. However, it is reported that
]
recently developed nitrile oxide cycloaddition reactions between nitrile oxides derived from
O-alkyloxime-substituted nitroalkanes and various alkenes to construct 2-isoxazolines with
electron-withdrawing groups. Although this method proceeds smoothly with nitroalkanes
Molecules 2021, 26, 3491. https://doi.org/10.3390/molecules26123491
https://www.mdpi.com/journal/molecules

Molecules 2021, 26, 3491
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and various alkenes, it requires the preparation of O-alkyloxime-substituted nitroalkanes
as precursors. To simplify this reaction, we tested several other bases and identified
chloramine-T a commercially available agent, to give superior results [23]. We found that
chloramine salts showed highly attractive practical characteristics: easy and amenable
preparation at large scales, nontoxic by-products, excellent reactivity and high stability
to air and heat. In this study, we successfully developed a chloramine-T catalytic system
for 1,3-dipolar cycloaddition of dipolarophiles with α-nitroketones. To the best of our
knowledge, it is the first time that chloramine-T has been used in 1,3-dipolar cycloaddition
reactions to obtain isoxazolines from α-nitroketones.
O
N
CO2Bu
HN
H
O
O
N
HN
CO2CH3
N
N
O
H
H
O
N
AcOH
H2N
O
insect growth regulators
antithrombotic agents
HN
OMe
N
O
N
O
O
MeO
MeO
H
O
O
5
O
H3CO
MeO
OMe
O
N
OMe
immunopotentiating activity
anticancer activity
Figure 1. Examples of important isoxazolines.
Figure 2. Application of 2-isoxazoline as a key building block.
2. Results and Discussion
Benzoylnitromethane 1a (1 equiv) was reacted with allylbenzene 2a (5 equiv) in the
presence of various bases in acetonitrile at 80 ◦C. The results are summarized in Table 1
(entries 1–6). No reaction occurred in the base-free system. Chloramine-T was the best
among the bases tested herein. It is conceivable that 0.5 equivalents of chloramine-T can
provide a better yield (Table 1, entries 6–9). According to the results, a few solvents were
screened for optimization. Cycloaddition was found to be reliant on the solvent. Although
H2O inhibited the cycloaddition, the reaction worked in DMSO and DMF, while CH3CN
as the solvent provided the best results (Table 1, entries 10–13), producing 3a with a yield
◦
◦
of 77%. Increasing the temperature to 90 C or lowering it to 60 C resulted in a lesser yield
(Table 1, entries 14 and 15). Thus, the reaction in optimal conditions was conducted at
80 ◦C for 18 h with 0.5 equiv of chloramine-T in the presence of acetonitrile as the solvent;
and 3a was obtained with a yield of 77%.

Molecules 2021, 26, 3491
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Table 1. Reaction condition optimization a.
Yield b (%) of 3a
Entry
Catalyst
Amount of Base (mol)
1
2
3
4
–
Imidazole
4-Dimethylaminopyridine
Triethylamine
N,N,N’,N’-
–
<5
43
45
55
0.5
0.5
0.5
5
0.5
48
Tetramethylethylenediamine
Chloramine-T
Chloramine-T
Chloramine-T
Chloramine-T
Chloramine-T
Chloramine-T
Chloramine-T
Chloramine-T
Chloramine-T
Chloramine-T
6
7
8
0.5
1.0
0.25
0.1
0.5
0.5
0.5
0.5
0.5
0.5
77
52
68
65
46
40
11
36
70
59
9
10 c
11 d
12 e
13 f
14 g
15 h
a
General conditions: 1a (0.125 mmol), 2a (0.625 mmol), chloramine-T (0.0625 mmol), CH3CN (0.2 mL) at 80 ◦
C
b
c
d
e
for 18 h, unless stated otherwise. Isolated yield. DMF as the solvent. DMSO as the solvent. H2O as the
solvent. CH3NO2 as the solvent. Reaction at 90 ◦C. h Reaction at 60 ◦C.
f
g
Under the optimized reaction conditions, various substrates were subjected to 1,3-
dipolar cycloaddition (Scheme 1). Several electronically varied
jected to cycloaddition. Efficiency was considered as the sensitivity of cycloaddition to
electronic substituents. Electron-deficient -nitroketones (3b 3d, Scheme 1) provided prod-
ucts in slightly better yields related to electron-rich -nitroketones (3e and 3f Scheme 1).
α-nitroketones were sub-
α
–
α
,
Phenacyl nitro derivatives incorporating tert-butyl and phenyl at the para-position were
also successful in the cycloaddition (3g and 3h, Scheme 1). Simple nitroketones were
efficiently coupled with allylbenzene (3i, Scheme 1).
Next, we investigated the scope of the alkenes in Scheme 2. Alkene alternative with
contrasting and electronically varied substituents reacted with benzoylnitromethane 1a
smoothly under the standard conditions to obtain the desired products in excellent yields.
Moreover, the electron-rich allylbenzenes and allylalkanes produced the product in good
yields (5a–5e, Scheme 2). Similarly, the electron-deficient ones, such as allyl chloride,
produced the product in excellent yields (5f, Scheme 2). Good yields were also obtained in
the cycloaddition of cyclohexene (5g, Scheme 2).

Molecules 2021, 26, 3491
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O
N
O
Chloramine-T
CH3CN, 80oC
R1
O
N
NO2
+
R1
Ph
3
1
2a
O
Br
O
O
Br
N
O
N
O
O
Ph
Ph
Ph
3b 73%
3a 77%
3c 67%
O
O
O
N
N
N
N
O
O
O
O
Br
H3CO
Ph
Ph
Ph
Ph
3d 72%
3e 68%
3f 54%
O
O
O
N
N
O
O
O
Ph
Ph
Ph
3g 63%
3i 30%
3h 57%
Scheme 1. Scope of cycloaddition.
O
O
R2
R3
N
Chloramine-T
NO2
+
O
CH CN, 80
℃
3
R2
N
R3
5
4
1a
O
O
O
N
N
O
O
Me
O
Me
Me
5b 66%
5c 64%
5a 71%
O
O
O
N
N
N
O
O
O
C8H17
OMe
Cl
5d 72%
5e 89%
5f 83%
O
N
O
5g 54%
Scheme 2. Scope of alkenes.

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F◦inally, 1a was reacted with 1-hexyne in the presence of chloramine-T in acetonitrile
at 70 C for 18 h. Isoxazoles 7a and 7b were obtained with a yield of 68% and 64%
(Scheme 3). This result demonstrated that this reaction is also suitable for cycloadditions to
form isoxazoles.
Scheme 3. The reaction of 1a with 6 in the presence of chloramine-T in CH3CN.
A possible mechanism for the reaction is shown in Scheme 4. In acetonitrile, the ion
pair
9, which is formed between nitronate
1 and the protonated base 8, undergoes cy-
cloaddition with dipolarophile
2
to obtain intermediate 10. Subsequently, the ion pair
intermediate adduct 10 releases chloramine-T
8
to produce the 2-hydroxyoxazolidine 11
,
which is then dehydrated to give the product
3
. Finally, another nitronate reacts with
1
chloramine-T 8 to obtain the new ion pair intermediate 9.
Cl
H
N
S
O
O
N
O
O
Na
R1
O
9
H
O
O
N
R3
R2
R1
O
O
2
1
Cl
H
H
O
H N
Cl
S
O
O
O
N
S
O
N
R1
Na
O
Na
R2
10
R3
Chloramine-T, 8
H2O
H
O
N
O
Cl
H
O
R1
N
11
H
N
S
O
R2
Na
O
R3
Cl
OH
12
S
O
O
Na
O
8
N
O
3
R1
R3
R2
Scheme 4. A plausible mechanism for the condensation of nitro compounds and dipolarophiles.

Molecules 2021, 26, 3491
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3. Experimental Section
3.1. General Experimental Methods
The structures of produced compounds were firmly confirmed by 13C NMR and 1H
NMR spectra and supported by HRMS, IR data (see the Supplementary Materials).
1H NMR (400 MHz) and 13C NMR (101 MHz) were recorded at room temperature by
using a DRX-400 spectrometer (Bruker, Germany) in CDCl3. Chemical shifts were given in
parts per million (ppm) on the delta (
value, for H NMR: CDCl3
δ
) scale. The solvent peak was used as a reference
δ
7.26; for 13C NMR: CDCl3 at 77.16 ppm. IR spectra were
1
recorded using an Avatar 360 FT-IR ESP spectrometer Nicolet (Waltham, MA, USA) at
room temperature. HR-ESI-MS spectra were acquired using an Agilent 6210 ESI/TOF mass
spectrometer (Agilent Technologies, Santa Clara, CA, USA). Analytical TLC was run on
silica gel plates (GF254, Yantai Institute of Chemical Technology, Yantai, China). Spots on
the plates were observed under UV light. Column chromatography was performed on
silica gels (200~300 mesh and 300–400 mesh; Qingdao Marine Chemical Factory, Qingdao,
China). Super-dry solvent CH3CN, DMSO and DMF were purchased from Aldrich and
used as supplied. The
in the literature [16].
α-nitroketones were synthesized using the same method as reported
3.2. General Procedure for the Cycloaddition of Alkenes and α-Nitroketones
Chloramine-T (0.0625 mmol, 0.5 equiv) was added to a solution of
1 (0.125 mmol,
1 equiv) and
2
(0.625 mmol, 5 equiv) (or
4
(0.625 mmol, 5 equiv) or
6
(0.625 mmol, 5 equiv))
◦
in CH3CN (0.2 mL). The mixture was then stirred at 80 C until the starting material
disappeared, as monitored by TLC. Subsequently, the mixture was directly purified by
flash chromatography (with ethyl acetate/petroleum ether as the eluent) to obtain the
desired product (3, 5 or 7).
3.2.1. (5-Benzyl-4,5-dihydroisoxazol-3-yl)(phenyl)methanone (3a)
The compound (with a yield of 77%) was prepared following the general procedure
1
described in Section 3.2. H NMR (400 MHz, CDCl3)
δ
8.22–8.12 (m, 2H), 7.63–7.57 (m, 1H),
7.51–7.44 (m, 2H), 7.38–7.33 (m, 2H), 7.28 (m, 3H), 5.08 (ddt, J = 10.8, 7.9, 6.3 Hz, 1H),
3.37 (dd, J = 17.6, 10.8 Hz, 1H), 3.19–3.08 (m, 2H), 2.98 (dd, J = 14.0, 6.5 Hz, 1H);
13C NMR (101 MHz, CDCl3)
δ 186.2, 157.5, 135.8, 135.6, 133.3, 130.1(2C), 129.3(2C), 128.5(2C),
128.1(2C), 126.8, 83.3, 40.7, 38.1; IR ν
max 3033, 1654, 1581, 710, 672 cm−1; HRMS (EI) m/z
calcd for C17H16NO2 [M + H]+ 266.1176, found 266.1178. These data are consistent with
the data reported in the literature [11].
3.2.2. (5-Benzyl-4,5-dihydroisoxazol-3-yl)(2-bromophenyl)methanone (3b)
1
The compound was prepared following the general procedure. Yield 73%. H NMR
(400 MHz, CDCl3)
7.18 (m, 2H), 7.15 (m, 1H), 5.05 (ddt, J = 11.0, 7.6, 6.3 Hz, 1H), 3.22 (dd, J = 17.5, 10.9 Hz,
1H), 3.04–2.94 (m, 2H), 2.88 (dd, J = 14.0, 6.5 Hz, 1H); 13C NMR (101 MHz, CDCl3)
189.2,
158.1, 139.2, 135.8, 133.4, 132.1, 129.8, 129.7(2C), 128.8(2C), 127.2, 127.1, 120.0, 85.2, 41.0, 36.7;
IR
max 3034, 1680, 1585, 755, 694 cm−1; HRMS (EI) m/z calcd for C17H15NO2Br [M + H]+
δ 7.51 (d, J = 7.6 Hz, 1H), 7.29–7.25 (m, 2H), 7.24 (m, 2H), 7.21 (m, 1H),
δ
ν
344.0281, found 344.0279.
3.2.3. (5-Benzyl-4,5-dihydroisoxazol-3-yl)(3-bromophenyl)methanone (3c)
1
The compound was prepared following the general procedure. Yield 67%. H NMR
(400 MHz, CDCl3) 8.24 (m, 1H), 8.07 (m, 1H), 7.70 (m, 1H), 7.37–7.33 (m, 2H), 7.32 (m, 1H),
7.27 (m, 3H), 5.16–5.03 (m, 1H), 3.34 (dd, J = 17.6, 10.9 Hz, 1H), 3.16–3.05 (m, 2H), 2.98 (dd,
J = 14.0, 6.4 Hz, 1H); 13C NMR (101 MHz, CDCl3)
185.0, 157.6, 137.5, 136.4, 135.9, 133.2,
129.9, 129.6(2C), 128.9, 128.8(2C), 127.2, 122.6, 83.9, 40.9, 38.1; IR max 3038, 1691, 1616, 910,
811, 742 cm−1; HRMS (EI) m/z calcd for C17H15NO2Br [M + H]+ 344.0281, found 344.0293.
δ
δ
ν

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3.2.4. (5-Benzyl-4,5-dihydroisoxazol-3-yl)(4-bromophenyl)methanone (3d)
1
The compound was prepared following the general procedure. Yield 72%. H NMR
1
(400 MHz, CDCl3) H NMR (400 MHz, CDCl3)
δ 8.04–7.97 (m, 2H), 7.62–7.56 (m, 2H),
7.35–7.30 (m, 2H), 7.25 (m, 3H), 5.07 (ddt, J = 10.9, 7.9, 6.3 Hz, 1H), 3.34 (dd, J = 17.6, 10.9 Hz,
1H), 3.13–3.05 (m, 2H), 2.96 (dd, J = 14.0, 6.5 Hz, 1H).; 13C NMR (101 MHz, CDCl3)
185.4,
157.9, 136.1, 134.6, 132.0(2C), 131.9(2C), 129.7(2C), 129.2, 128.9(2C), 127.2, 83.9, 41.1, 38.3;
δ
IR ν
max 3046, 1696, 1615, 801, 750, 686 cm−1; HRMS (EI) m/z calcd for C17H15NO2Br
[M + H]+ 344.0281, found 344.0276.
3.2.5. (5-Benzyl-4,5-dihydroisoxazol-3-yl)(p-tolyl)methanone (3e)
1
The compound was prepared following the general procedure. Yield 68%. H NMR
(400 MHz, CDCl3) δ 8.08–8.03 (m, 2H), 7.33 (m, 2H), 7.28 (m, 2H), 7.25 (m, 3H), 5.05 (ddt,
mboxemphJ = 10.8, 7.9, 6.3 Hz, 1H), 3.35 (dd, J = 17.6, 10.8 Hz, 1H), 3.15–3.07 (m, 2H),
2.96 (dd, J = 14.0, 6.6 Hz, 1H), 2.42 (s, 3H); 13C NMR (101 MHz, CDCl3)
δ 186.1, 157.9,
144.7, 136.2, 133.4, 130.6(2C), 129.6(2C), 129.2(2C), 128.8(2C), 127.1, 83.5, 41.1, 38.6, 21.9;
IR νmax 3023, 2923, 1650, 1600, 831, 750, 693 cm−1; HRMS (EI) m/z calcd for C18H18NO2
[M + H]+ 280.1332, found 280.1336.
3.2.6. (5-Benzyl-4,5-dihydroisoxazol-3-yl)(4-methoxyphenyl)methanone (3f)
1
The compound was prepared following the general procedure. Yield 54%. H NMR
(400 MHz, CDCl3)
5.04 (ddt, J = 10.8, 7.9, 6.4 Hz, 1H), 3.88 (s, 3H), 3.36 (dd, J = 17.6, 10.8 Hz, 1H), 3.16–3.07 (m, 2H),
2.96 (dd, J = 14.0, 6.6 Hz, 1H); 13C NMR (101 MHz, CDCl3)
184.7, 164.2, 157.9, 136.3,
δ 8.23–8.15 (m, 2H), 7.36–7.30 (m, 2H), 7.29–7.25 (m, 3H), 6.97–6.91 (m, 2H),
δ
132.9(2C), 129.6(2C), 128.8(2C), 127.1, 113.8(2C), 83.3, 55.7, 41.1, 38.8; IR νmax 3022, 2801,
1618, 1531, 802, 719, 676 cm−1; HRMS (EI) m/z calcd for C18H18NO3 [M + H]+ 296.1281,
found 296.1285.
3.2.7. (5-Benzyl-4,5-dihydroisoxazol-3-yl)(4-tert-butylphenyl)methanone (3g)
1
The compound was prepared following the general procedure. Yield 63%. H NMR
(400 MHz, CDCl3)
J = 10.8, 7.9, 6.3 Hz, 1H), 3.32 (dd, J = 17.6, 10.8 Hz, 1H), 3.14–3.04 (m, 2H), 2.93 (dd,
J = 14.0, 6.5 Hz, 1H), 1.34 (d, J = 4.4 Hz, 9H); 13C NMR (101 MHz, CDCl3)
186.0, 157.8,
δ 8.10–8.05 (m, 2H), 7.49–7.43 (m, 2H), 7.34–7.23 (m, 5H), 5.02 (ddt,
δ
157.4, 136.2, 133.3, 130.3(2C), 129.5(2C), 128.7(2C), 126.9, 125.4(2C), 83.4, 40.9, 38.4, 35.2,
31.1(3C); IR νmax 3030, 1660, 1601, 1403, 1375, 860, 750, 700 cm−1; HRMS (EI) m/z calcd
for C21H24NO2 [M + H]+ 322.1802, found 322.1808.
3.2.8. [1,10-Biphenyl]-4-yl(5-benzyl-4,5-dihydroisoxazol-3-yl)methanone (3h)
1
The compound was prepared following the general procedure. Yield 57%. H NMR
(400 MHz, CDCl3)
δ 8.25–8.19 (m, 2H), 7.69–7.68 (m, 1H), 7.67 (m, 1H), 7.65 (m, 1H),
7.63 (m, 1H), 7.49 (m, 1H), 7.47 (m, 1H), 7.46 (m, 1H), 7.43 (m, 1H), 7.35–7.33 (m, 1H),
7.32 (m, 1H), 7.30–7.28 (m, 2H), 5.08 (ddt, J = 10.8, 7.9, 6.3 Hz, 1H), 3.38 (dd, J = 17.6,
10.8 Hz, 1H), 3.17–3.09 (m, 2H), 2.98 (dd, J = 14.0, 6.5 Hz, 1H); 13C NMR (101 MHz, CDCl3)
δ
186.0, 157.9, 146.4, 139.9, 136.2, 134.6, 131.0(2C), 129.6(2C), 129.1(2C), 128.8(2C), 128.5(2C),
−1
127.5(2C), 127.1(2C), 83.7, 41.1, 38.5; IR
ν
max 3029, 1655, 1648, 1401, 1362, 842, 746, 693 cm
;
HRMS (EI) m/z calcd for C23H20NO2 [M + H]+ 342.1489, found 342.1483. These data are
consistent with the data reported in the literature [11].
3.2.9. Methyl 5-benzyl-4,5-dihydroisoxazole-3-carboxylate (3i)
The compound was prepared following the general procedure. Yield 30%.1H NMR
(400 MHz, CDCl3)
1H), 3.86 (s, 3H), 3.18 (dd, J = 17.7, 10.9 Hz, 1H), 3.11 (dd, J = 14.0, 6.1 Hz, 1H), 2.94 (dd,
J = 14.8, 5.3 Hz, 1H), 2.92–2.85 (m, 1H); 13C NMR (101 MHz, CDCl3)
161.2, 151.3, 136.0,
129.5(2C), 128.8(2C), 127.1, 84.5, 52.8, 40.8, 37.9; IR max 3418, 3032, 1717, 1584, 1449, 1366,
δ 7.32 (m, 2H), 7.26 (m, 1H), 7.22 (m, 2H), 5.06 (ddd, J = 14.7, 10.9, 6.7 Hz,
δ
ν

Molecules 2021, 26, 3491
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1265, 1126, 949, 746, 702, 582 cm−1; HRMS (EI) m/z calcd for C12H14NO3 [M + H]+ 220.0974,
found 220.0980.
3.2.10. (5-(2-Methylbenzyl)-4,5-dihydroisoxazol-3-yl)(phenyl)methanone (5a)
The compounds was prepared following the general procedure as isomers. Yield 71%. 1H
NMR (400 MHz, CDCl3)
5.19–5.08 (m, 1H), 3.42 (ddd, J = 17.5, 10.7, 0.9 Hz, 1H), 3.22 (dt, J = 12.6, 7.5 Hz, 2H), 2.99 (dd,
J = 14.3, 6.7 Hz, 1H), 2.44 (s, 3H); 13C NMR (101 MHz, CDCl3)
186.5, 157.9, 136.6, 135.9,
δ 8.30–8.23 (m, 2H), 7.66 (m, 1H), 7.57–7.49 (m, 2H), 7.30–7.23 (m, 4H),
δ
134.6, 133.6, 130.6, 130.4(2C), 130.0, 128.4(2C), 127.1, 126.3, 82.9, 38.6, 38.1, 19.8; IR νmax 3028,
2940, 1660, 1570, 750, 690 cm−1; HRMS (EI) m/z calcd for C18H18NO2 [M + H]+ 280.1332,
found 280.1335.
3.2.11. (5-(3-Methylbenzyl)-4,5-dihydroisoxazol-3-yl)(phenyl)methanone (5b)
The compound was prepared following the general procedure. Yield 66%. 1H
NMR (400 MHz, CDCl3)
(m, 1H), 7.09 (m, 3H), 5.12–5.00 (m, 1H), 3.35 (dd, J = 17.5, 10.8, 1H), 3.17–3.04 (m, 2H),
2.97–2.87 (m, 1H), 2.36 (s, 3H); 13C NMR (101 MHz, CDCl3)
186.6, 157.8, 138.4, 136.1,
δ 8.15 (d, J = 7.2 Hz, 2H), 7.59 (m, 1H), 7.47 (m, 2H), 7.22
δ
135.9, 133.7, 130.4(2C), 130.4, 128.7, 128.5(2C), 127.9, 126.6, 83.8, 40.9, 38.5, 21.5; IR νmax
3048, 2908, 1661, 1581, 862, 750, 691 cm−1; HRMS (EI) m/z calcd for C18H18NO2 [M + H]+
280.1332, found 280.1340.
3.2.12. (5-(4-Methylbenzyl)-4,5-dihydroisoxazol-3-yl)(phenyl)methanone (5c)
1
The compound was prepared following the general procedure. Yield 64%. H NMR
(400 MHz, CDCl3)
J = 11.0, 7.8 Hz, 1H), 3.35 (dd, J = 17.6, 10.8 Hz, 1H), 3.15–3.04 (m, 2H), 2.93 (dd, J = 14.0,
6.6 Hz, 1H), 2.34 (s, 3H); 13C NMR (101 MHz, CDCl3)
186.7, 157.9, 136.8, 136.1, 133.8,
δ 8.16–8.10 (m, 2H), 7.59 (m, 1H), 7.46 (m, 2H), 7.16 (m, 4H), 5.05 (dd,
δ
133.2, 130.5(2C), 129.6(2C), 129.6(2C), 128.6(2C), 83.9, 40.7, 38.5, 21.3; IR νmax 3039, 2909,
1710, 1609, 822, 741, 680 cm−1; HRMS (EI) m/z calcd for C18H18NO2 [M + H]+ 280.1332,
found 280.1339.
3.2.13. (5-(4-Methoxybenzyl)-4,5-dihydroisoxazol-3-yl)(phenyl)methanone (5d)
1
The compound was prepared following the general procedure. Yield 72%. H NMR
(400 MHz, CDCl3)
5.08–4.96 (m, 1H), 3.78 (s, 3H), 3.34 (dd, J = 17.6, 10.8 Hz, 1H), 3.14–2.99 (m, 2H), 2.91 (dd,
J = 14.1, 6.4 Hz, 1H); 13C NMR (101 MHz, CDCl3)
186.6, 158.7, 157.8, 135.9, 133.6,
δ 8.12 (m, 2H), 7.58 (m, 1H), 7.45 (m, 2H), 7.18 (m, 2H), 6.86 (m, 2H),
δ
130.6(2C), 130.4(2C), 128.4(2C), 128.1, 114.2(2C), 83.8, 55.3, 40.0, 38.3; IR νmax 3050, 2850,
1670, 1580, 820, 750, 691 cm−1; HRMS (EI) m/z calcd for C18H18NO3 [M + H]+ 296.1281,
found 296.1285.
3.2.14. (5-Octyl-4,5-dihydroisoxazol-3-yl)(phenyl)methanone (5e)
1
The compound was prepared following the general procedure. Yield 89%. H NMR
(400 MHz, CDCl3)
6.6 Hz, 1H), 3.39 (dd, J = 17.4, 10.9 Hz, 1H), 3.00 (dd, J = 17.4, 8.5 Hz, 1H), 1.79 (m, 1H),
1.69–1.57 (m, 1H), 1.45–1.19 (m, 12H), 0.88 (m, 3H); 13C NMR (101 MHz, CDCl3)
186.7,
157.9, 136.0, 133.6, 130.5(2C), 128.5(2C), 83.7, 38.9, 35.3, 31.9, 29.6, 29.5, 29.3, 25.4, 22.8,
δ 8.25–8.12 (m, 2H), 7.58 (m, 1H), 7.46 (m, 2H), 4.79 (ddt, J = 10.9, 8.4,
δ
14.2; IR ν
max 3062, 2948, 1635, 1541, 760, 710 cm−1; HRMS (EI) m/z calcd for C18H26NO2
[M + H]+ 288.1958, found 288.1961. These data are consistent with the data reported in the
literature [11].
3.2.15. (5-(Chloromethyl)-4,5-dihydroisoxazol-3-yl)(phenyl)methanone (5f)
1
The compound was prepared following the general procedure. Yield 83%. H NMR
(400 MHz, CDCl3)
J = 11.1, 7.1, 5.7, 4.5 Hz, 1H), 3.76–3.62 (m, 2H), 3.50 (dd, J = 17.9, 11.1 Hz, 1H), 3.36 (dd,
J = 17.9, 7.1 Hz, 1H); 13C NMR (101 MHz, CDCl3)
186.0, 157.5, 135.7, 133.9, 130.5(2C),
δ 8.24–8.14 (m, 2H), 7.66–7.55 (m, 1H), 7.53–7.44 (m, 2H), 5.05 (dddd,
δ

Molecules 2021, 26, 3491
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128.6(2C), 81.2, 45.1, 37.7; IR
ν
max 3025, 1660, 1580, 700 cm−m; HRMS (EI) m/z calcd for
C11H11NO2Cl [M + H]+ 224.0473, found 224.0466. These data are consistent with the data
reported in the literature [11].
3.2.16. (3a,4,5,6,7,7a-Hexahydrobenzo[d]isoxazol-3-yl)(phenyl)methanone (5g)
1
The compound was prepared following the general procedure. Yield 54%. H NMR
(400 MHz, CDCl3)
1H), 3.46–3.38 (m, 1H), 2.20 (dd, J = 15.2, 3.5 Hz, 1H), 2.11–2.01 (m, 1H), 1.82 (tt, J = 15.3,
4.7 Hz, 1H), 1.65–1.52 (m, 3H), 1.35–1.24 (m, 2H); 13C NMR (101 MHz, CDCl3)
187.0,
max 3060, 2940,
δ 8.18 (m, 2H), 7.61–7.56 (m, 1H), 7.47 (m, 2H), 4.59 (dt, J = 7.9, 3.9 Hz,
δ
163.8, 136.4, 133.6, 130.4(2C), 128.5(2C), 82.3, 44.3, 25.6, 25.0, 21.7, 19.9; IR
ν
1660, 1550, 747, 704 cm−m; HRMS (EI) m/z calcd for C14H16NO2 [M + H]+ 230.1176, found
230.1182. These data are consistent with the data reported in the literature [11].
3.2.17. Ethyl 3-benzoyl-4,5-dihydroisoxazole-5-carboxylate (7a)
1
The compound was prepared following the general procedure. Yield 68%. H NMR
(400 MHz, CDCl3)
δ
8.33–8.28 (m, 2H), 7.71–7.65 (m, 1H), 7.59–7.51 (m, 2H), 7.43 (s, 1H),
184.7,
max 3058, 2945,
4.48 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3)
δ
162.3, 161.3, 156.4, 135.3, 134.6, 130.9(2C), 128.9(2C), 110.2, 62.8, 14.3; IR
ν
1655, 1545, 740, 702 cm−m; HRMS (EI) m/z calcd for C13H14NO2 [M + H]+ 248.0917,
found 248.0912.
3.2.18. (5-Butylisoxazol-3-yl)(phenyl)methanone (7b)
1
The compound was prepared following the general procedure. Yield 64%. H NMR
(400 MHz, CDCl3)
2H), 1.73 (dt, J = 15.2, 7.5 Hz, 2H), 1.42 (dq, J = 14.6, 7.4 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H);
13C NMR (101 MHz, CDCl3)
186.2, 174.8, 161.9, 135.9, 133.9, 130.7(2C), 128.6(2C), 101.7,
29.6, 26.4, 22.3, 13.8. IR
δ 8.29 (m, 2H), 7.61 (m, 1H), 7.49 (m, 2H), 6.51 (ms, 1H), 2.82 (t, J = 7.6 Hz,
δ
ν
max 3075, 2950, 2875, 1670, 1590, 740, 690 cm−m; HRMS (EI) m/z
calcd for C14H16NO2 [M + H]+ 230.1176, found 230.1171. These data are consistent with
the data reported in the literature [11].
4. Conclusions
Isoxazolines and isoxazoles are biologically active molecules. The development and
improvement of syntheses directed towards isoxazolines and isoxazoles is a continuing
pursuit. Herein, we have developed an effective cycloaddition of various α-nitroketones
with alkenes or alkynes by using the cheap base chloramine-T. The low cost and ease of
handling of this moderate base are its outstanding properties. The cycloaddition described
in this study is an integrated approach for synthesizing isoxazolines and isoxazoles. We are
currently investigating other ways to integrate isoxazolines.
Supplementary Materials: The following are available online. The Supplementary Materials contain
experimental protocols, analytical data for products and NMR spectra.
Author Contributions: X.P., Y.M. and J.W.: conceptualization; X.P. and X.X.: methodology; X.P.,
X.X., Y.Z. and K.Z.: data analysis; X.P., Y.M., X.L. and Y.L.: original manuscript writing; X.P., X.Y.
and J.W.: revision and supervision. All authors have read and agreed to the published version of
the manuscript.
Funding: This study was supported by The Open Project of Key Laboratory of Xinjiang Phytomedicine
Resource and Utilization, Ministry of Education (grant numbers 20150203 and XPRU202004); Na-
tional Science and Technology Major Projects for New Drug Development of China (grant number
2018ZX09735-005); and Youth Innovative Talent Cultivation Projects of Shihezi University (grant
number CXPY202005).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.

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Data Availability Statement: The data presented in this study are available in the article and
Supplementary Materials.
Acknowledgments: We would like to thank Lei Liu and Jinchuan Zhou (Shandong University) for
their help with the experimental design and writing of the manuscript. Liang Guo and Pengyu Dai
(Traditional Chinese Medicine University of Guangzhou) are acknowledged for assistance with NMR.
Conflicts of Interest: The authors declare no conflict of interest.
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