One-pot synthesis of novel N,N-bis(isoxazol-5-yl)methyl tertiary arylamines via sequential diprop-3-ynylation and 1,3-dipolar cycloaddition from primary amines

Article abstract of DOI:10.1177/1747519819868203

A simple and efficient one-pot multicomponent approach for the synthesis of tertiary arylamines bearing N,N-bis(isoxazol-5-yl)methyl groups is developed through reactions including sequential diprop-3-ynylation of primary amines with propargyl bromide in

Full text of DOI:10.1177/1747519819868203

868203CHL0010.1177/1747519819868203Journal of Chemical ResearchZhang et al.
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Research Paper
Journal of Chemical Research
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One-pot synthesis of novel N,N-bis(isoxazol-5-yl)
methyl tertiary arylamines via sequential
diprop-3-ynylation and 1,3-dipolar cycloaddition
from primary amines
https://doi.org/10.1177/1747519819868203
DOI: 10.1177/1747519819868203
journals.sagepub.com/home/chl
Xiao-Lan Zhang1,2, Mei-Hong Wei2, Shou-Ri Sheng2
and Xiao-Ling Liu2
Abstract
A simple and efficient one-pot multicomponent approach for the synthesis of tertiary arylamines bearing N,N-bis(isoxazol-
5-yl)methyl groups is developed through reactions including sequential diprop-3-ynylation of primary amines with
propargyl bromide in the presence of calcium hydride in N,N-dimethylformamide, and 1,3-dipolar cycloaddition with
nitrile oxides generated in situ from hydroximyl chlorides in DMF-Et3N. This protocol provides advantages such as high
regioselectivity, easy operation, and moderate-to-good product yields with a wide substrate scope under mild conditions.
Keywords
1,3-dipolar cycloaddition, diprop-3-ynylation, nitrile oxides, N,N-bis(isoxazol-5-yl)methyl tertiary arylamines, one-pot
procedure
Date received: 08 March 2019; accepted: 15 July 2019
Copies of 1H NMR and 13C NMR spectra of all compounds
of isoxazoles, the major routes typically involve 1,3-dipolar
Introduction
cycloadditions of alkenes/alkynes and nitrile oxides.7–11
Amines and isoxazoles are examples of nitrogen-contain-
Introduction of the isoxazole scaffold into amine molecules
ing compounds occupying a significant position in many
represents a meaningful research area for the exploration of
fields such as organic chemistry, natural products, materials
biologically active compounds and pharmaceutical agents.
science, and pharmaceuticals. A secondary or tertiary
As far as we know, several synthetic methods have been
amino group is often embedded as a structural motif in vari-
developed for the construction of isoxazolyl-containing
ous biologically active compounds, which are important
intermediates in the synthesis of pharmaceutically active
substances, dyes, and fine chemicals.1 The formation of
1College of Chemistry and Chemical Engineering, Shangrao Normal
C–N bonds between primary amines and organic halides
has been applied as the major method to prepare secondary
and tertiary amines.2–4 Isoxazoles are important five-mem-
bered heteroaromatic molecules because of their wide
applications in organic synthesis, pharmacy, chemistry,
biologically active molecules, and advanced organic mate-
rials.5,6 Among various synthetic methods for the synthesis
University, Shangrao, P. R. China
2College of Chemistry and Chemical Engineering, Jiangxi Normal
University, Nanchang, P. R. China
Corresponding author:
Xiao-Ling Liu, College of Chemistry and Chemical Engineering, Jiangxi
Normal University, Nanchang 330022, P. R. China.
Email: liuxiaoling@jxnu.edu.cn

2
Journal of Chemical Research 00(0)
Scheme 1. Optimization of the one-pot reaction from aniline 1a.
primary,12–16 secondary, and tertiary amines.17–21 However,
there are very few reports on the synthesis of tertiary ary-
lamines with isoxazolyl groups.21 Therefore, the develop-
ment of simple, efficient, and economical protocols for the
synthesis of isoxazole-containing tertiary arylamines using
readily accessible starting material will be of great use. It is
well known that multicomponent reactions (MCRs) are
very useful synthetic methods because they allow rapid and
convergent construction of complex molecules without the
isolation of intermediates.22–24 Moreover, this process is
especially useful when the reaction intermediates are unsta-
ble and difficult to isolate. Obviously, in order to construct
isoxazole scaffolds, the generation of terminal alkynes in
situ from suitable precursors, followed by reaction with
nitrile oxides in a one-pot process, would avoid the difficul-
ties associated with the volatile nature of terminal alkynes.
Herein, we report a highly regioselective one-pot MCR
protocol for the facile synthesis of N,N-bis(isoxazol-5-yl)
methyl tertiary arylamines involving in situ generation of
terminal alkynes, N,N-di(prop-2-yn-1-yl) arylamines via
diprop-3-ynylation of primary amines with propargyl bro-
mide and 1,3-dipolar cycloaddition with nitrile oxides
under mild reaction conditions.
Table 1. Optimization of the diprop-2-ynylation conditions.a
Entry
Solvent
Base (mol%)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
DMF
K2CO3 (20)
K2CO3 (20)
K2CO3 (20)
K2CO3 (20)
K2CO3 (20)
Et3N (20)
DIPEA (20)
CaH2 (20)
CaH2 (30)
CaH2 (40)
CaH2 (40)
CaH2 (50)
6
6
6
6
6
6
6
6
6
6
8
8
80c
78
65
68
60
72
82
85
90
92
95
96
DMSO
Dioxane
MeCN
THF
DMF
DMF
DMF
DMF
DMF
DMF
9
10
11
12
DMF
DMF: N,N-dimethylformamide; DMSO: dimethylsulfoxide;THF:
tetrahydrofuran; DIPEA: N,N-diisopropylethylamine.
aUnless otherwise noted, all reactions were performed with 1.0 mmol
of aniline, 4.0 mmol of propargyl bromide, and 5 mL of solvent at room
temperature.
bIsolated yield after column chromatography, based on aniline.
cCited in Ji et al.25
In our initial attempt involving treatment of the reaction
system with 2 equiv. of 3a without adding another base for
6 h at room temperature resulted in 4aa in only 35% iso-
lated yield. A further attempt to run the [3 + 2] cycloaddi-
tion reaction at an elevated temperature did not work well.
However, when 3 equiv. of Et3N were added to the reaction
system, the corresponding product 4aa was isolated in 72%
yield. Indeed, the use of 2.5 equiv. of 3a was found to
increase the yield to 76%. In addition, it was found that
using additional Et3N and 3a did not increase the yield or
shorten the reaction time. To our delight, when the reaction
proceeded at 65 °C for 3 h, the desired product 4aa was
isolated in 82% yield as the exclusive product.
The structure of 4aa was characterized by nuclear mag-
netic resonance (NMR) spectroscopic data. In the 1H NMR
spectrum of 4aa, a characteristic singlet appeared at 6.95
ppm due to the isoxazolyl C5–H proton and a singlet at 4.61
ppm for ArNCH2 along with other protons. In the 13C NMR
spectrum of 4aa, the ArNCH2 carbon appeared at 48.23
ppm, carbons of C4 and C5 of the triazole ring appeared at
102.34 and 169.85 ppm, respectively, along with other car-
bons at expected chemical shifts.
Results and discussion
Initially, the diprop-3-ynylation conditions, such as the
base and solvent, for the reaction of aniline (1a) with prop-
argyl bromide were investigated (Scheme 1). It was
reported that N,N-di(prop-2-yn-1-yl)aniline (2a) could be
obtained in 80% yield by reaction of 1a with propargyl bro-
mide in N,N-dimethylformamide (DMF) at room tempera-
ture in the presence of potassium carbonate.25 Encouraged
by this positive result, other polar solvents and bases were
screened (Table 1, entries 2–8). Clearly, good yields of 2a
in the model reaction were obtained in DMF and dimethyl-
sulfoxide (DMSO) in the presence of different bases such
as potassium carbonate, N,N-diisopropylethylamine
(DIPEA), and calcium hydride (CaH2) (Table 1, entries 1,
2, 7, and 8). Among them, CaH2 was shown to be a very
effective base for the reaction (Table 1, entry 8). After a
considerable number of experiments, 2a was produced in
95% yield when the reaction was carried out in DMF at
room temperature in the presence of CaH2 (40 mol%) for 8
h (Table 1, entry 11).
Finally, the optimized reaction conditions were extended
to a variety of primary aromatic amines and hydroximyl
chlorides with different substituents (Scheme 2), and the
corresponding results were summarized in Table 2. As
observed in Table 2, for most of the examined substrates, the
reactions were performed smoothly and the corresponding
tertiary arylamines containing N,N-bis(isoxazol-5-yl)methyl
groups were obtained. It is noteworthy that no significant
Second, after completion of the diprop-3-ynylation, the
excess propargyl bromide was removed by vacuum distilla-
tion. Without further isolation and purification of interme-
diate 2a, the subsequent [3 + 2] cycloaddition reaction
with phenyl nitrile oxide, generated in situ from
N-hydroxybenzimidoyl chloride (3a), affording N,N-bis[(3-
phenylisoxazol-5-yl)methyl]aniline (4aa) was investigated.

Zhang et al.
3
Scheme 2. Access to N,N-bis(isoxazol-5-yl)methyl tertiary arylamines 4 by a diprop-3-ynylation and 1,3-dipolar cycloaddition
sequence.
Table 2. Sequential transformation of various arylamines and chlorooximes into N,N-bis(isoxazol-5-yl)methyl tertiary arylamines 4.a
Entry
Ar (1)
R (3)
Product (4)
Yield (%)b
1
2
3
4
5
6
7
8
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (3a)
4aa
4ab
4ac
4ad
4ba
4bb
4bc
4ca
4cc
4cd
4ce
4cf
4cg
4dh
4di
4aj
4ak
82
70
76
71
81
72
75
80
78
72
86
84
88
62
45
0
2-CH3C6H4 (3b)
3-CH3C6H4 (3c)
3-CH3OC6H4 (3d)
C6H5 (3a)
2-CH3C6H4 (3b)
3-CH3C6H4 (3c)
C6H5 (3a)
3-CH3C6H4 (3c)
3-CH3OC6H4 (3d)
4-ClC6H4 (3e)
4-BrC6H4 (3f)
4-NO2C6H4 (3g)
C6H5CH2 (3h)
CH3CH2CH2 (3i)
4-HOC6H4 (3j)
4-(Me2N)C6H4 (3k)
3-CH3C6H4 (1b)
3-CH3C6H4 (1b)
3-CH3C6H4 (1b)
2-CH3C6H4 (1c)
2-CH3C6H4 (1c)
2-CH3C6H4 (1c)
2-CH3C6H4 (1c)
2-CH3C6H4 (1c)
2-CH3C6H4 (1c)
4-ClC6H4 (1d)
4-ClC6H4 (1d)
C6H5 (1a)
9
10
11
12
13
14
15
16
17
C6H5 (1a)
0
aAll reactions were performed in 5 mL of DMF with 1.0 mmol of primary aromatic amine, 4.0 mmol of propargyl bromide, and 3.0 mmol of the
chlorooxime.
bIsolated yield based on the primary aromatic amine after column chromatography.
difference in reactivity was observed for the examined ary- does not require isolation of the N,N-dipropargylated
lamines substituted with 3-Me, 2-Me, and 4-Cl groups on arylamine intermediates, and has considerable advantages
the benzene rings (Table 2, entries 5–15). In general, aro- in terms of its use of easily available substrates, its mild
matic nitrile oxides bearing electron-withdrawing groups reaction conditions, its simple operation, and the moderate
such as chloro, bromo, and nitro (3e–g), as well as electron- to good yields obtained.
donating groups such as methyl and methoxy (3b–d), and
even N-hydroxy-2-methylbenzimidoyl chloride 3b bearing
a hindered methyl substituent afforded the desired products
Experimental
in moderate to good yields (Table 2, entries 2–4, 6, 7, and
9–13). It was also observed that electron-deficient aromatic
nitrile oxides were preferred over electron-rich nitrile oxides
in this MCR. However, other electron-rich benzonitrile
oxides such as 4-hydroxy-benzonitrile oxide and 4-(N,N-
dimethylamino)benzonitrile oxide did not participate in this
reaction (Table 2, entries 16 and 17). In addition, phenylace-
tonitrile oxide produced the corresponding product in mod-
erate yield (Table 2, entry 14), while the aliphatic nitrile
oxide n-butyl-nitrile oxide gave a low yield of the product
4di (Table 2, entry 15).
Melting points were measured with a Beijing-Taike X-4
1
apparatus and were uncorrected. H NMR and 13C NMR
spectra were recorded on an Avance-Bruker 400 MHz
NMR spectrometer, operating at 400 and 100 MHz,
respectively. Chemical shifts are reported in ppm relative
to TMS or the deuterated solvent as the internal reference.
Fourier transform infrared (FTIR) analyses were per-
formed with a PerkinElmer SP One FTIR spectrophotom-
eter. Microanalyses were performed with a Carlo Erba
1106 Elemental Analyzer. Hydroximyl chlorides 3a−k are
known compounds and were prepared from the corre-
sponding readily available aldehydes via the reported
method.26 Other reagents and solvents were purchased
from commercial suppliers and were used as received
Conclusion
In summary, a facile and efficient, one-pot method for the without further purification. All experiments were carried
preparation of N,N-bis(isoxazol-5-yl)methyl tertiary ary- out in air. Analytical thin-layer chromatography (TLC)
lamines from primary amines, propargyl bromide, and was carried out on Merck 0.2 mm silica gel 60 F254 ana-
hydroximyl chlorides has been developed. The procedure lytical aluminum plates, and the products were visualized

4
Journal of Chemical Research 00(0)
by UV detection. Column chromatography was performed 6.55 (s, 2H), 4.69 (s, 4 H), 3.70 (s, 6H). 13C NMR (100
on Merck silica gel 60 (250–400 mesh).
MHz, CDCl3): δ 169.19, 161.21, 158.34, 147.18, 131.19,
129.53, 128.86, 124.16, 119.25, 117.54, 115.30, 113.84,
104.10, 55.68, 47.50. IR (KBr): ν 3430, 3045, 2927, 2848,
1605, 1508, 1248, 1178, 1030, 897, 752, 694 cm−1. Anal.
calcd for C28H25N3O4: C, 71.96; H, 5.35; N, 8.99; found: C,
71.85; H, 5.46; N, 8.92%.
Preparation of N,N-bis(isoxazol-5-yl)
methyl tertiary arylamines 4aa–di; general
procedure
To a stirred solution of primary aromatic amine 1 (1.0
mmol) in DMF (5 mL) was added CaH2 (20 mg, 0.4 mmol) N,N-Bis[(3-phenylisoxazol-5-yl)methyl]-3-methylaniline
1
and propargyl bromide (480 mg, 4.0 mmol). The resulting (4ba). Yellow solid, m.p. = 145–146 °C. H NMR (400
mixture was stirred at room temperature until complete MHz, CDCl3): δ 7.78–7.75 (m, 5H), 7.44–7.43 (m, 9H),
conversion of the amine into the N,N-di(prop-2-yn-1-yl) 6.47 (s, 2H), 4.50 (s, 4H), 2.52 (s, 3H). 13C NMR (100
arylamine 2 had occurred (as monitored by TLC). The MHz, CDCl3): δ 169.43, 162.42, 146.23, 135.69, 133.91,
excess of propargyl bromide was then removed under 130.83, 130.11, 128.90, 127.59, 126.83, 125.88, 122.05,
reduced pressure. Next, hydroximyl chloride 3 (2.5 mmol) 101.53, 48.52, 19.21. IR (KBr): ν 3031, 2972, 2870, 1604,
and Et3N (3.0 mmol) were added to the reaction mixture, 1495, 1385, 1288, 1125, 862, 765, 700 cm−1. Anal. calcd
which was warmed to 65 °C and stirred until completion of for C27H23N3O2: C, 76.94; H, 5.50; N, 9.97; found: C,
the reaction (as monitored by TLC). The resulting solution 76.82; H, 5.64; N, 9.91%.
was filtered through a short pad of Celite 545 and the sol-
vent was removed under reduced pressure. The crude prod- N,N-Bis{[(3-(o-tolyl)isoxazol-5-yl)]methyl}-3-methylaniline
1
uct was purified by column chromatography on silica gel (4bb). Yellow solid, m.p. = 62–63 °C. H NMR (400
(petroleum ether/EtOAc = 10:1) to afford the target com- MHz, CDCl3): δ 7.73–7.70 (m, 2H), 7.32–7.20 (m, 8H),
pound 4.
6.78 (s, 2H), 6.33 (s, 2H), 4.66 (s, 4H), 2.44 (s, 6H), 2.34 (s,
3H). 13C NMR (100 MHz, CDCl3): δ 169.04, 163.12,
N,N-Bis[(3-phenylisoxazol-5-yl)methyl]aniline (4aa). Yellow 146.21, 136.80, 133.47, 131.10, 130.93, 129.53, 129.42,
solid, m.p. = 112–113 °C. 1H NMR (400 MHz, CDCl3): δ 128.86, 126.00, 125.05, 117.12, 113.57, 103.51, 47.65,
7.84–7.82 (m, 5H), 7.50–7.48 (m, 8H), 7.33 (s, 2H), 6.95 20.56, 19.21. IR (KBr): ν 3040, 2978, 2875, 1603, 1489,
(s, 2H), 4.61 (s, 4H). 13C NMR (100 MHz, DMSO-d6): δ 1385, 1287, 1122, 857, 768 cm−1. Anal. calcd for
169.85, 162.17, 144.93, 132.19, 130.67, 129.32, 128.90, C29H27N3O2: C, 77.48; H, 6.05; N, 9.35; found: C, 77.58; H,
128.17, 127.05, 126.08, 102.34, 48.23. IR (KBr): ν 3050, 6.16; N, 9.43%.
2965, 1607, 1466, 1368, 1269, 1136, 1065, 742 cm−1. Anal.
calcd for C26H21N3O2: C, 76.64; H, 5.19; N, 10.31; found: N,N-Bis{[(3-(m-tolyl)isoxazol-5-yl)methyl]-3-methylaniline
1
C, 76.72; H, 5.29; N, 10.35%.
(4bc). Yellow solid, m.p. = 86–87 °C. H NMR (400
MHz, CDCl3): δ 7.51–7.45 (m, 5H), 7.25–7.07 (m, 6H),
N,N-Bis[(3-(o-tolyl)isoxazol-5-yl)methyl]aniline (4ab). Yellow 6.86–6.78 (m, 1H), 6.37 (s, 2H), 4.38 (s, 4H), 2.43 (s, 3H),
solid, m.p. = 53–55 °C. H NMR (400 MHz, CDCl3): δ 2.30 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 169.27,
1
7.44–7.34 (m, 4H), 7.26–7.13 (m, 7H), 7.06 (dd, J = 8.6, 162.52, 144.55, 138.67, 136.07, 131.43, 130.86, 128.81,
2.4 Hz, 1H), 6.94 (d, J = 8.6 Hz, 1H), 6.23 (s, 2H), 4.44 (s, 128.70, 127.58, 127.41, 126.23, 123.98, 122.07, 101.60,
4H), 2.33 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 168.29, 48.49, 21.37. IR (KBr): ν 3037, 2974, 2883, 1606, 1491,
163.05, 144.29, 136.87, 131.28, 131.13, 130.61, 129.42, 1382, 1285, 1126, 865, 772, 765 cm−1. Anal. calcd for
128.49, 127.72, 126.04, 125.14, 104.26, 48.46, 21.10. IR C29H27N3O2: C, 77.48; H, 6.05; N, 9.35; found: C, 77.60; H,
(KBr): ν 3035, 2972, 2869, 1602, 1488, 1384, 1291, 1125, 6.14; N, 9.44%.
751 cm−1. Anal. calcd for C28H25N3O2: C, 77.25; H, 5.75;
N, 9.65; found: C, 77.32; H, 5.89; N, 9.73%.
N,N-Bis[(3-phenylisoxazol-5-yl)methyl]-2-methylaniline
(4ca). Yellow solid; m.p. = 127–128 °C. H NMR (400
1
N,N-Bis[(3-(m-tolyl)isoxazol-5-yl)methyl]aniline (4ac). Yel- MHz, CDCl3): δ 7.76–7.53 (m, 4H), 7.52–7.51 (m, 1H),
low solid, m.p. = 83–84 °C. 1H NMR (400 MHz, CDCl3): 7.43–7.42 (m, 6H), 7.21 (d, J = 1.8 Hz, 1H), 7.08 (dd, J
δ 7.57–7.51 (m, 4H), 7.30–7.20 (m, 6H), 6.87–6.82 (m, = 8.6, 2.0 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.38 (s, 2H),
3H), 6.43 (s, 2H), 4.72 (s, 4H), 2.35 (s, 6H). 13C NMR (100 4.33 (s, 4H), 2.41 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
MHz, CDCl3): δ 169.86, 162.68, 147.13, 138.68, 130.90, 169.42, 162.37, 146.34, 136.42, 131.27, 130.94, 130.41,
129.60, 128.84, 128.68, 127.47, 124.00, 119.09, 113.59, 130.09, 128.90, 126.81, 126.60, 123.87, 101.55, 49.03,
100.79, 47.48, 21.37. IR (KBr): ν 3033, 2975, 2872, 1605, 17.96. IR (KBr): ν 3033, 2977, 2886, 1604, 1500, 1384,
1490, 1386, 1290, 1127, 757, 698 cm−1. Anal. calcd for 1285, 1127, 745 cm−1. Anal. calcd for C27H23N3O2: C,
C28H25N3O2: C, 77.25; H, 5.75; N, 9.65; found: C, 77.38; H, 76.94; H, 5.50; N, 9.97; found: C, 76.85; H, 5.62; N,
5.90; N, 9.71%.
8.90%.
N,N-Bis{[3-(3-methoxyphenyl)isoxazol-5-yl]methyl}aniline N,N-Bis{[3-(m-tolyl)isoxazol-5-yl]methyl}-2-methylaniline
1
1
(4ad). Yellow solid, m.p. = 65–67 °C. H NMR (400 (4cc). Yellow solid, m.p. = 57–58 °C. H NMR (400
MHz, CDCl3): δ 7.29–7.04 (m, 8H), 6.83–6.73 (m, 5H), MHz, CDCl3): δ 7.73–7.70 (m, 2H), 7.55–7.52 (m, 3H),

Zhang et al.
5
7.32 (t, J = 7.6 Hz, 2H), 7.23 (dd, J = 9.9, 4.9 Hz, 3H), 4-Chloro-N,N-bis[(3-benzylisoxazol-5-yl)methyl]aniline
7.08 (dd, J = 8.5, 2.4 Hz, 1H), 6.93 (d, J = 8.5 Hz, 1H), (4dh). Yellow solid, m.p. = 97–99 °C. δ 7.35–7.33 (m,
6.37 (s, 2H), 4.33 (s, 4H), 2.41 (s, 3H), 2.39 (s, 6H). 13C 6H), 7.19–7.16 (m, 4H), 7.08 (d, J = 8.6 Hz, 2H), 6.75 (d,
NMR (100 MHz, CDCl3): δ 169.27, 162.47, 146.39, J = 8.6 Hz, 2H), 6.30 (s, 2H), 4.63 (s, 4H), 4.29 (s, 4H). 13C
138.67, 131.38, 131.25, 130.68, 129.23, 128.95, 128.86, NMR (100 MHz, CDCl3): δ 170.27, 161.52, 147.96,
128.82, 127.39, 126.59, 123.95, 101.60, 49.02, 21.37, 134.66, 131.15, 129.12, 128.73, 127.88, 123.00, 115.17,
19.20. IR (KBr): ν 3033, 2975, 2887, 1604, 1490, 1384, 101.22, 47.22, 32.42. IR (KBr): ν 3034, 2970, 2785, 1603,
1282, 1122, 862, 770, 745 cm−1. Anal. calcd for C29H27N3O2: 1490, 1235, 1026, 906, 835, 760, 699 cm−1. Anal. calcd for
C, 77.48; H, 6.05; N, 9.35; found: C, 77.61; H, 6.16; N, C28H24ClN3O2: C, 71.56; H, 5.15; N, 8.94; found: C, 71.42;
9.47%.
H, 5.24; N, 8.86%.
N,N-Bis{[3-(3-methoxyphenyl)isoxazol-5-yl]methyl}-2-methyl- 4-Chloro-N,N-bis[(3-propylisoxazol-5-yl)methyl]aniline
1
aniline (4cd). Yellow solid, m.p. = 65–66 °C. H NMR (4di). Yellow liquid. δ 7.56 (d, J = 8.8 Hz, 2H), 7.01 (d, J
(400 MHz, CDCl3): δ 7.32 (d, J = 8.9 Hz, 3H), 7.23–7.21 = 8.8 Hz, 2H), 6.26 (s, 2H), 4.38 (s, 4H), 2.37 (t, J = 7.2
(m, 4H), 7.11 (d, J = 7.5 Hz, 1H), 7.04 (t, J = 7.1 Hz, 2H), Hz, 4H), 1.68–1.67 (m, 4H), 1.11 (t, J = 7.2 Hz, 6H). 13
C
6.89 (dd, J = 8.9, 3.1 Hz, 2H), 6.56 (s, 2H), 4.39 (s, 4H), NMR (100 MHz, CDCl3): δ 169.67, 160.92, 146.80,
3.78 (s, 6H), 2.43 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 132.46, 128.94, 115.22, 100.76, 47.02, 30.07, 19.78, 13.89.
169.17, 160.98, 158.33, 147.74, 134.46, 131.30, 130.94, IR (film): ν 3034, 2962, 2932, 1608, 1455, 1016, 760, 698
128.82, 126.62, 125.27, 124.17, 122.69, 117.44, 115.23, cm−1. Anal. calcd for C18H24ClN3O2: C, 61.79; H, 6.91; N,
104.78, 55.66, 49.14, 18.03. IR (KBr): ν 3028, 2951, 1602, 12.01; found: C, 61.93; H, 6.80; N, 12.11%.
1467, 1238, 1031, 823, 647 cm−1. Anal. calcd for
C29H27N3O4: C, 72.33; H, 5.65; N, 8.73; found: C, 72.16; H, Declaration of conflicting interests
5.77; N, 8.85%.
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
N,N-Bis{[3-(4-chlorophenyl)isoxazol-5-yl]methyl}-2-methylani-
1
line (4ce). Yellow solid, m.p. = 123–124 °C. H NMR
(400 MHz, CDCl3): δ 7.73–7.71 (m, 2H), 7.66 (d, J = 8.8
Hz, 4 H), 7.43–7.40 (m, 2H), 7.38 (d, J = 8.4 Hz, 4H), 6.34
(s, 2H), 4.36 (s, 4H), 2.45 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 170.18, 161.37, 147.90, 136.05, 131.54, 130.93,
129.14, 128.85, 128.04, 126.68, 125.33, 122.32, 101.25,
Funding
The author(s) disclosed receipt of the following financial sup-
port for the research, authorship, and/or publication of this arti-
cle: We are grateful to the Research Program of Jiangxi Province
Department of Education (Nos GJJ170934, GJJ160289, and
GJJ11380), the Opening Foundation of National Research
49.28, 19.20. IR (KBr): ν 3036, 2956, 2788, 1604, 1495, Center for Carbohydrate Synthesis (No. GJDTZX-KF-201414),
1386, 1235, 1028, 905, 834, 760, 705 cm−1. Anal. calcd for
and the Opening Foundation of the Key Laboratory of Functional
Small Organic Molecules of Ministry of Education (No.
C27H21N3Cl2O2: C, 66.13; H, 4.32; N, 8.57; found: C, 66.25;
KLFS-KF-201411) for the financial support.
H, 4.41; N, 8.49%.
ORCID iD
N,N-Bis{[3-(4-bromophenyl)isoxazol-5-yl]methyl}-2-methyl-
aniline (4cf). Yellow solid, m.p. = 132–133 °C. 1H NMR
(400 MHz, CDCl3): δ 7.73–7.70 (m, 2H), 7.60–7.50 (m,
8H), 7.05 (dd, J = 8.0, 19.6 Hz, 2H), 6.34 (s, 2H), 4.35 (s,
4H), 2.45 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 170.21,
161.43, 147.90, 132.20, 131.54, 130.92, 128.56, 127.81,
126.68, 125.34, 124.32, 122.32, 101.21, 49.29, 19.20. IR
(KBr): ν 3036, 2956, 2788, 1604, 1495, 1382, 1233, 1073,
905, 832, 757, 695 cm−1. Anal. calcd for C27H21N3Br2O2:
C, 55.98; H, 3.65; N, 7.25; found: C, 55.85; H, 3.76; N,
7.16%.
Xiao-Ling Liu
https://orcid.org/0000-0002-1733-9946
Supplemental material
Supplemental material for this article is available online.
References
1. Lawrence SA. Amines: synthesis, properties and applica-
tions. Cambridge: Cambridge University Press, 2004.
2. Gagewy J. Chem Rev 2008; 108: 5227.
3. Karaki F, Ohgane K, Fukuda H, et al. Bioorg Med Chem
2014; 22: 3587.
4. Corpet M and Gosmini C. Synthesis 2014; 46: 2258.
5. Grünanger P and Vita-Finzi P. Isoxazoles: The Chemistry of
Heterocyclic Compounds. New York: John Wiley, 1991.
6. Pinho eM and Teresa MVD. Recent advances on the syn-
thesis and reactivity of isoxazoles. Curr Org Chem 2005; 9:
925–958.
7. Padwa A (ed.). 1,3-Dipolar Cycloaddition Chemistry. New
York: John Wiley, 1984.
8. Heaney F. Eur J Org Chem 2012; 3043.
N,N-Bis{[3-(4-nitrophenyl)isoxazol-5-yl]methyl}-2-methylani-
line (4cg). Yellow solid, m.p. = 153–154 °C. H NMR
1
(400 MHz, CDCl3): δ 8.27 (d, J = 8.8 Hz, 4H), 7.73–7.68
(m, 4H), 7.43 (d, J = 8.8 Hz, 4H), 6.45 (s, 2H), 4.37 (s,
4H), 2.51 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 170.23,
162.33, 148.34, 147.93, 134.45, 131.58, 130.96, 128.85,
128.04, 126.69, 124.33, 122.35, 101.28, 49.31, 19.29. IR
(KBr): ν 3072, 2935, 2855, 1604, 1510, 1495, 1445, 1382,
1345, 1135, 1108, 925, 850 cm−1. Anal. calcd for
C27H21N5O6: C, 63.40; H, 4.14; N, 13.69; found: C, 63.25;
H, 4.26; N, 13.57%.
9. Hu F and Szostak M. Adv Synth Catal 2015; 357: 2583.
10. Singh MS, Chowdhury S and Koley S. Tetrahedron 2016;
72: 1603.

6
Journal of Chemical Research 00(0)
11. Morita T, Yugandar S, Fuse S, et al. Tetrahedron Lett 2018; 19. Samai S, Chanda T, Ila H, et al. Eur J Org Chem 2013; 4026.
59: 1159.
20. Averina EB, Vasilenko DA, Samoilichenko YV, et al.
Synthesis 2014; 46: 1107.
21. Andreev MV, Medvedeva AS, Larina LL, et al. Mendeleev
Commun 2017; 27: 175.
12. Elnagdi MH, Elmoghayar MRH, Hafez EAA, et al. J Org
Chem 1975; 40: 2604.
13. Bourbeau MP and Rider JT. Org Lett 2006; 8: 3679.
14. Wenli M, Peterson B, Keelson A, et al. J Comb Chem 2009; 22. Zhu J and Bienaymé H (eds). Multicomponent Reactions.
11: 697.
Weinheim: Wiley, 2005.
15. Johnson L, Powers J, Ma F, et al. Synthesis 2013; 45: 171.
23. Döling A, Wang W and Wang K. Chem Rev 2012; 112:
16. Shimkin KW, Gildner PG and Watson DA. Org Lett 2016;
3083.
18: 988.
24. Rotstein BH, Zaretsky S, Rai V, et al. Chem Rev 2014; 114:
17. Moore JE, Spinks D and Harritya JPA. Tetrahedron Lett
8323.
2004; 45: 3189.
25. Ji W-Q, Li P-H, Yang S, et al. Chem Commun 2017; 53:
8482.
18. Girardin M, Alsabeh PG, Lauzon S, et al. Org Lett 2009; 11:
1159.
26. Dubrovskiy AV and Larock RC. Org Lett 2010; 12: 1180.