Catalyst- and solvent-free mechanochemical synthesis of isoxazoles from N-hydroxybenzimidoyl chlorides and enamino carbonyl compounds

Article abstract of DOI:10.1016/j.tet.2018.09.044

A regioselective, solvent-free and catalyst-free synthesis of isoxazoles has been successfully developed under ball milling conditions. Milling the mixtures of N-hydroxybenzimidoyl chlorides and enamino carbonyl compounds in a ball mill at a frequency of

Full text of DOI:10.1016/j.tet.2018.09.044

Accepted Manuscript
Catalyst- and solvent-free mechanochemical synthesis of isoxazoles from N-
hydroxybenzimidoyl chlorides and enamino carbonyl compounds
Hui Xu, Guang-Peng Fan, Zi Liu, Guan-Wu Wang
PII:
S0040-4020(18)31140-2
10.1016/j.tet.2018.09.044
TET 29816
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 13 July 2018
Revised Date: 6 September 2018
Accepted Date: 22 September 2018
Please cite this article as: Xu H, Fan G-P, Liu Z, Wang G-W, Catalyst- and solvent-free
mechanochemical synthesis of isoxazoles from N-hydroxybenzimidoyl chlorides and enamino carbonyl
compounds, Tetrahedron (2018), doi: https://doi.org/10.1016/j.tet.2018.09.044.
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Catalyst- and solvent-free mechanochemical
synthesis of isoxazoles from N-
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hydroxybenzimidoyl chlorides and enamino
carbonyl compounds
Hui Xu a, Guang-Peng Fan a, Zi Liu a, Guan-Wu Wang a, b,
a
CAS Key Laboratory of Soft Matter Chemistry, Hefei National Laboratory for Physical Sciences at
Microscale, iChEM (Collaborative Innovation Center of Chemistry for Energy Materials), Department of
Chemistry, University of Science and Technology of China, Hefei, Anhui, 230026, PR China
b State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu, 730000, PR China

1
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Tetrahedron
journal homepage: www.elsevier.com
Catalyst- and solvent-free mechanochemical synthesis of isoxazoles from N-
hydroxybenzimidoyl chlorides and enamino carbonyl compounds
Hui Xu a, Guang-Peng Fan a, Zi Liu a, Guan-Wu Wang a, b,
a CAS Key Laboratory of Soft Matter Chemistry, Hefei National Laboratory for Physical Sciences at Microscale, iChEM (Collaborative Innovation Center of
Chemistry for Energy Materials), Department of Chemistry, University of Science and Technology of China, Hefei, Anhui, 230026, PR China
b State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu, 730000, PR China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A regioselective, solvent-free and catalyst-free synthesis of isoxazoles has been successfully
developed under ball milling conditions. Milling the mixtures of N-hydroxybenzimidoyl
chlorides and enamino carbonyl compounds in a ball mill at a frequency of 14.6 Hz for 20‒60
min afforded isoxazoles in up to 86% yields. A possible reaction mechanism leading to the
formation of the observed isoxazoles is proposed.
Available online
2018 Elsevier Ltd. All rights reserved
.
Keywords:
Mechanochemistry
Solvent-free
Catalyst-free
Isoxazoles
N-Hydroxybenzimidoyl chlorides
Enamino carbonyl compounds
———
Corresponding author.
E-mail address: gwang@ustc.edu.cn (G.-W. Wang).

2
Tetrahedron
1. Introduction
Scheme 2. The expected and observed products from the
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mechanochemical reaction of 1a and 2a.
Isoxazoles are core skeleton of many biological molecules,
natural products and functional materials [1]. Thus, the
development of efficient methodologies for the synthesis of
isoxazoles has attracted considerable attention. During the past
several decades, many synthetic methods have been developed
for the synthesis of isoxazoles, including the typical [3+2]
cycloaddition reaction between alkynes and nitrile oxides [2]; the
reactions of hydroxylamine with 1,3-dicarbonyl compounds [3],
silylalkynones [4], 2-cyano-3-ethoxythiocrotonamide [5], the
cyclization of alkynyl oxime ethers [6], and the reaction of α-
nitro carbonyl compounds with methyl ketones or terminal aryl
alkenes [7]. However, these methods frequently suffer from
drawbacks such as requirements of strong bases, strong acids,
high temperatures and the use of transition-metal catalysts,
providing poor regioselectivity, and the need of organic solvents.
Thus, development of a more simple and efficient method for the
synthesis of isoxazoles is highly desirable.
It was surprising that methyl 3-(4-chlorophenyl)-5-
methylisoxazole-4-carboxylate (3a) was obtained exclusively in
76% yield after milling 1a and 2a in a molar ratio of 1:1 in a
stainless-steel jar (5 mL, 12 mm × 50 mm, 61.556 g) containing
two stainless-steel balls (2 × 0.519 g, 5 mm in diameter) by using
a Spex 8000 M mill at a frequency of 14.6 Hz for 20 min (Table
1, entry 1). It has been known that the product yield for a specific
mechanochemcial reaction could be influenced by various
parameters such as the reagent ratio, milling frequency, milling
time and grinding materials [8a–c]. The milling frequency is
fixed and can not be varied for the Spex 8000 M mill. Therefore,
Table1
Optimization for the synthesis of isoxazole 3a under ball milling
conditionsa.
Recently, solvent-free reactions have drawn chemists’
increasing attention. As one type of solvent-free reactions,
mechanochemistry exhibits many advantages over liquid-phase
counterparts in term of higher product yield, better selectivity,
shorter reaction time, simpler work-up procedure, elimination of
harmful organic solvent, etc [8].
In general, the reactions between alkynes and nitrile oxides
through [3+2] cycloaddition afford isoxazoles, while those
between alkenes and nitrile oxides provide isoxazolines (Scheme
1). With our continuous interest in organic reactions under ball
milling conditions [9], herein we disclose that the reaction of N-
hydroxybenzimidoyl chlorides with enamino carbonyl
compounds regioselectively afford isoxazoles derivatives instead
of the expected isoxazolines derivatives. Intriguingly, the present
reaction is a catalyst-free as well as solvent-free process.
Entry
Ratio of Reagentsb
Time (min)
Yield (%)c
1
2
3
4
5
6
7
8
1:1
20
20
20
20
5
10
60
120
20
20
20
20
76
81
76
78
51
74
82
80
81
78
81
78
1.1:1
1.2:1
1:1.1
1.1:1
1.1:1
1.1:1
1.1:1
1.1:1
1.1:1
1.1:1
1.1:1
9d
10e
11f
12g
a
The reaction mixture of 1a and 2a in different molar ratio was milled for
a given time.
b The reagent ratio referred to 1a:2a.
c Isolated yields obtained by chromatography over silica gel.
d The reaction was performed with a stainless-steel jar (5 mL, 12 mm × 50
mm, 61.556 g) and two zirconium balls (2 × 0.418 g, 5 mm in diameter).
Scheme 1. Synthesis of isoxazoles and isoxazolines.
e
The reaction was performed with a agate jar (4.5 mL, 12 mm × 43 mm,
62.746 g) and a agate ball (0.509 g, 7 mm in diameter).
f
The reaction was performed with a polymethyl methacrylate jar (15 mL,
2. Results and discussion
19 mm × 57 mm, 21.721 g) and two stainless-steel balls (2 × 0.519 g, 5 mm
in diameter).
g
In our initial studies, the reaction of 4-chloro-N-
The reaction was performed with a Teflon jar (5 mL, 13 mm × 39 mm,
hydroxybenzimidoyl
chloride
(1a)
with
methyl
3-
40.945 g) and a Teflon ball (0.582 g, 8 mm in diameter).
(methylamino)but-2-enoate (2a) was chosen as a model reaction
to examine whether the desired [3+2] cycloaddition could be
realized under ball milling conditions. It was expected that the
1,3-dipolar addition product was methyl 3-(4-chlorophenyl)-4-
methyl-4-(methylamino)-4,5-dihydroisoxazole-5-carboxylate or
different reagent ratios, milling times and grinding materials were
explored in order to achieve higher product yield. With the
amount of 1a increasing to 1.1 equiv, the yield of 3a reached to
81% (Table 1, entry 2). The yield could not be improved further
when 1a was increased to 1.2 equiv (Table 1, entry 3). When the
molar ratio of 1a:2a was 1:1.1, 3a was isolated in 78% yield
(Table 1, entry 4). Then keeping the 1a:2a ratio as 1.1:1, the
reaction time was screened. Product 3a was isolated in 51% yield
after milled for 5 min (Table 1, entry 5). Further increasing the
reaction time to 10 min, the product yield reached to 74% (Table
1, entry 6). However, the yield could not to be further improved
even prolonging reaction time to 1 h and 2 h (Table 1, entries 7
and 8). The reaction of 1a with 2a for 20 min afforded the same
product yield (81%) when the two grinding balls were replaced
by two zirconium balls (2 × 0.418 g, 5 mm in diameter, entry 9
vs. entry 2). In addition, milling jars of other materials such as
agate (4.5 mL, 12 mm × 43 mm, 62.746 g), polymethyl
methyl
3-(4-chlorophenyl)-5-methyl-5-(methylamino)-4,5-
dihydroisoxazole-4-carboxylate (Scheme 2).

3
methacrylate (15 mL, 19 mm × 57 mm, 21.721 g) and Teflon (5
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mL, 13 mm × 39 mm, 40.945 g) were also employed, product 3a
were obtained in 78%, 81% and 78%, respectively (Table 1,
entries 10–12). The results demonstrated that the material of the
grinding jar and ball had no significant influence on the product
yield in our case.
With the optimized reaction conditions in hand (Table 1, entry
2), the substrate scope was then investigated. The reactions of
various N-hydroxybenzimidoyl chlorides with N-substituted β-
enamino carbonyl compounds were explored, and the results are
summarized in Table 2. Firstly, a range of N-substituted β-
enamino carbonyl compounds were used to explore their
reactivity towards 4-chloro-N-hydroxybenzimidoyl chloride (1a).
In general, when the R4 group of N-substituted β-enamino
carbonyl compounds was an aliphatic group, the same product 3a
was isolated in good yields (75–86%). However, when R4 was the
phenyl group, 3a was obtained in only 26% yield even
prolonging the reaction time to 60 min. As seen from the above
results, the β-enamino carbonyl compound prepared from a 1,3-
dicarbonyl compound and isopropyl amine provided the highest
yield. It was found that the mechanochemical reaction of ethyl 3-
(isopropylamino)but-2-enoate, an analogous enanimo ethyl ester,
with 1a for 20 min gave 3b in 86% yields, while milling the
reaction mixture of 3-(isopropylamino)-N-phenylbut-2-enamide,
an enamino amide, with 1a for 20 min afforded 3c in 71% yield.
In addition, 4-(isopropylamino)pent-3-en-2-one, an enamino
ketone in this case, with 1a for 1 h afforded 3d in 64% yield.
Furthermore, when the methyl group in R3 of enamines was
replaced by the ethyl and phenyl groups, the corresponding
products 3e and 3f were obtained in 79% and 36%, respectively.
Then, we chose methyl 3-(isopropylamino)but-2-enoate as the
reaction partner for various N-hydroxybenzimidoyl chlorides to
further investigate the substrate scope of this reaction. As
revealed in Table 2, a variety of electron-donating groups and
electron-withdrawing groups, such as –CH3 (3h and 3i), –OCH3
(3j), –Cl (3a and 3k), –Br (3l), –NO2 (3m), were compatible with
the reaction conditions, and provided the corresponding products
in moderate to good yields (53–86%). It should be noted that the
N-hydroxybenzimidoyl chlorides with electron-withdrawing
groups was less reactive and required a longer reaction time than
those substrates with electron-donating groups. N-Hydroxy-2-
methylbenzimidoyl chloride reacted with 3-(isopropylamino)but-
2-enoate for 1 h afforded 3i in 53% yield, which demonstrated
that substitution at the ortho-position of the phenyl ring of N-
hydroxybenzimidoyl chloride had a detrimental influence on the
product yield. To our delight, 3n was obtained in 54% yield
when N-hydroxycinnamimidoyl chloride was employed as the
reaction partner for 3-(isopropylamino)but-2-enoate. The reaction
was highly regioselective, and no regioisomers were formed in
all
a
The reaction mixture of 1 (1.1 equiv.) and 2 (1 equiv.) was milled for a
given time.
b Isolated yield.
cases as deduced by comparison of the NMR data with the
previously reported data [10].
The crystalline state and physical properties of the reagents,
and thus the intimate mixing and contacts between the reagents
can influence the reaction efficiency and selectivity [8a].
Formation of a low-temperature eutectic or melting may not be
mandatory for the success of mechanochemical reactions because
there have been evidences for the mechanochemical reactions to
occur in the solid state or gas phase [8d]. The used reagents were
a combination of either solid-solid or solid-liquid, the liquid-
assisted grinding (LAG) technique was not employed, and no
grinding auxiliary was added in our present solvent-free reaction.
Although the details for the physical changes of the reagents and
close contacts between them during the reaction process are
unknown in our case, a possible reaction mechanism at the
molecular level based on those of the common liquid-phase
reactions is shown in Scheme 3. The nitrile oxide A is generated
by removal of HCl from the N-hydroxybenzimidoyl chloride 1
with the enamino carbonyl compound 2, accompanied with the
formation of the enamino salt B. 1,3-Dipolar cycloaddition
Table 2
Isoxazoles synthesized from N-hydroxybenzimidoyl chlorides
and enamines under ball milling conditionsa,b.

4
Tetrahedron
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between A and B would give the cycloadduct C. Final
temperature for 20–60 min. The combined reaction mixtures
elimination of the amino moiety along with HCl from
intermediate C afford the product 3. The proposed reaction
mechanism can also explain the observed regioselectivity, which
is determined by the [2+3] cycloaddition step.
from two vessels were collected and dissolved in ethyl acetate.
The solution was filtrated to remove the residue and then
evaporated to dryness under reduced pressure. Finally, the
resulting product 3 was purified by column chromatography over
silica gel using ethyl acetate/petroleum ether as the eluent.
4.2.1.
Methyl
3-(4-chlorophenyl)-5-methylisoxazole-4-
carboxylate (3a)
1
Yield 86% (86.7 mg). H NMR (400 MHz, CDCl3) δ 7.58 (d,
J = 8.5 Hz, 2H), 7.42 (d, J = 8.5 Hz, 2H), 3.79 (s, 3H), 2.73 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 176.2, 162.3, 161.7, 136.1,
130.7, 128.4, 126.9, 108.2, 51.7, 13.7; HRMS (EI–TOF) m/z
[M]+ calcd for C12H1035ClNO3, 251.0349; found, 251.0346.
4.2.2. Ethyl 3-(4-chlorophenyl)-5-methylisoxazole-4-carboxylate
(3b)
Scheme 3. The possible reaction mechanism.
1
Yield 86% (91.5 mg). H NMR (400 MHz, CDCl3) δ 7.59 (d,
J = 8.6 Hz, 2H), 7.41 (d, J = 8.6 Hz, 2H), 4.25 (q, J = 7.1 Hz,
2H), 2.73 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 176.0, 161.8, 161.7, 136.0, 130.8, 128.3, 127.0, 108.4,
60.9, 14.1, 13.6; HRMS (EI–TOF) m/z [M]+ calcd for
C13H1235ClNO3, 265.0506; found, 265.0502.
3. Conclusion
In summary, an efficient, environmentally friendly and
regioselective synthesis of isoxazoles has been developed from
readily available N-hydroxybenzimidoyl chlorides and enamino
carbonyl compounds under mechanical milling conditions.
Milling the mixtures of N-hydroxybenzimidoyl chlorides and
enamino carbonyl compounds in a ball mill at a frequency of
14.6 Hz for 20‒60 min afford isoxazoles in a yield up to 86%.
The preparation of starting materials is facile and can be applied
to a wide variety of substrates. The milder reaction conditions,
higher yields, better selectivity and no use of any solvent and
catalyst make present method appealing towards the
regioselective and high-yielding synthesis of isoxazoles. A
plausible reaction mechanism is proposed to explain the
formation of isoxazoles as well as the observed regioselectivity.
4.2.3.
3-(4-Chlorophenyl)-5-methyl-N-phenylisoxazole-4-
carboxamide (3c)
1
Yield 71% (92.8 mg). H NMR (400 MHz, CDCl3) δ 7.62 (d,
J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.34-7.27 (m, 4H),
7.20-7.09 (m, 2H), 2.74 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
174.8, 159.5, 159.0, 137.2, 137.1, 130.5 (2C), 129.7 (2C), 129.3
(2C), 126.4, 125.1, 119.9 (2C), 111.6, 13.1; HRMS (EI–TOF)
m/z [M]+ calcd for C17H1335ClN2O2, 312.0666; found, 312.0663.
4.2.4. 1-(3-(4-Chlorophenyl)-5-methylisoxazol-4-yl)ethanone (3d)
1
Yield 64% (60.4 mg). H NMR (400 MHz, CDCl3) δ 7.47 (s,
4H), 2.71 (s, 3H), 2.15 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
192.7, 174.7, 161.0, 136.3, 130.5, 129.0, 127.4, 117.2, 30.6, 13.7;
HRMS (EI–TOF) m/z [M]+ calcd for C12H10ClNO2, 235.0400;
found, 235.0398.
4. Experimental section
4.1. General information
4.2.5. Ethyl 3-(4-chlorophenyl)-5-ethylisoxazole-4-carboxylate
(3e)
All reagents were obtained from commercial sources and used
directly. NMR spectra were recorded on a 400 MHz NMR
1
Yield 79% (88.5 mg). H NMR (400 MHz, CDCl3) δ 7.58 (d,
1
spectrometer (400 MHz for H NMR; 101 MHz for 13C NMR).
J = 8.6 Hz, 2H), 7.41 (d, J = 8.6 Hz, 2H), 4.25 (q, J = 7.1 Hz,
2H), 3.15 (q, J = 7.6 Hz, 2H), 1.37 (t, J = 7.6 Hz, 3H), 1.24 (t, J =
7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 180.4, 161.7, 161.6,
135.9, 130.8 (2C), 128.2 (2C), 127.1, 107.4, 60.8, 21.3, 14.0,
11.5; HRMS (EI–TOF) m/z [M]+ calcd for C14H1435ClNO3,
279.0662; found, 279.0668.
1H NMR chemical shifts were determined relative to internal
TMS at δ 0.0 ppm. 13C NMR chemical shifts were determined
relative to CDCl3 at δ 77.1 ppm. Data for 1H NMR and 13C NMR
are reported as follows: chemical shift (δ, ppm), multiplicity (s =
singlet, d = doublet, t = triplet, m = multiplet, q = quartet). High-
resolution mass spectra (HRMS) were measured with EI-TOF in
a positive mode. Ball-milling reactions were performed in a Spex
SamplePrep 8000 mixer mill at a rate of 875 cycles per minute
(14.6 Hz) at room temperature.
4.2.6. Ethyl 3-(4-chlorophenyl)-5-phenylisoxazole-4-carboxylate
(3f)
1
Yield 36% (47.3 mg). H NMR (400 MHz, CDCl3) δ 7.94-
7.88 (m, 2H), 7.62 (d, J = 8.3 Hz, 2H), 7.57-7.48 (m, 3H), 7.45 (d,
J = 8.3 Hz, 2H), 4.21 (q, J = 7.1 Hz, 2H), 1.13 (t, J = 7.1 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 173.0, 162.3, 162.2, 136.2, 131.5,
130.6 (2C), 129.0 (2C), 128.63 (2C), 128.62 (2C), 127.2, 126.8,
108.3, 61.5, 13.8; HRMS (EI–TOF) m/z [M]+ calcd for
C18H1435ClNO3, 327.0662; found, 327.0658.
4.2. General procedure for the synthesis of isoxazoles from N-
hydroxybenzimidoyl chlorides and enamino carbonyl compounds
A mixture of a N-hydroxybenzimidoyl chloride 1 (0.22 mmol)
and an enamino carbonyl compound 2 (0.2 mmol) was added to a
stainless-steel jar (5 mL, 12 mm × 50 mm, 61.556 g) containing
two stainless-steel balls (2 × 0.519 g, 5 mm in diameter). The
mass ratio of the reaction mixture to balls were from 1:12.5 to
1:15.8. The same mixture was also added to a second parallel jar.
The two reaction vessels were vibrated in Spex SamplePrep 8000
mixer mill at a frequency of 875 cycles per minute at room
4.2.7. Methyl 5-methyl-3-phenylisoxazole-4-carboxylate (3g) [10]
1
Yield 63% (54.7 mg). H NMR (400 MHz, CDCl3) δ 7.64-
7.60 (m, 2H), 7.49-7.41 (m, 3H), 3.76 (s, 3H), 2.72 (s, 3H).
4.2.8. Methyl 5-methyl-3-(p-tolyl)isoxazole-4-carboxylate (3h)

5
1
Yield 85% (78.5 mg). H NMR (400 MHz, CDCl3) δ 7.51 (d,
Acknowledgements
ACCEPTED MANUSCRIPT
J = 8.1 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 3.76 (s, 3H), 2.70 (s,
3H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 175.8, 162.52,
162.51, 139.8, 129.2, 128.8, 125.5, 108.2, 51.6, 21.4, 13.6;
HRMS (EI–TOF) m/z [M]+ calcd for C13H13NO3, 231.0895;
found, 231.0897.
We are grateful for financial support from the National
Natural Science Foundation of China (No. 21372211).
Appendix A. Supplementary data
4.2.9. Methyl 5-methyl-3-(o-tolyl)isoxazole-4-carboxylate (3i)
Supplementary data related to this article can be found at
https://doi.
1
Yield 53% (49.0 mg). H NMR (400 MHz, CDCl3) δ 7.38-
7.31 (m, 1H), 7.29-7.21 (m, 3H), 3.67 (s, 3H), 2.75 (s, 3H), 2.20
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 175.4, 162.6, 162.2,
137.1, 129.9, 129.6, 129.4, 128.5, 125.3, 109.3, 51.6, 19.7, 13.5;
HRMS (EI–TOF) m/z [M]+ calcd for C13H13NO3, 231.0895;
found, 231.0898.
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4.2.10.
carboxylate (3j)
Methyl
3-(4-methoxyphenyl)-5-methylisoxazole-4-
1
Yield 81% (80.0 mg). H NMR (400 MHz, CDCl3) δ 7.59 (d,
J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H), 3.78 (s,
3H), 2.71 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 175.8, 162.6,
162.2, 160.9, 130.7, 120.6, 113.6, 108.1, 55.3, 51.6, 13.7; HRMS
(EI–TOF) m/z [M]+ calcd for C13H13NO4, 247.0845; found,
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4.2.11. Methyl 3-(3,4-dichlorophenyl)-5-methylisoxazole-4-
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carboxylate (3k)
1
Yield 59% (67.5 mg). H NMR (400 MHz, CDCl3) δ 7.78 (d,
J = 1.8 Hz, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.50 (dd, J = 8.3, 1.8
Hz, 1H), 3.81 (s, 3H), 2.74 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 176.4, 162.0, 160.6, 134.3, 132.4, 131.3, 130.1, 128.7, 128.4,
108.2, 51.8, 13.7; HRMS (EI–TOF) m/z [M+] calcd for
C12H935Cl2NO3, 284.9959; found, 284.9955.
4.2.12.
Methyl
3-(4-bromophenyl)-5-methylisoxazole-4-
(b) A. Stolle, T. Szuppa, S.E.S. Leonhardt, B. Ondruschka, Chem. Soc.
Rev. 40 (2011) 2317–2329.
(c) G.-W. Wang, Chem. Soc. Rev. 42 (2013) 7668–7700.
(d) S.-E Zhu, F. Li, G.-W. Wang, Chem. Soc. Rev. 42 (2013) 7535–
7570.
(e) J. G. Hernández, C. Bolm, J. Org. Chem. 82 (2017) 4007–4019.
(f) J.-L. Do, T. Friščić, ACS Cent. Sci. 3 (2017) 13–19.
(g) D. Tan, T. Friščić, Eur. J. Org. Chem. (2018) 18–33.
(h) J.G. Hernández, C.G. Avila-Ortiz, E. Juaristi, in: G.A. Molandery,
P. Knochel, (Eds.), Useful Chemical Activation Alternatives in Solvent-
Free Organic Reactions. Comprehensive Organic Synthesis, second ed.,
Vol. 9, Elsevier, Oxford, 2014, pp. 287–314.
carboxylate (3l)
1
Yield 76% (90.0 mg). H NMR (400 MHz, CDCl3) δ 7.58 (d,
J = 8.6 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 3.78 (s, 3H), 2.72 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 176.2, 162.2, 161.7, 131.3,
131.0, 127.4, 124.4, 108.1, 51.7, 13.6; HRMS (EI–TOF) m/z
[M]+ calcd for C12H1079BrNO3, 294.9844; found, 294.9846.
4.2.13.
Methyl
5-methyl-3-(4-nitrophenyl)isoxazole-4-
carboxylate (3m)
1
Yield 67% (70.2 mg). H NMR (400 MHz, CDCl3) δ 8.31 (d,
J = 8.9 Hz, 2H), 7.84 (d, J = 8.9 Hz, 2H), 3.81 (s, 3H), 2.77 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 176.6, 161.9, 161.0, 148.7,
134.9, 130.6, 123.2, 108.3, 51.9, 13.7; HRMS (EI–TOF) m/z
[M]+ calcd for C12H10N2O5, 262.0590; found, 262.0595.
(i) E. Machuca, E. Juaristi, in: R. Brindabany, A. Stolle (Eds.),
Asymmetric Organocatalytic Reactions under Ball Milling. Ball Milling
towards Green Synthesis: Applications, Projects, Challenges, Royal
Society of Chemistry, Cambridge, 2015, pp. 81–95.
[9] (a) L. Li, J.-J. Wang, G.-W. Wang, J. Org. Chem. 81 (2016) 5433–5439.
(b) H.-G. Li, G.-W. Wang, J. Org. Chem. 82 (2017) 6341–6348.
(c) H. Xu, H.-W. Liu, H.-S. Lin, G.-W. Wang, Chem. Commun. 53
(2017) 12477–12480.
4.2.14. (E)-Methyl 5-methyl-3-styrylisoxazole-4-carboxylate (3n)
1
(d) Z. Liu, H. Xu, G.-W. Wang, Beilstein J. Org. Chem. 14 (2018) 430–
435.
(e) H.-G. Li, L. Li, H. Xu, G.-W. Wang, Curr. Org. Chem. 22 (2018)
923-929
(f) H. Xu, H.-W. Liu, K. Chen, G.-W. Wang, J. Org. Chem. 83 (2018)
6035–6049.
Yield 54% (52.5 mg). H NMR (400 MHz, CDCl3) δ 7.61-
7.54 (m, 3H), 7.40-7.34 (m, 3H), 7.31 (tt, J = 7.2, 1.2 Hz, 1H),
3.89 (s, 3H), 2.68 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 175.5,
162.7, 159.5, 136.12, 136.09, 128.9, 128.7, 127.3, 114.4, 108.0,
51.8, 13.5; HRMS (EI–TOF) m/z [M]+ calcd for C14H13NO3,
243.0895; found, 243.0890.
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(2008) 1385–1389.