An environmentally benign synthesis of isoxazolines and isoxazoles mediated by potassium chloride in water

Article abstract of DOI:10.1016/j.tetlet.2014.02.118

An effective and environmentally benign procedure for the synthesis of isoxazolines and isoxazoles has been developed by a cycloaddition of nitrile oxides with alkenes or alkynes in water. In this approach, potassium chloride is first oxidized into chlorine in water by the environmentally friendly oxidant Oxone, then aldoximes are oxidized into nitrile oxides by the in situ generated hypochlorous acid, finally a 1,3-dipolar cycloaddition between nitrile oxides and alkenes or alkynes occurs to provide the corresponding isoxazolines and isoxazoles in good yields.

Full text of DOI:10.1016/j.tetlet.2014.02.118

Tetrahedron Letters 55 (2014) 2308–2311
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An environmentally benign synthesis of isoxazolines and isoxazoles
mediated by potassium chloride in water
Liuquan Han a, Bijun Zhang a, Min Zhu b, Jie Yan a,
⇑
a College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310032, Zhejiang, PR China
b College of Biological and Environmental Sciences, Zhejiang Shuren University, Hangzhou 310015, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An effective and environmentally benign procedure for the synthesis of isoxazolines and isoxazoles has
been developed by a cycloaddition of nitrile oxides with alkenes or alkynes in water. In this approach,
potassium chloride is first oxidized into chlorine in water by the environmentally friendly oxidant
OxoneÒ, then aldoximes are oxidized into nitrile oxides by the in situ generated hypochlorous acid, finally
a 1,3-dipolar cycloaddition between nitrile oxides and alkenes or alkynes occurs to provide the corre-
sponding isoxazolines and isoxazoles in good yields.
Received 14 December 2013
Revised 24 February 2014
Accepted 27 February 2014
Available online 6 March 2014
Keywords:
Cycloaddition
Isoxazoline
Ó 2014 Elsevier Ltd. All rights reserved.
Isoxazole
Potassium chloride
Introduction
efficient synthesis of isoxazolines and isoxazoles using water as the
sole solvent is still desired.
Isoxazolines and isoxazoles are two major classes of five-mem-
bered nitrogen containing heterocycles, which are found in a large
Potassium hydrogen persulfate (KHSO5), or OxoneÒ (2KHSO5–
KHSO4–K2SO4), is an effective oxidant. Due to its good stability,
water-solubility, ease of transport, nontoxic ‘green’ nature, nonpol-
luting byproducts, and cost-effectiveness, this solid reagent has be-
come a popular reagent for oxidative transformations.8 Recently,
Zhdankin and co-workers have developed a novel cycloaddition
of nitrile oxides with alkenes using KI as the catalyst and OxoneÒ
as the terminal oxidant, which occurred in MeOH–H2O (20:1)
and provided isoxazolines in good yields.9 However, this protocol
is not suitable to prepare isoxazoles since alkynes were not active
in the reaction when they were used in place of alkenes. In order to
improve the application of OxoneÒ and develop a new process for
the synthesis of isoxazolines and isoxazoles, we have investigated
the reaction of nitrile oxides with alkenes or alkynes in the pres-
ence of potassium chloride (KCl) and OxoneÒ in water. Herein, an
environmentally benign synthesis of isoxazolines and isoxazoles
has been developed.
number of natural products and biologically active compounds.1
A
variety of synthetic methods has been developed for preparation of
isoxazolines and isoxazoles, of which the most convenient and
attractive route is probably the 1,3-dipolar cycloaddition of nitrile
oxides to alkenes or alkynes.2 Nitrile oxides are commonly gener-
ated from aldoximes via oxidations using different oxidants. Or-
ganic hypervalent iodine reagents, due to their low toxicity,
ready availability, easy handling, and reactivity similar to that of
heavy metal reagents, have been recently used as effective oxi-
dants for the above purpose.3 Other oxidants, such as NBS, NCS,
NaOCl, t-BuOCl, and t-BuOI also have been used in the cycloaddi-
tion.4 Due to most of the 1, 3-dipolar cycloadditions of nitrile oxi-
des to alkenes or alkynes usually occurring in organic solvents or
mixed solvent systems, utilization of water as a medium, an envi-
ronmentally benign system, is less common. Hailes and Bala have
investigated an intramolecular 1,3-dipolar cycloaddition in water
albeit longer time is required to get good yield.5 Rohloff et al. have
reported a one-pot 1,3-dipolar cycloaddition in water but only tol-
erating water-soluble olefins and acetylenes as substrates.6 Sarma
group have developed a one-pot high-throughput synthesis of
isoxazolines in bleach with moderate or low yield.7 Therefore, from
both environmental and economic viewpoints, to develop an
Discussion and results
At first, an inexpensive and readily available KCl was attempted
to mediate the cycloaddition of nitrile oxides and alkenes, and a
mixture of benzaldoxime (1.0 equiv), styrene (2.0 equiv), OxoneÒ
(2.0 equiv) and KCl (1.0 equiv) in methanol was stirred at room
temperature for 12 h, the desired cycloaddition product 3,5-diphe-
nylisoxazoline was observed with only a trace amount (Table 1, en-
try 1). With the observation of the bad solubility of KCl and OxoneÒ
⇑
Corresponding author. Tel.: +86 13805734975; fax: +86 (571)88320238.
E-mail address: jieyan87@zjut.edu.cn (J. Yan).
http://dx.doi.org/10.1016/j.tetlet.2014.02.118
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

L. Han et al. / Tetrahedron Letters 55 (2014) 2308–2311
2309
Table 1
Optimization of the cycloaddition of nitrile oxide from benzaldoxime with styrene mediated by KCl
N OH
N
Oxone, KCl
solvent, r.t.
O
Ph
Entry
OxoneÒ (equiv)
KCl (equiv)
PhCH@CH2 (equiv)
Solvent
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.2
1.5
2.5
1.5
1.5
1.5
1.0
1.0
1.0
1.0
1.0
1.0
0
0.2
0.5
1.0
1.5
NaCl (1.0)
NH4Cl (1.0)
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.0
1.2
1.5
2.5
3.0
2.5
2.5
2.5
2.5
2.5
2.5
CH3OH
MeOH–H2O (4:1)
MeOH–H2O (3:1)
MeOH–H2O (2:1)
MeOH-H2O (1:1)
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
12
12
12
12
12
2
24
4
4
4
4
4
4
4
4
4
4
4
4
4
4
Trace
21
33
36
71
85
Trace
68
72
86
32
80
84
56
52
64
98
96
78
96
94
94
98
97
2
3
5
a
Isolated yield.
Table 2
The result of cycloaddition of nitrile oxides from aldoximes to alkenes or alkynes
Entry
Aldoxime 1
CH=NOH
Alkene/alkyne 2
Isoxazoline/isoxazole 3
Yielda (%)
98
N
O
1
1a
2a
Ph
3a
3b
N
O
2
3
4
1a
1a
1a
81
85
79
2b
Ph
N
N
Br
O
2c
Br
3c
Ph
O
2d
Ph
3d
CO Me
N
2
2e
O
5
6
7
1a
1a
1a
88
73
92
CO2Me
3e
N
N
O
2f
3f
CH2Br
2g
O
CH2Br
3g
3h
N
CH=NOH
O
1b
8
9
2a
2a
2a
92
83
Ph
N
MeO
F
CH=NOH
O
1c
MeO
F
Ph
3i
N
CH=NOH
O
10
89
1d
Ph
3j
(continued on next page)

2310
L. Han et al. / Tetrahedron Letters 55 (2014) 2308–2311
Table 2 (continued)
Entry
Aldoxime 1
CH=NOH
Alkene/alkyne 2
Isoxazoline/isoxazole 3
Yielda (%)
77b
N
O
11
12
2a
Cl
1e
1f
Cl
Ph
3k
3l
N
CH=NOH
OH
O
2a
2a
87
OH
Ph
O
N
NOH
13
56b
1g
Ph
3m
3o
N
O
2h
2i
14
15
1a
1a
1a
87
80
85
Ph
3n
N
N
O
CO2Me
2j
O
16
CO Me
2
3p
a
Isolated yield; the reaction time was 5 h.
The reaction time was 5 h.
b
OH
O
in methanol, water was added in methanol to form mixed solvent
in different ratios. With the ratio of water increased, the reaction
yield increased as well (entries 2–5). If only water was utilized,
the cycloaddition provided a good yield (85%) in 2 h although the
reaction was a biphasic process (entry 6). Encouraged by this re-
sult, we optimized other reaction conditions. As shown in Table 1,
if KCl was absent, only a trace amount of product was observed
(entry 7) and 1.0 equivalent of KCl was found to result the highest
yield (86%) after 4 h (entries 8–11). Other chlorides, such as NaCl
and NH4Cl were also active under the same reaction conditions
(entries 12, 13). The amounts of styrene and OxoneÒ were also
optimized to 2.5 equiv of styrene and 1.5 equiv of OxoneÒ (entries
14–21). The reaction completed in 3 h in the scales of our experi-
ments, in which the product 3,5-diphenylisoxazoline was obtained
in near quantitative yield (entries 21–24).
Having established the optimal conditions, the cycloaddition of
1.0 equiv of aldoximes (1), 2.5 equiv of alkenes (2), 1.5 equiv of Ox-
oneÒ, and 1.0 equiv of KCl in water at room temperature for 3 h, a
series of corresponding isoxazolines (3) were thus obtained, and
the results are summarized in Table 2. When benzaldoxime (1a)
was used as starting substrate, the reaction was compatible with
the studied alkenes and provided the corresponding isoxazolines
in good to excellent yields (Table 2, entries 1–7). Other benzaldox-
imes with various electron-donating and electron-withdrawing
groups on the benzene ring (1b–1f) also reacted smoothly with
styrene (2a), giving the respective isoxazolines in good to excellent
yields (entries 8–12). Phenylacetaldoxime (1g), an aliphatic aldox-
imes, could react with 2a and afforded the desired product in a
moderate yield after 5 h (entry 13). Encouraged by the results ob-
tained with alkene, we then tried to prepare isoxazoles from al-
kynes. Three different alkynes were attempted to react with 1a
and finally the corresponding isoxazoles were obtained in good
N
2
HOCl
R
O
H O
2
1
R
N
Cl
2
1
R
N
-
Oxone
Cl
1
alkene/alkyne
R
Scheme 2. Proposed mechanism for the synthesis of isoxazolines and isoxazoles.
yields (entries 14–16). Thus, the new procedure could be applied
in the synthesis of both isoxazolines and isoxazoles (Scheme 1).10
A plausible mechanism is proposed, which is similar to that re-
ported by Zhdankin and co-workers9 (Scheme 2). It includes that
potassium chloride is first oxidized into chlorine in water by Ox-
oneÒ, then aldoximes are oxidized into nitrile oxides by the
in situ generated hypochlorous acid. Finally, a 1,3-dipolar cycload-
dition between the nitrile oxides and alkenes or alkynes furnishes
the corresponding isoxazolines or isoxazoles.
Conclusions
We have developed a convenient and environmentally benign
procedure for the synthesis of isoxazolines and isoxazoles. Com-
pared to previously reported methods, this procedure utilizes the
readily available and inexpensive KCl and ‘green’ oxidant OxoneÒ
to mediate the 1,3-dipolar cycloaddition between nitrile oxides
and alkenes or alkynes in water. The advantages of this procedure
include mild reaction conditions, simple and environmentally be-
nign procedure, short reaction time, and good yields. Furthermore,
this method is suitable for the synthesis of not only isoxazolines
but also isoxazoles, which extends the scope of 1,3-dipolar cyclo-
addition between nitrile oxides and alkenes or alkynes in water.
N
Oxone, KCl
water, rt, 3h
R
O
1
R
CH=NOH
R
1
2
Acknowledgment
2
R
1
3
2
Financial support from the Natural Science Foundation of China
(Project 21072176) is greatly appreciated.
Scheme 1. The cycloaddition of nitrile oxides from aldoximes to alkenes or alkynes
mediated by KCl.

L. Han et al. / Tetrahedron Letters 55 (2014) 2308–2311
2311
3. (a) Das, B.; Holla, H.; Mahender, G.; Banerjee, J.; Reddy, M. R. Tetrahedron Lett.
2004, 45, 7347; (b) Mendelsohn, B. A.; Lee, S.; Kim, S.; Teyssier, F.; Aulakh, V. S.;
Ciufolini, M. A. Org. Lett. 2009, 11, 1539; (c) Jawalekar, A. M.; Reubsaet, E.;
Rutjes, F. P. J. T.; van Delft, F. L. Chem. Commun. 2011, 3198; (d) Das, B.; Holla,
H.; Mahender, G.; Venkateswarlu, K.; Bangar, B. P. Synthesis 2005, 1572; (e)
Raihan, M. J.; Kavala, V.; Kuo, C.-W.; Raju, B. R.; Yao, C.-F. Green Chem. 2010, 12,
1090; (f) Chatterjee, N.; Pandit, P.; Halder, S.; Patra, A.; Maiti, D. K. J. Org. Chem.
2008, 73, 7775; (g) Yoshimura, A.; Middleton, K. R.; Todora, A. D.; Kastern, B. J.;
Koski, S. R.; Maskaev, A. V.; Zhdankin, V. V. Org. Lett. 2013, 15, 4010.
4. (a) Amstrong, S. K.; Collington, E. W.; Knight, J. G.; Naylor, A.; Warren, S. J.
Chem. Soc., Perkin Trans. 1 1993, 1433; (b) Katritzky, A. R.; Button, M. A. C.;
Denisenko, S. N. J. Heterocycl. Chem. 2000, 37, 1505; (c) Lee, G. A. Synthesis 1982,
508; (d) Gi, H.-J.; Xiang, Y.; Schinazi, R. F.; Zhao, K. J. Org. Chem. 1997, 62, 88; (e)
Ye, Y.; Zheng, Y.; Xu, G. Y.; Liu, L. Z. Heteroat. Chem. 2003, 14, 254; (f) Kanemasa,
S.; Matsuda, H.; Kamimura, A.; Kakinami, T. Tetrahedron 2000, 56, 1057; (g)
Kumar, V.; Kaushik, M. P. Tetrahedron Lett. 2006, 47, 1457; (h) Dubrovskiy, A.
V.; Larock, R. C. Org. Lett. 2010, 12, 1180; (i) Minakata, S.; Okumura, S.;
Nagamachi, T.; Takeda, Y. Org. Lett. 2011, 13, 2966.
Supplementary data
Supplementary data associated with this article can be found, in
the
online
version,
at
http://dx.doi.org/10.1016/j.tetlet.
2014.02.118.
References and notes
1. (a) Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410; (b) Shankar, B. B.; Yang, D. Y.;
Girton, S.; Gangully, A. K. Tetrahedron Lett. 1998, 39, 2447; (c) Sammelson, R. E.;
Ma, T.; Galietta, L. J. V.; Verkman, A. S.; Kurth, M. J. Bioorg. Med. Chem. Lett.
2003, 13, 2509; (d) Bal, G.; der Venken, P. V.; Antonov, D.; Lambeir, A.-M.;
Grellier, P.; Croft, S. L.; Augustyns, K.; Haemers, A. Bioorg. Med. Chem. Lett. 2003,
13, 2875; (e) Park, K. K.; Ko, D. H.; You, Z.; Khan, M. O. F.; Lee, H. J. Steroids 2006,
71, 183; (f) Gopalsamy, A.; Shi, M.; Golas, J.; Vogan, E.; Jacob, J.; Johnson, M.;
Lee, F.; Nilakantan, R.; Petersen, R.; Svenson, K.; Chopra, R.; Tam, M. S.; Wen, Y.;
Ellingboe, J.; Arndt, K.; Boschelli, F. J. Med. Chem. 2008, 51, 373; (g) Lamani, R. S.;
Shetty, N. S.; Kamble, R. R.; Khazi, I. A. M. Eur. J. Med. Chem. 2009, 44, 282; (h)
Pulkkinen, J. T.; Honkakoski, P.; Perakyla, M.; Berczi, I.; Laatikainen, R. J. Med.
Chem. 2008, 51, 3562; (i) Castellano, S.; Kuck, D.; Viviano, M.; Yoo, J.; Lopez-
Vallejo, F.; Conti, P.; Tamborini, L.; Pinto, A.; Medina-Franco, J. L.; Sbardella, G. J.
Med. Chem. 2011, 54, 7663; (j) Sperry, J.; Wright, D. Curr. Opin. Drug Discovery
Dev. 2005, 8, 723; (k) Lee, Y. S.; Park, S. M.; Kim, B. H. Bioog. Med. Chem. Lett.
2009, 19, 1126; (l) Shin, K. D.; Lee, Y. S.; Shin, D. S.; Lee, S.; Son, K. H.; Koh, S.;
Paik, Y. K.; Kwon, B. M. J. Biol. Chem. 2005, 50, 41439; (m) Frolund, B.;
Jorgensen, A. T.; Tagmose, L.; Stensbol, T. B.; Vestergaard, H. T.; Engblom, C.;
Kristiansen, U.; Sanchez, C.; Krogsgaard-Larsen, P.; Liljefors, T. J. Med. Chem.
2002, 45, 2454.
2. (a) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley:
New York, 1984; Vols. 1 and 2, (b) Torssell, K. B. G. Nitrile Oxides, Nitrones, and
Nitronates in Organic Synthesis; VCH: New York, 1988; (c) Jaeger, V.; Colinas, P.
A. In Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Towards
Heterocycles and Natural Products; Padwa, A., Ed.; Wiley: Hoboken, 2002; vol.
59, p 361; (d) Grundmann, C. Synthesis 1970, 344; (e) Larsen, K. E.; Torssell, K. B.
G. Tetrahedron 1984, 40, 2985; (f) Tang, S.; He, J.; Sun, Y.; He, L.; She, X. Org. Lett.
2009, 11, 3982; (g) Waldo, J. P.; Larock, R. C. Org. Lett. 2005, 7, 5203; (h) Waldo,
J. P.; Larock, R. C. Org. Lett. 2007, 9, 643; (i) Dadiboyena, S.; Xu, J.; Hamme, A. T.,
II Tetrahedron Lett. 2007, 48, 1295.
5. Hailes, H. C.; Bala, K. Synthesis 2005, 3423.
6. Rohloff, J. C.; Robinson, J., III; Gardner, J. O. Tetrahedron Lett. 1992, 33, 3113.
7. Biswas, K.; Kumar, A.; Das Sarma, K. ACS Comb. Sci. 2013, 15, 255.
8. (a) Travis, B. R.; Sivakumar, M.; Hollist, G. O.; Borhan, B. Org. Lett. 2003, 5, 1031;
(b) Yang, D.; Zhang, C. J. Org. Chem. 2001, 66, 4814; (c) Ashford, S. W.; Grega, K.
C. J. Org. Chem. 2001, 66, 1523; (d) Molander, G. A.; Cavalcanti, L. N. J. Org. Chem.
2011, 76, 623.
9. Yoshimura, A.; Zhu, C. J.; Middleton, K. R.; Todora, A. D.; Kastern, B. J.; Maskaev,
A. V.; Zhdankin, V. V. Chem. Commun. 2013, 4800.
10. A typical procedure for the synthesis of isoxazolines and isoxazoles: Aldoxime 1
(0.5 mmol), alkene 2 (1.25 mmol), and KCl (0.5 mmol) were added to a flask
before water (3 ml) was added. OxoneÒ (0.75 mmol) was then added into the
stirred mixture. The mixture was stirred at room temperature for 3 h after the
reaction completed. The mixture was transformed into a separating funnel, and
the flask was washed with CH2Cl2 (4 ml). Extraction of the mixture with CH2Cl2
(2 Â 4 ml), the combined organic phase was dried over anhydrous Na2SO4,
filtered, and the filtration was concentrated under reduced pressure. The
residue was purified on a silica gel plate with Thin-Layer Chromatography
technique (10:1 petroleum ether–EtOAc) to provide the corresponding
isoxazoline 3.