An expeditious synthesis of isoxazoline using cetyltrimethylammonium cerium nitrate: A phase transferring oxidative 1,3-dipolar cycloaddition

Article abstract of DOI:10.1016/j.cclet.2010.05.015

An expeditious and effective method for synthesis of isoxazoline from aldoximes and activated alkenes using cetyltrimethylammonium cerium nitrate at room temperature is described. Reaction was completed within short time period in high yields at room temp

Full text of DOI:10.1016/j.cclet.2010.05.015

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Chinese Chemical Letters 21 (2010) 1287–1290
www.elsevier.com/locate/cclet
An expeditious synthesis of isoxazoline using
cetyltrimethylammonium cerium nitrate: A phase
transferring oxidative 1,3-dipolar cycloaddition
b
Parvin Kumar a, , Ashwani Kumar
*
a Department of Chemistry, Guru Nanak Khalsa P G College, Yamuna Nagar, Haryana 135001, India
b Drug Discovery and Research Laboratory, Department of Pharmaceutical Sciences,
Guru Jambheshwar University of Science & Technology, Hissar, Haryana 125001, India
Received 8 March 2010
Abstract
An expeditious and effective method for synthesis of isoxazoline from aldoximes and activated alkenes using cetyltrimethy-
lammonium cerium nitrate at room temperature is described. Reaction was completed within short time period in high yields at
room temperature.
# 2010 Parvin Kumar. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Cetyltrimethylammonium cerium nitrate; Isoxazoline; Oxime; Activated alkene; 1,3-Dipolar addition
Isoxazole and its dihydro derivative isoxazoline is essential motif found in several important bioactive molecules
and act as a starting material for the synthesis of certain biological active compounds [1]. Muscimol formed from the
mushroom Amanita muscaria has powerful psychotropic effects. Muscimol shows activity in brain nerve cell, which
use g-aminobutyric acid (GABA) as a neurotransmitter. Some of the compounds [2] containing isoxazole or
isoxazoline ring have been known to be antipsychotic, analgesic, antituberculosis, antitumor and semi-synthetic
antibiotic drugs such as muscimol, valdecoxib, cycloserine, isoxazoline and oxacilline (Fig. 1).
Cerium (IV) ammonium nitrate (CAN) is one of the most interesting oxidants in organic synthesis since it is stable
in different solvents and is commercially available. The use of this reagent for numerous reactions involving C–S, C–
N, C–Se and C–Cl bond formation has been evaluated [3–6]. However, application of CAN is limited due to poor
solubility in common organic solvents. Therefore, phase transfer oxidant cetyltrimethylammonium cerium nitrate
[7,8] is a good alternative of CAN and soluble in water as well as in common organic solvents.
Encouraged by these observations, in this communication synthesis of isoxazoline from aldoximes and activated
alkenes using cetyltrimethylammonium cerium nitrate is demonstrated.
The reagent is easily prepared by addition of a weighed amount of cerium ammonium nitrate (0.01 mol) to an
aqueous solution of cetyltrimethylammonium bromide (0.025 mol) [8,9]. Aldoximes of benzaldehyde, 2-
chlorobenzaldehyde and 3-nitrobenzaldehyde were synthesized and then reacted with activated alkenes (methyl
* Corresponding author.
E-mail address: drpkawasthignkc@rediffmail.com (P. Kumar).
1001-8417/$ – see front matter # 2010 Parvin Kumar. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.05.015

[(Fig._1)TD$FIG]
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P. Kumar, A. Kumar / Chinese Chemical Letters 21 (2010) 1287–1290
Fig. 1. Known drugs having isoxazole or isoxazoline ring.
[(Scheme_1)TD$FIG]
Scheme 1.
acrylate, acrylonitrile and vinyl acetate) in the presence of cetyltrimethylammonium cerium nitrate to produce
isoxazolines in high yields (Scheme 1) (Table 1).
All reactions were carried out at room temperature and completed with in a short time period (0.5–1 h).
Reactions proceed smoothly and the effect of an electron donating or an electron-withdrawing group on the
aromatic ring of the aldoximes was not observed. However, when aldoxime of m-hydroxybenzaldehyde was used, a
dark brown coloured solution was obtained and no isoxazoline ring was formed. This might be due to oxidation of
phenolic group. The influence of various solvents was also investigated using H2O, CH2Cl2, CHCl3, CH3CN and
THF. All organic solvent gave comparable result and best reaction temperature was room temperature. However, in
water deoximination product was obtained as major product. The probable mechanism of the reaction is shown in
Scheme 2. The mechanism involves 1,3-dipolar addition of nitrile oxides, formed from the aldoximes, to the
activated alkenes. Using optimized reaction conditions [10], various isoxazolines were synthesized in high yield.
1
The appearance of doublet of doublet in the region d 5.3–6.8 (1H, dd) in H NMR spectra of compound 3 clearly
indicates that other regioisomers 4 (2H, –OCH2–) were not at all formed. The literature survey shows that cerium
ammonium nitrate has been already used in the synthesis of isoxazolines [11]. Due to insolubility or partially
solubility of cerium ammonium nitrate in organic solvent, reaction time period was long and more deoximination
occurred, led to low yield.
In conclusion, cetyltrimethylammonium cerium nitrate has been employed for the first time as a mild and efficient
reagent for 1,3-dipolar intermolecular cycloaddition reaction. The procedure proved to be simple either in conducting
the reaction or in isolation of the products.
Table 1
Cetyltrimethylammonium cerium nitrate mediated synthesis of isoxazolines 3.
Serial no.
Product
Ar
R
Time (min)
Yield
Mp (8C)
Lit. mp (8C) [11,12]
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
m-NO2–C6H4–
o-Cl–C6H4–
C6H5–
CN
30
30
30
30
30
30
45
45
45
93
92
93
92
94
93
92
90
92
107–108
106–107
Semisolid
–
CN
Viscous oil
Viscous oil
100–101
CN
m-NO2–C6H4–
o-Cl–C6H4–
C6H5–
COOCH3
COOCH3
COOCH3
OCOCH3
OCOCH3
OCOCH3
99–100
Semisolid
–
Viscous oil
Viscous oil
103–104
3g
3h
3i
m-NO2–C6H4–
o-Cl–C6H4–
C6H5–
104–105
Semisolid
–
Viscous oil
Viscous oil

[(Scheme_2)TD$FIG]
P. Kumar, A. Kumar / Chinese Chemical Letters 21 (2010) 1287–1290
1289
Scheme 2.
References
[1] (a) R.E. Sammelson, T. Ma, L.J.V. Galietta, et al. Bioorg. Med. Chem. Lett. 13 (2003) 2509;
(b) G. Bal, P.V. Venken, D. Antonov, et al. Bioorg. Med. Chem. Lett. 13 (2003) 2875;
(c) A. Lang, Y. Lin, in: A.R. Katrizky (Ed.), Comprehensive Heterocyclic Chemistry, vol. 6, Pergamon Press, Oxford, 1984, p. 1;
(d) K.J. Hwang, H.J. Kim, J.H. Lee, Korean J. Med. Chem. 4 (1994) 2.
[2] (a) A. Quilico, in: R.H. Wiley (Ed.), Five and Six Membered Compound with Nitrogen and Oxygen, Wiley Interscience, 1962, p. 1;
(b) B.J. Wakefield, D.J. Wright, Adv. Heterocycl. Chem. 25 (1979) 147;
(c) P. Krogsgaard-Larsen, L. Brehm, K. Schaumberg, Acta Chem. Scand. B 35 (1981) 311;
(d) D.G. Martin, D.J. Duchamp, C.G. Chidester, Tetrahedron Lett. 14 (1973) 2549;
(e) T. Kusumi, C.C. Chang, M. Wheeler, et al. Tetrahedron Lett. 22 (1981) 3451;
(f) A.P. Kozikowski, Acc. Chem. Res. 17 (1984) 410;
(g) B.B. Shankar, D.Y. Yang, S. Girton, et al. Tetrahedron Lett. 39 (1998) 2447.
[3] (a) V. Nair, J. Matthew, J. Prabhakaran, Chem. Soc. Rev. 26 (1997) 127;
(b) J.R. Hwu, K.Y. King, Curr. Sci. 81 (2001) 1043;
(c) V. Nair, S.B. Panicker, L.G. Nair, et al. Synlett (2003) 156.
[4] T. Sugai, N. Watanabe, H. Ohta, Tetrahedron: Asymmetry 2 (1991) 371.
[5] (a) S.C. Roy, C. Guin, K.K. Rana, et al. Synlett (2001) 226;
(b) S.C. Roy, B. Banerjee, Synlett (2002) 1677.
[6] (a) S.Y. Wang, S.J. Ji, Tetrahedron 62 (2006) 1527;
(b) G. Savitha, P.T. Perumal, Tetrahedron Lett. 47 (2006) 3589;
(c) V. Nair, K. Mohanan, T.D. Suja, et al. Tetrahedron Lett. 47 (2006) 705;
(d) R. Varala, R. Enugala, S. Nuvula, et al. Synlett (2006) 1009;
(e) V. Sridharan, C. Avendano, J.C. Menendez, Tetrahedron 63 (2007) 673.
[7] E.V. DehmLow, J.K. Makrandi, J. Chem. Res. (S) (1986) 32.
[8] B.K. Mishra, M. Kunar, A. Sharma, B.B. Nayak, Indian J. Chem. 40B (2001) 724.
[9] Synthesis of cetyltrimethylammonium cerium (IV) nitrate: Cerium (IV) ammonium nitrate (0.01 mol) in 10 mL water was added slowly to an
aqueous solution of cetyltrimethylammonium bromide (0.025 mol) with continuous stirring on a magnetic stirrer. Ayellow coloured compound
appeared slowly. Stirring was continued for 30 min. The resulting yellow coloured compound was filtered with water for several times till no
trace of bromide ion was detected in the filtrate. It was vacuum dried and kept in a dark bottle inside desiccator, yield 93%. Anal. Calcd. for
C38H84N8O15Ce: C, 42.22; H, 7.77; N, 13.37. Found: C, 42.50; H, 7.96; N, 13.32%.
[10] General experimental procedure for synthesis of 3: An aldoxime 1 (1.0 mmol) and methyl acrylate/acrylonitrile/vinyl acetate (1.2 mmol) were
taken in anhydrous CH2Cl2 (25 mL). Cetyltrimethylammonium cerium nitrate (2.36 g, 2.2 mmol) was added and the reaction mixture was
stirred at room temperature for the time as indicated in Table 1. The reaction was monitored by TLC. After completion, water (20 mL) was
added and shaken well. Separated the organic layer and again washed with water (10 mL), dried over MgSO4 and concentrated. The residue
was subjected to column chromatography over silica gel using hexane–ethylacetate (5:2) as eluent to obtain pure isoxazoline 3. Spectral data of
synthesized oxazoline are given below: 3a 1H NMR (CDCl3, 400 MHz): d 8.46 (d, 1H, J = 2.1 Hz), 8.35 (dd, 1H, J = 8.0, 2.1 Hz), 8.09 (dd, 1H,
J = 8.0, 2.0 Hz), 7.69 (m, 1H), 5.48 (dd, 1H, J = 8.0, 5.8 Hz), 3.83 (dd, 1H, J = 11.5, 8.0 Hz), 3.71 (dd, 1H, J = 11.5, 5.8 Hz); MS (EI): m/z
217.05 (Mꢀ+) (Found: C, 55.39; H, 3.33; N, 19.27. C10H7N3O3 requires: C, 55.30; H, 3.25; N, 19.35%). 3b 1H NMR (CDCl3, 400 MHz): d 7.74
(dd, 1H, J = 7.9, 2.2 Hz), 7.50–7.28 (m, 3H), 5.38 (dd, 1H, J = 8.0, 4.3 Hz), 3.94 (dd, 1H, J = 11.6, 8.0 Hz), 3.79 (dd, 1H, J = 11.6, 4.3 Hz); MS
1
(EI): m/z 206.02, 208.02 (Mꢀ+) (Found: C, 58.23; H, 3.37; N, 13.44. C10H7ClN2O. requires: C, 58.13; H, 3.41; N, 13.56; %). 3c H NMR
(CDCl3, 400 MHz): d 7.76 (m, 2H), 7.45 (m, 3H), 5.35 (dd, 1H, J = 8.0, 5.7 Hz), 3.83 (dd, 1H, J = 11.5, 8.0 Hz), 3.71 (dd, 1H, J = 11.5,
5.7 Hz); MS (EI): m/z 172.06 (Mꢀ+) (Found: C, 69.64; H, 4.78; N, 16.32. C10H8N2O requires: C, 69.76; H, 4.68; N, 16.27%). 3d 1H NMR
(CDCl3, 400 MHz): d 8.44 (d, 1H, J = 2.2 Hz), 8.30 (dd, 1H, J = 8.0, 2.2 Hz), 8.10 (dd, 1H, J = 8.0, 2.0 Hz), 7.68 (m, 1H), 5.28 (dd, 1H,
J = 8.2, 3.8 Hz), 3.83 (s, 3H), 3.78 (dd, 1H, J = 11.5, 8.2 Hz), 3.62 (dd, 1H, J = 11.5, 3.8 Hz); MS (EI): m/z 250.06 (Mꢀ+) (Found: C, 52.92; H,
4.12; N, 11.24. C11H10N2O5 requires: C, 52.80; H, 4.03; N, 11.20%). 3e 1H NMR (CDCl3, 400 MHz): d 7.73 (dd, 1H, J = 7.9, 2.2 Hz), 7.42–
7.25 (m, 3H), 5.16 (dd, 1H, J = 7.9, 3.9 Hz), 3.79 (dd, 1H, J = 11.6, 7.9 Hz), 3.62 (dd, 1H, J = 11.6, 3.9 Hz), 3.85 (s, 3H); MS (EI): m/z 239.03,
241.03 (Mꢀ+) (Found: C, 55.22; H, 4.27; N, 5.74. C11H10ClNO3 requires: C, 55.13; H, 4.21; N, 5.84%). 3f 1H NMR (CDCl3, 400 MHz): d 7.76
(d, 2H, J = 7.5 Hz), 7.45 (m, 3H), 5.17 (dd, 1H, J = 8.1, 4.2 Hz), 3.79 (dd, 1H, J = 11.6, 8.1 Hz), 3.62 (dd, 1H, J = 11.6, 4.2 Hz), 3.85 (s, 3H);
MS (EI): m/z 205.07 (Mꢀ+) (Found: C, 64.45; H, 5.51; N, 7.02. C11H11NO3 requires: C, 64.38; H, 5.40; N, 6.83%). 3g 1H NMR (CDCl3,
400 MHz): d 8.45 (d, 1H, J = 2.2 Hz), 8.30 (dd, 1H, J = 8.0, 2.2 Hz), 8.09 (dd, 1H, J = 8.0, 2.0 Hz), 7.67 (m, 1H), 6.83 (dd, 1H, J = 8.2,
3.8 Hz), 3.68 (dd, 1H, J = 11.5, 8.2 Hz), 3.40 (dd, 1H, J = 11.5, 3.8 Hz), 2.12, (s, 3H); MS (EI): m/z 250.06 (Mꢀ+) (Found: C, 52.94; H, 3.97; N,

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P. Kumar, A. Kumar / Chinese Chemical Letters 21 (2010) 1287–1290
11.14. C11H10N2O5 requires: C, 52.80; H, 4.03; N, 11.20%). 3h 1H NMR (CDCl3, 400 MHz): d 7.79 (dd, 1H, J = 8.1, 1.9 Hz), 7.48–7.23 (m,
3H), 6.80 (dd, 1H, J = 8.8, 3.9 Hz), 3.82 (dd, 1H, J = 11.6, 8.8 Hz), 3.42 (dd, 1H, J = 11.6, 3.9 Hz), 2.16 (s, 3H); MS (EI): m/z 239.03, 241.03
(Mꢀ+) (Found: C, 55.24; H, 4.19; N, 5.92. C11H10ClNO3 requires: C, 55.13; H, 4.21; N, 5.84%). 3i 1H NMR (CDCl3, 400 MHz): d 7.76 (m, 2H),
7.45 (m, 3H), 6.73 (dd, 1H, J = 8.6, 3.6 Hz), 3.78 (dd, 1H, J = 11.6, 8.6 Hz), 3.50 (dd, 1H, J = 11.6, 3.6 Hz), 2.16 (s, 3H); MS (EI): m/z 205.07
(Mꢀ+) (Found: C, 64.22; H, 5.33; N, 6.98. C11H11NO3 requires: C, 64.38; H, 5.40; N, 6.83%).
[11] B. Das, G. Mahender, H. Holla, et al. ARKIVOC III (2005) 27.
[12] B. Das, H. Holla, G. Mahender, et al. Tetrahedron Lett. 45 (2004) 7347.