A simple and efficient method for the synthesis of nitrile oxide from aldoxime using trichloroisocyanuric acid

Article abstract of DOI:10.1081/SCC-100105879

Treatment of the aldoxime derived from vanilin with trichloroisocyanuric acid in the presence of olefins as dipolarophiles caused the formation of nitrile oxides and subsequent 1,3-dipolar cycloaddition forming the corresponding isoxazoline derivatives in good yields.

Full text of DOI:10.1081/SCC-100105879

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A SIMPLE AND EFFICIENT METHOD FOR THE
SYNTHESIS OF NITRILE OXIDE FROM ALDOXIME USING
TRICHLOROISOCYANURIC ACID
Rogério da Conceição Rodrigues a & Alcino Palermo de Aguiar b
a Departamento de Engenharia Química, Instituto Militar de Engenharia, Rio de Janeiro,
22290-270, Brazil
b Departamento de Engenharia Química, Instituto Militar de Engenharia, Rio de Janeiro,
22290-270, Brazil
Published online: 16 Aug 2006.
To cite this article: Rogério da Conceição Rodrigues & Alcino Palermo de Aguiar (2001): A SIMPLE AND EFFICIENT METHOD
FOR THE SYNTHESIS OF NITRILE OXIDE FROM ALDOXIME USING TRICHLOROISOCYANURIC ACID, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 31:20, 3075-3080
To link to this article: http://dx.doi.org/10.1081/SCC-100105879
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SYNTHETIC COMMUNICATIONS, 31(20), 3075–3080 (2001)
A SIMPLE AND EFFICIENT METHOD
FOR THE SYNTHESIS OF NITRILE
OXIDE FROM ALDOXIME USING
TRICHLOROISOCYANURIC ACID
Rogerio da Conceicao Rodrigues
and Alcino Palermo de Aguiar*
Departamento de Engenharia Quımica,
Instituto Militar de Engenharia, 22290-270,
Rio de Janeiro, Brazil
ABSTRACT
Treatment of the aldoxime derived from vanilin with trichloro-
isocyanuric acid in the presence of olefins as dipolarophiles
caused the formation of nitrile oxides and subsequent 1,3-di-
polar cycloaddition forming the corresponding isoxazoline
derivatives in good yields.
INTRODUCTION
1,3-Dipolar cycloadditions offer a convenient one-step route for the
construction of five membered heterocycles.1 Cycloaddition of nitrile oxides
to alkenes is a synthetically important tool since the product isoxazolines
(4,5-dihydroisoxazoles) are useful intermediates for the preparation of
*Corresponding author.
3075
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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DA CONCEICAO RODRIGUES AND AGUIAR
bifunctional compounds,2 for example, b-hydroxy ketones, b-hydroxy
nitriles and g-amino alcohols. The usual synthetic methods for nitrile
oxide preparation are the oxidative dehydrogenation of aldoximes,3 the
reaction using primary nitro compounds,4 the dehydrohalogenation of
hydroximoyl halides,5 and the ring-fragmentation of furoxans.6 We wish
to report herein a new simple and efficient method for the direct conversion
of aldoximes into their nitrile oxides using trichloroisocianuric acid as oxi-
dation agent (in situ). Although different methods are known to form nitrile
oxides, the methodology in the present communication, using trichloroiso-
cyanuric acid, has not been reported in the literature.
RESULTS AND DISCUSSION
At first, vanilin was treated with benzyl bromide giving the etherified
product (mp 64–65ꢀC)7 in 85% yield,8 which was then treated with
NH2OH.HCl affording 1 in 93% yield.9 The hydroximoyl chloride 2
was obtained from the reaction of the respective aldoxime with an equimo-
lar amount of trichloroisocyanuric acid in dichloromethane at room
temperature. Finally, the alkene was added to this mixture, which was
then stirred for 24 h at room temperature (Scheme 1). The cycloaddition
reactions affored four new 4,5-dihydroisoxazoles regioselectively10 in good
yields (Table).
Scheme 1.

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NITRILE OXIDE
Table 1. Cycloaddition of Nitrile Oxides to Terminal Alkenes
3077
This reaction was investigated using alkene/nitrile oxide ratios 1 : 1,
2 : 1 and 3 : 1, with the reactions using lower ratios giving poorer yields and
evidence of polymerization of the nitrile oxide.11 The reactions were accom-
panied by thin layer cromatography until disappearance of the aldoxime,
then the reaction products were isolated by flash chromatography12 using
ethyl acetate–hexane (1 : 2) as eluent, affording the respective 4,5-dihydro-
isoxazoles in 30–60% yield. All products were characterized by FTIR, MS,
1
13C and H NMR techniques.
The regiochemistry for all the formed products can be predicted by
frontier molecular orbital theory13 which demonstrated that, in some cases,
the most substituted carbon will bind to the oxygen of the nitrile oxide as
a consequence of the interation HOMO-LUMO of the reagents.
EXPERIMENTAL
1 H and 13C NMR spectra were recorded in CDCl3 on a Varian Unity-
1
1
300 (300 MHz H and 75 MHz for 13C) and Bruker DPX 200 (200 MHz H
and 50 MHz for 13C) espectrometers, using TMS as an internal standard.
HRMS were recorded at 70 eV on Kratos MS50. Infrared spectra were

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DA CONCEICAO RODRIGUES AND AGUIAR
recorded with a Nicolet Magna IR 750. All melting points are uncorrected
and measured in a Fisher-Johns apparatus. TLC was carried out on pre-
coated Merck silica gel aluminum plates 60 F254. Column chromatography
was performed using silica gel 60 (230–240 mesh).
General Procedure
To a solution of trichloroisocyanuric acid (0.198 g–0.85 mmol),
0.15 mL of pyridine, and 15 mL de CH2Cl2 are added the aldoxime (1)
(mp 130–131ꢀC) in 5 mL of CH2Cl2. The mixture was stirred for about
24 h as RT and the alkenes in the ratios 1:1, 2:1 or 3:1 were added followed
by triethylamine (0.40 mL–2.80 mmol). An exoterm reaction ensued and the
mixture became dark yellow. After stirring for further 24 h at RT, the mix-
ture was diluted to 50 mL with CH2Cl2 and washed with aqueous saturated
NaHCO3 solution (2 ꢁ 70 mL), dried over MgSO4 and concentrated to dry-
ness under vacuum. Purification by flash chromatography (20 g of silica gel)
using ethyl acetate–hexane (1 : 2) gave the respectives 4,5-dihydroisoxazoles
in 30–60%.
3-(3-methoxy-4-(phenylmethoxy)-5-cyano-4,5-dihydroisoxazole
(5):
(mp 104–105ꢀC) HRMS (m/z-%) (Mþ ¼ 308.1171-100%); IR (neat, cmꢂ1
)
1681 (C¼N), 1600 (C¼C), 1270 (C-O-C), 13C NMR (75 MHz, CDCl3, APT)
d 155.9 (C-3), 150.5 (C-9), 149.6 (C-8), 136.1 (C-13), 128.5 (C-14/18), 127.9
(C-16), 127.1 (C-15/17), 120.6 (C-11), 120.1 (C-6), 117.1 (CN), 112.6 (C-10),
109.1 (C-7), 70.5 (C-12), 66.3 (C-5), 55.8 (C-19), 40.9 (C-4). 1H NMR
(300 MHz, CDCl3) d 3.68 (m, H-4), 3.91 (s, H-19), 5.20 (s, H-12), 5.31
3
3
3
(dd, JH5-4A ¼ 9.9 Hz, JH5-4B ¼ 6.8 Hz, H-5), 6.88 (d, JH-H ¼ 8.3 Hz,
3
4
H-10), 6.97 (dd, JH-H ¼ 8.3 Hz, JH-H ¼ 2.0 Hz, H-11), 7.40 (m, H-7,
14, 15, 16, 17, 18).
3-(3-methoxy-4-(phenylmethoxy)-5-bromomethane-4,5-dihydroisoxa-
zole (6): (mp 93–94ꢀC) HRMS (m/z-%) (Mþ ¼ 375.0484 – 100%); IR (neat,
cmꢂ1) 3070 (¼C-H), 1599 (C¼C), 1263 (C-O-C); 13C NMR (75 MHz,
CDCl3) d 155.6 (C-3), 150.0 (C-9), 149.6 (C-8), 136.4 (C-13), 128.5 (C-14/
18), 127.9 (C-16), 127.1 (C-15/17), 122.0 (C-11), 120.2 (C-6), 112.8 (C-10),
109.0 (C-7), 79.4 (C-5), 70.6 (C-12), 55.9 (C-19), 39.5 (C-4), 33.1 (CH2Br);
1H NMR (300 MHz, CDCl3) d 3.42 (m, H4A,4B and CH2Br), 3.92 (s, H-19),
3
4.97 (m, H-5), 5.20 (s, H-12), 6.86 (d, JH-H ¼ 8.1 Hz, H-10), 6.97 (dd,
4
3JH-H ¼ 8.1 Hz, JH-H ¼ 2.1 Hz, H-11), 7.37 (m, H-7, 14, 15, 16, 17, 18).
3-(3-methoxy-4-(phenylmethoxy)-5-ethoxy-4,5-dihydroisoxazole (7):
)
(mp 80–81ꢀC) HRMS (m/z-%) (Mþ ¼ 327.1435-100%); IR (neat, cmꢂ1
2974 (CH3as), 2937 (CH2as), 2871 (CH3s), 1600 (C¼C), 1265 (C-O-C);
13C NMR (50 MHz, CDCl3 PENDANT) d 156.9 (C-3), 150.2 (C-9), 149.8

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NITRILE OXIDE
3079
(C-8), 136.7 (C-13), 128.7 (C-14/18), 128.1 (C-16), 127.3 (C-15/17), 122.5
(C-6), 120.6 (C-11), 113.2 (C-10), 109.4 (C-7), 103.0 (C-5), 70.9 (C-12), 63.8
(OCH2C), 56.1 (C-19), 41.8 (C-4), 15.2 (OCCH3); 1H NMR (200 MHz,
3
2
CDCl3) d 1.22 (t, JH-H ¼ 7.1 Hz, OCCH3), 3.16 (dd, J4A-4B ¼ 17.2 Hz,
3J4A-H5 ¼ 1.4 Hz, H-4), 3.36 (dd, J4B-4A ¼ 17.2 Hz, J4B-H5 ¼ 6.4 Hz, H-4),
2
3
3.59 (m, OCH2C, 1H), 3.90 (m, OCH2C, 1H), 3.91 (s, H-19), 5.18 (s,
3
3
H-12), 5.65 (dd, JH5-4B ¼ 6.4 Hz, JH5-4A ¼ 1.4 Hz, H-5), 6.85 (d,
3JH-H ¼ 8.3 Hz, H-10), 6.98 (dd, JH-H ¼ 8.3 Hz, JH-H ¼ 1.6 Hz, H-11), 7.35
3
4
(m, H-7, 14, 15, 16, 17, 18).
3-(3-methoxy-4-(phenylmethoxy)-5-methylcarboxylate-4,5-dihydroiso-
xazole (8): (mp 111–112ꢀC) HRMS (m/z-%) (Mþ ¼ 341.1254-100%); IR
(neat, cmꢂ1) 1742 (C¼O), 1601 (C¼C), 1238 (C-O-C); 13C NMR (75 MHz,
CDCl3) d 170.8 (CO2), 155.7 (C-3), 150.1 (C-9), 149.6 (C-8), 136.3 (C-13),
128.5 (C-14/18), 127.9 (C-16), 127.1 (C-15/17), 121.4 (C-11), 120.4 (C-6),
112.7 (C-10), 109.2 (C-7), 77.7 (C-5), 70.6 (C-12), 55.9 (C-19), 52.7
1
(CO2CH3), 38.9 (C-4); H NMR (300 MHz, CDCl3) d 3.58 (m, H-4), 3.79
(s, CO2CH3), 3.90 (s, H-19), 5.13 (m, H-5), 5.18 (s, H-12), 6.85 (d,
3
4
3JH-H ¼ 8.3 Hz, H-10), 6.97 (dd, JH-H ¼ 8.3 Hz, JH-H ¼ 2.0 Hz, H-11), 7.40
(m, H-7, 14, 15, 16, 17, 18).
CONCLUSION
We have developed a facile and effective procedure to convert hydro-
ximoyl chloride into the corresponding nitrile oxide which gives 4,5-dihy-
droisoxazoles via 1,3-dipolar cycloaddition. Further studies involving
bioactive14 comportment of our products are in progress as well synthesis
of new 4,5-dihydroisoxazoles.
ACKNOWLEDGMENT
We thanks CAPES and FAPERJfor the financial support of this
work, and Dr. Edson Ferreira da Silva, Monica Zucolotto, Dr. Elisabete
Cruz and Lab. NMR of IQ/UFRJfor spectral analysis.
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Received in the USA December 4, 2000

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