One step regioselective synthesis of 5-aminoisoxazoles from nitrile oxides and α-cyanoenamines

Article abstract of DOI:10.3390/90700527

The 1,3-dipolar cycloaddition of nitrile oxides to 1-cyanoenamines gives 5-aminoisoxazoles regioselectively. Moderate to good yields could be obtained depending on the method used to generate the nitrile oxides. The intermediate isoxazolines could not be isolated.

Full text of DOI:10.3390/90700527

Molecules 2004, 9, 527-534
molecules
ISSN 1420-3049
http://www.mdpi.org
One Step Regioselective Synthesis of 5-Aminoisoxazoles from
Nitrile Oxides and α-Cyanoenamines
Amar Saad 1,*, Michel Vaultier 2 and Aïcha Derdour 1
1
Université d’Oran Es-sénia, Laboratoire de Synthèse Organique Appliquée, Département de
Chimie, Faculté des Sciences, BP 1524 El M’naouar, 31000 Oran, Algeria; Fax : +213-41-416021.
Université de Rennes 1, Laboratoire de Synthèse et Electrosynthèse Organiques, UMR 6510. Bât.
2
10A, Campus de Beaulieu, Avenue du Général Leclerc 35042, Rennes Cedex, France; E-mail:
Michel.vaultier@univ-rennes1.fr
* To whom correspondence should be addressed: saadamar@Yahoo.fr
Received: 26 February 2004 / Accepted: 5 April 2004 / Published: 30 June 2004
Abstract: The 1,3-dipolar cycloaddition of nitrile oxides to 1-cyanoenamines gives
5-aminoisoxazoles regioselectively. Moderate to good yields could be obtained
depending on the method used to generate the nitrile oxides. The intermediate
isoxazolines could not be isolated.
Keywords: 1-Cyanoenamines; nitrile oxides; 1,3-dipolar cycloaddition; 5-amino-
isoxazoles.
Introduction
Many 5-aminoisoxazoles are of biological interest and display fungicidal [1], antihelmintic [3] or
bactericidal properties [1,4] or are useful for treatment of cerebrovascular disorders [2]. Few literature
methods describe the preparation of 5-aminoisoxazoles. The nucleophilic substitution by an amine
with a 5-chloroisoxazole was described for the first time by Schäfer [5], while the intramolecular
cyclisation of thioenamines [6] and the dipolar cycloaddition involving a nitrile oxide and either a
nitrodienamine [7], an enyne [8], or ethylene dienamine [9], all lead to 5-aminoisoxazoles in moderate
yields.

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Result and Discussion
We report a simple one-pot procedure for the preparation of 5-aminoisoxazoles in toluene using a
1,3-dipolar cycloaddition reaction between nitrile oxides and captodative α-cyanoenamines, as
described below.
The 1,3-dipoles 1a-c were prepared by dehydrohalogenation of a chloroxime for R = p-ClPh (1a,
method A) or dehydration of a primary nitro derivative by the Mukayama method [10] for R = Me
(1b, method B), while nitromethane (method C) [11] was a particular case, as in contrast to the
secondary aliphatic nitro derivatives, which in the presence of phenylisocyanate and triethylamine
(method B) easily gave the corresponding nitrile oxides, nitromethane leads under the same
conditions to the formation of the corresponding cyanoformanilide N-oxide and not the desired
fulminic acid. 1-Cyanoenamine compounds 2a-c were prepared from α-chloroacetaldehyde following
the procedure described by Temin [12] and improved by Boucher and Stella [13b]. The reactivity of
these compounds has been the subject of many studies. They have significant dienophilic properties
[13-14], and have been used in (2+2) [15] and (3+2) cycloaddition reactions [16]. The 1,3-dipolar
cycloadditions of these 1-cyanoenamines with nitrile oxides 1a-c were carried out in toluene at room
temperature overnight and led directly to the corresponding 5-aminoisoxazoles 5 without requiring
isolation of the transient isoxazolines 3, which spontaneously eliminated HCN as shown in Scheme 1.
Scheme 1: Synthesis of 5-aminoisoxazoles 4a-i.
R
R
CN
-HCN
O
R-C
N
+
CN
NR1R2
N
N
64-94%
NR1R2
NR1R2
O
O
(4a-i)
(1 a-c)
(2 a-c)
(3a-i)
The cycloaddition reactions of the nitrile oxides 1 with the cyanoenamines 2 proved to be highly
regioselective, leading to a single regioisomer. The regioselectivity of the cycloaddition reactions of
nitrile oxides with dipolarophiles and their mechanism have been explained in the literature [17]. As
in the case of the cycloaddition reactions of arylazides [16], the α-cyanoenamines 2 behave as the
synthetic equivalents of the corresponding aminoacetylenes [18].

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Table I. Preparation of 5-aminoisoxazoles
Yield (%) a
R
Products
NR1R2
N
N
O
4a
4b
4c
4d
4e
4f
p-ClPh
p-ClPh
p-ClPh
Me
75
94
N
N
N
N Me
O
70
N
N
85
Me
70
N Me
O
Me
75
4g
4h
4i
PhNHCO
PhNHCO
PhNHCO
64b
58b
65b
N
N
N Me
a Yields of isolated, pure products.
b
The 5-aminoisoxazoles 4g-i were
obtained by refluxing overnight after
stirring 12 hours at room temperature.
The yields were generally good and depended on the method used to generate the nitrile oxides.
For methods A (compounds 4a-c) and B (compounds 4d-f) the yields ranged from70 to 95%, whereas
for method C (compounds 4g-i), yields ranging from 58 to 65% were obtained.
Conclusions
The 1,3-dipolar cycloaddition of nitrile oxides with α-cyanoenamines is a one step, very efficient
and simple method for the preparation of 5-aminoisoxazoles.
Experimental
General
1
Melting points and boiling points are uncorrected. Unless stated otherwise H-NMR and
13C-NMR spectra were recorded for CDCl3 solutions at 300 MHz and 75.5 MHz, respectively, on a

Molecules 2004, 9
530
Bruker AM300 spectrometer using TMS as internal standard. IR spectra were recorded on a BioRad
FTS 175C spectrophotometer using KBr pellets. Column chromatography purifications were carried
out using silica gel (60-230 mesh).
Synthesis of Nitrile Oxides 1a-c.
p-Chlorobenzonitrile oxide (1a) was obtained by the procedure described in ref. [19] (method A)
from the corresponding chloroxime, by elimination of hydrochloric acid using triethylamine at low
temperature. The nitrile oxides 1b and 1c were generated in situ by dehydration of nitroethane for 1b
(method B) and nitromethane for 1c (method C).
Synthesis of α-Cyanoenamines 2a-c
1-Morpholinoacrylonitrile (2a) was obtained by Temin’s procedure, as modified by Boucher and
Stella for the synthesis of 2-(N-methylanilino)acrylonitrile [13b]. The reaction was carried out by
mixing a 50% aqueous solution of chloroacetaldehyde (39.25 g, 0.25 mol) and morpholine (0.25 mol)
at room temperature for 2 h. An aqueous solution of potassium cyanide (0.30 mol) was then added
slowly to the stirred solution, followed by dropwise addition of triethylamine to the mixture. The
solid formed was filtered off and recrystallized from cyclohexane to give a 54% yield of a colorless
1
solid; mp = 61-63°C; IR (film, cm-1): 2220 (CN), 1590 (C=C); H-NMR: δ (ppm) = 3.30 (m, J =
13
5.0Hz, 4H), 3.75 (m, J = 5.0Hz, 4 H), 4.66 (d, J = 1.8Hz, 1 H), 4.85 (d, J = 1.8Hz, 1 H); C-NMR
(50.0MHz): δ = 48.0 (-CH2-N-CH2-), 55.9 (-CH2-O-CH2-), 101.3 (CH2=C), 115.5 (CN),
130.1 (CH2=C).
1-Piperidinoacrylonitrile (2b) was obtained by the procedure described for preparation of 2a by
mixing a 50% aqueous solution of chloroacetaldehyde (39.25 g, 0.25 mol), piperidine (0.25 mol) and
potassium cyanide (0.30 mol) at room temperature for 2 h. The mixture was treated with
triethylamine and extracted with ether (3 x 40 mL). The solvent was removed and the crude product
was purified by distillation to give 16.3g. (48%) of a colorless liquid; bp = 43-45°C/5x10-2 torr.; IR
(film, cm-1): 2220 (CN), 1590 (C=C); 1H-NMR: δ (ppm) = 1.6 (m, 6 H, -CH2-CH2-CH2-), 2.99 (m,4
H, -CH2-N-CH2-), 4.55 (d, J = 1.8Hz, 1 H, vinylic), 4.72 (d, J = 1.8Hz, 1 H, vinylic); 13C-
NMR: δ (ppm) = 23.7 (-CH2-CH2-CH2-), 24.8 (-CH2-CH2-CH2-), 48.8 (-CH2-N-CH2-), 99.9
(CH2=C), 116.3(CN), 130.4(CH2=C).
1-(N-methyl)-piperazinoacrylonitrile (2c) was obtained by the same procedure as described for
(2a) from 0.25 mol of a 50% aqueous solution of α-chloroacetaldehyde and 0.25 mol of N-methyl-
piperazine. The reaction yielded 13.2 g (35%) of 2c as a colorless liquid; bp = 60-65°C/5x10-2 torr;
IR (film, cm-1): 2220 (CN), 1590 (C=C); 1H-NMR: δ (ppm) = 2.32 (s, 3 H, CH3), 2.47 (m, 4 H, -CH2-
N-CH2-), 3.04 (m, 4 H), 4.61 (d, J =1.9Hz, 1 H, vinylic), 4.80 (d, J = 1.9Hz, 1 H, vinylic);

Molecules 2004, 9
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13C-NMR: δ (ppm) = 46.0 (-N-CH3), 47.8 (-CH2-N-CH2-), 54.0 (-CH2-N-CH2-), 101.3 (CH2=C),
115.5 (CN), 130.1 (CH2=C).
General procedures for the synthesis of aminoisoxazoles 4.
Method A
Warning: The reaction releases hydrogen cyanide (a negligible quantity), so it is imperative to work
under a hood with good ventilation. A 50 mL two-neck round bottom flask, flamed dried under N2
and containing p-chlorobenzonitrile (2 mmol) in dry toluene (10 mL) was cooled in an ice bath while
a solution of the 1-cyanoenamine (2 mmol) in dry toluene (10 mL) was added dropwise. The reaction
mixture was stirred overnight at room temperature. The solvent was removed and the obtained oil was
recrystallised from an appropriate solvent.
1-[3-(4-Chlorophenyl)-isoxazol-5-yl)morpholine (4a). White solid; yield = 75 %; mp = 137-138°C
(recrystallised from ethyl ether); 1H-NMR: δ (ppm) = 3.35 (dd, J = 5.0Hz, J = 4.8 Hz, 4 H,-CH2-N-
CH2-), 3.80 (dd, J = 5.0Hz; J = 4.8Hz, 4 H,-CH2-O-CH2-), 5.30 (s,1 H, C4-H), 7.40-7.64 (2d, J =
13
8.6Hz; 4 H; C6H4); C-NMR: δ (ppm) = 46.7-65.9 [-(CH2)2-N-(CH2)2-O], 76.6 (C4); 127.8/128.3/
128.9/135.6 (Carom), 162.5 (C5), 171.4 (C3); Anal. Calcd. for C13H13ClN2O2: C, 58.99; H, 4.95; N,
10.58; found: C, 59.43; H, 5.23; N, 10.27.
1-[3-(4-Chlorophenyl)isoxazol-5-yl)piperidine (4b). White solid; yield = 94 %; mp = 110-112°C
1
(recrystallised from 1:1 hexane/ether); H-NMR: δ (ppm) = 2.00 [m, 6 H,-(CH2)3-], 3.33 (m, 4
13
H, -CH2-N-CH2-), 5.23 (s ,1 H, C4-H), 7.40-7.64 (2d, J = 8.6Hz; 4 H, C6H4); C-NMR: δ (ppm) =
23.8-47.6 (-(CH2)5-N-), 127.8/128.6/128.8/135.5 (Carom), 162.5 (C5), 171.6 (C3); Anal. Calcd. for
C14H15ClN2O: C, 64.00; H, 5.75; N, 10.66; found: C, 63.65; H, 6.08; N, 10.22.
1-[3-(4-Chloro-phenyl)isoxazol-5-yl)]-4-methylpiperazine (4c). Colorless solid; yield = 70 %; mp =
127-128°C (recrystallised from 1:1 hexane/ether); 1H-NMR: δ (ppm) = 2.33 (s, 3 H, CH3), 2.51 (dd, J
= 5.0Hz, J = 5.1Hz, 4 H, -CH2-N-CH2-), 3.39 (dd, J = 5.0Hz, J = 5.1Hz, 4 H, -CH2-N-CH2-), 5.27 (s,
1H, C4-H), 7.4-7.64 (2d, J = 8.6Hz, 4 H, C6H4); 13C-NMR: δ (ppm) = 171.3 (C3), 162.5 (C5),
127.8/128.4/128.8/135.5 (Carom.), 76.4 (C4), 46.4-53.8 [-(CH2)2-N-(CH2)2-N-], 46.1 (-N-CH3); Anal.
Calcd. for C14H16ClN3O: C, 60.50; H, 5.81; N, 15.13; found: C, 60.16 ; H, 5.67; N, 14.85.
Method B
Warning: The reaction releases hydrogen cyanide (a negligible quantity), so it is imperative to work
under a hood with good ventilation. Triethylamine (5 drops) was added slowly to a 50 mL two-neck
round bottom flask, flame dried under N2, containing the 1-cyanoenamine (5 mmol), nitroethane (6

Molecules 2004, 9
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mmol, 1.2 equivalents) and distilled phenylisocyanate (9 mmol, 1.8 equivalents) in dry toluene (15
mL). Diphenylurea precipitated. Stirring was continued overnight at room temperature. The urea was
filtered off and the solution concentrated in vacuo. The obtained products were purified by column
chromatography on silica gel or distillation.
4-(3-Methylisoxazol-5-yl)morpholine (4d). Colorless solid; yield = 85 %; mp = 42-45°C; TLC: Rf =
1
0.66 (80:20 v/v ether/heptane); H-NMR: δ (ppm) = 2.15 (s, 3 H, CH3), 3.27 (dd, J =5.0Hz, J =
4.8Hz, 4 H, -CH2-N-CH2-), 3.37 (dd, J =5.0Hz, J =5.1Hz; 4 H, -CH2-O-CH2-), 4.89 (s, 1 H, C4-H);
13C-NMR: δ (ppm) = 170.8 (C3), 161.3 (C5), 79.4 (C4), 46.6-65.8 [-(CH2)2-N-(CH2)2-O-], 46.6
(-N-CH3), 11.7 (-CH3); Anal. Calcd. for C8H12N2O2: C,57.13; H, 6.19; N, 16.33; found: C, 56.88; H,
6.72; N, 16.45.
1-(3-Methylisoxazol-5-yl)piperidine (4e). Colorless solid; yield = 70%; mp = 60-63°C; TLC:
Rf=0.71 (80:20 ether/heptane); 1H-NMR: δ (ppm) = 1.61 [m, 6 H, -(CH2) 3], 2.15 (s, 3 H, CH3), 3.25
(m, 4 H, -CH2-N-CH2-), 4.81 (1H, C4-H); 13C-NMR: δ (ppm) = 171.1 (C3), 161.3 (C5), 78.5 (C4),
23.9/ 24.8/47.6 [-(CH2)5-N-], 11.8 (CH3); Anal. Calcd. for C9H14N2O: C,65.03; H, 8.49; N, 16.85;
found: C, 64.94; H, 8.12; N, 16.45.
1-Methyl-4-(3-methylisoxazol-5-yl)piperazine (4f). Colorless liquid; yield = 75%; bp = 87-90°C/
1
0.001 torr; H-NMR: δ (ppm) = 2.15 (s, 3 H, CH3 ), 2.32 (s, 3 H, N-CH3), 2.48 (dd, J = 5.0Hz, J =
5.2Hz, -CH2-N-CH2-), 3.31 (dd, 4 H, J = 5.0Hz, J = 5.2Hz, -CH2-N-CH2-), 4.80 (s, 1 H, C4-H);
13C-NMR: δ (ppm) = 170.7 (C3), 161.3 (C5), 79.2 (C4), 53.9 (-CH2-N-CH2 -), 48.5 (-CH2-N-CH2),
46.1 (N-CH3); 11.7(-CH3); HRMS: calculated for C9H15N3O: 181.1209; found: 181.1209.
Method C
Warning: The reaction releases hydrogen cyanide (a negligible quantity), so it is imperative to work
under a hood with good ventilation. Triethylamine (5 drops) was added slowly to a 50 mL two-neck
round bottom flask, flame dried under N2, containing the 1-cyanoenamine (5 mmol), nitromethane (6
mmol, 1.2 equivalents) and distilled phenylisocyanate (10 mmol, 2 equivalents) in dry toluene (25
mL). Diphenylurea precipitated. Stirring was continued for 6 hours and then the suspension was
refluxed overnight. The urea was filtered off and the solution concentrated in vacuo. The obtained
products were purified by column chromatography on silica gel or by recrystallisation from alcohol.
N-phenyl-5-(morpholin-1-yl-)isoxazole-3-carboxamide (4g). Colorless solid; yield = 64%; mp = 147-
148°C (recrystallised from ethyl alcohol); 1H-NMR: δ (ppm) = 3.33 (dd, J = 5.0Hz, J = 4.8Hz, 4 H, -
CH2-N-CH2-), 3.77 (dd, J = 5.0Hz, J = 4.8Hz, 4 H, -CH2-O-CH2-), 5.58 (s, 1 H, C4-H), 7.14/
7.32/7.64 (Harom.), 8.6 (s, 1 H, NH); 13C-NMR: δ (ppm) = 172.0 (CO), 159.9 (C3), 157.3 (C5),

Molecules 2004, 9
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120.1/124.8/129.1/137.1 (C phenyl), 78.6 (C4), 46.5-65.8 [-(CH2)2-N-(CH2)2-O]; Anal. Calcd. for
C14H15N3O3: C, 61.56; H, 5.53; N, 15.38; found: C, 61.35; H, 5.67; N, 15.24.
N-Phenyl-5-(piperidin-1-yl)isoxazole-3-carboxamide (4h). White solid; yield = 58%; mp = 120-
122°C; TLC: Rf=0.72 (80:20 ether/heptane); 1H-NMR: δ (ppm) = 1.67 [m, 6 H, -(CH3)2-], 3.33 (m, 4
H, -CH2-N-CH2-), 5.50 (s, 1 H, C4-H), 7.14-7.34-7.64 (Harom.), 8.49 (s, 1 H, NH); 13C-NMR: δ (ppm)
= 172.2 (CO), 159.8 (C3), 157.6 (C5), 119.9/124.6/129.0/137.2 (C phenyl), 77.4 (C4), 47.6 (-CH2 -
N-CH2-), 23.7-24.8 [-(CH2)3-]; Anal. Calcd. for C15H17N3O2: C, 66.40; H, 6.32; N, 15.49; found: C,
66.65; H, 6.15; N, 15.55.
5-(4-Methylpiperazin-1-yl)-N-phenylisoxazole-3-carboxamide (4i). White solid; yield = 65%; mp =
130-131°C; TLC: Rf=0.69 (80:20 ether/heptane); 1H-NMR: δ (ppm) = 2.31 (s, 3 H, N-CH3), 2.50 (dd,
J = 5.0Hz, J = 5.1Hz, 4 H, -CH2-N-CH2-), 3.40 (dd, J = 5.0Hz; J = 5.1Hz, -CH2-N-CH2-), 5.55 (s, 1
13
H, C4-H), 7.14-7.33-7.64 (Harom.), 8.49 (s, 1 H, NH); C-NMR: δ (ppm) = 171.9 (CO), 159.9 (C3),
157.3 (C5), 120.0/124.7/129.0/137.1 (C phenyl), 78.2 (C4), 46.8-53.8 [-(CH2)2-N-(CH2)2-], 46.2 (-N-
CH3), 46.8-53.8 [-(CH2)2-N-(CH2)2-]; Anal. Calcd. for C15H18N4O2: C, 62.92; H, 6.34; N, 19.57;
found: C, 62.93; H, 6.24; N, 19.67.
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