A method for generating nitrile oxides from nitroalkanes: A microwave assisted route for isoxazoles

Article abstract of DOI:10.1016/S0040-4020(03)00859-7

A convenient route has been developed for generation of nitrile oxides in situ from nitroalkanes under very mild conditions using microwave irradiation, using 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) and DMAP as catalyst.

Full text of DOI:10.1016/S0040-4020(03)00859-7

Tetrahedron 59 (2003) 5437–5440
A method for generating nitrile oxides from nitroalkanes: a
microwave assisted route for isoxazoles
*
Giampaolo Giacomelli, Lidia De Luca and Andrea Porcheddu
`
Dipartimento di Chimica, Universita di Sassari, via Vienna 2, Sassari I-07100 Italy
Received 30 January 2003; revised 6 May 2003; accepted 29 May 2003
Abstract—A convenient route has been developed for generation of nitrile oxides in situ from nitroalkanes under very mild conditions using
microwave irradiation, using 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) and DMAP as catalyst.
Isoxazolines and isoxazoles are obtained in very good yields compared to known methods. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
isoxazolines or isoxazoles under very mild conditions and in
good yields (Fig. 1).
The synthetic and mechanistic aspects of the application of
nitrile oxides in [3þ2] cycloaddition have been studied
extensively.1 Correspondingly, several procedures have
been reported for the generation of nitrile oxides. Nitrile
oxides undergo 1,3-dipolar cycloadditions with olefins and
acetylenes to provide isoxazolines and isoxazoles, respect-
ively. These products, besides being potential pharmaceu-
tical agents, are also precursors to useful intermediates such
as g-amino alcohols and b-hydroxy ketones.2 The dehy-
drogenation of aldoximes via the formation of halogenated
derivatives such as hydroximoyl chlorides and bromides,
has been frequently employed as effective procedure.3,4
Reaction of primary nitroalkanes with a dehydrating agent,
aromatic isocyanates5,6 or ethyl chloroformate7 has been
employed too. These methods suffer from limitations owing
to the presence of some functional groups in the first case
and the relatively high reaction temperature in the other that
may cause polymerization of the forming nitrile oxide.
2. Results and discussion
The procedure is based on treatment of DMTMM with four
equivalents of the dipolarophile in acetonitrile at 208C and
0.1 equiv of DMAP, followed after 15 min by addition of
the nitroalkane (Scheme 1). After 8–10 h the reaction
mixture is quenched with water and worked up to yield the
heterocyclic compound.
The formation of the nitrile oxide and consequently that of
isoxazolines and isoxazoles is slower than the correspond-
ing method that uses (Boc)2O,8 requiring longer times for
completion. The advantage of this procedure is that the only
side product is 4,6-dimethoxy-[1,3,5]triazin-2-ol, readily
removed by aqueous work-up. The yields of the reactions
are quantitative in all the cases, while the conversions
depend on the structure of the substrates (Table 1). In
particular, steric hindrance on the alkyl group bound to the
dipolarophile and obviously on the 4-position in the
heterocyclic compound seems to reduce the rate of the
reaction. Heating the reaction mixture at the reflux
temperature (828C) did not increase significantly the rate
and the yields decreased drastically, because of formation of
by-products.16
In the past, the treatment of a nitroalkane with di-tert-butyl
dicarbonate in the presence of small amounts of 4-
dimethylaminopyridine (DMAP) has allowed trapping of
dipolarophile agents leading to the cycloadduct under
milder conditions.8 During our ongoing studies on the use
of [1,3,5]triazine derivatives in organic synthesis,9,10 in
connection with our previous studies11 on the synthesis of
functionalized heterocycles,12,13 we noted that the use of 4-
(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium
chloride14 (DMTMM)15 in the presence of DMAP as
catalyst converted the nitroalkanes to nitrile oxide and
consequently can be used for their transformation into
Keywords: isoxazoline; solid-phase synthesis; microwave condition.
*
Corresponding author. Tel.: þ39-079-229531; fax: þ39-079-212069;
e-mail: ggp@uniss.it
Figure 1.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00859-7

5438
G. Giacomelli et al. / Tetrahedron 59 (2003) 5437–5440
Scheme 2.
formed using a flask equipped with a reflux condenser
mounted outside the apparatus. In this case, the use of
microwaves was crucial for the success of the reaction. A
MeCN solution of DMTMM, 4 equiv. of the dipolarophile,
0.1 equiv. of DMAP and of the nitroalkane were completely
converted and pure products 1 and 2 could be recovered
after usual work-up (Table 1).
The reaction has been tested for the synthesis of a-
aminoacids containing the isoxazole moiety.19 Thus, a
sample of (R)-4-ethynyl-2,2-dimethyloxazolidine-3-car-
boxylic acid tert-butyl ester, 3,20 was treated with 4 equiv.
of nitroethane in the presence of 1 equiv. of DMTMM and
DMAP. After 3 min of microwave irradiation, chemically
pure (S)-3-methyl-5-(2,2-dimethyl-3-tert-butoxycarbonyl-
oxazolidin-4-yl)isoxazole, 4,19 (.95% yield) was recovered
without loss of optical purity21 (Scheme 2).
This procedure can be conveniently applied to the synthesis
on polymeric support too. So, propargyl alcohol was
anchored on trityl chloride resin (Scheme 3), controlling
the loading by infrared spectroscopy.11 After being washed,
the resin was treated with excess DMTMM and nitroethane
in MeCN/THF. Successively, DMAP was added slowly to
generate the nitrile oxide, then the mixture irradiated for
5 min (5 cycles of 1 min, and 1 min of rest) and monitored
by infrared spectroscopy for the disappearance of the alkyne
stretch. The isoxazole, (3-methylisoxazol-5-yl)methanol,11
was then cleaved off the resin under standard conditions.
Scheme 1.
Recently, this laboratory has focused on the application of
microwave heating in organic synthesis. Carrying out
reactions using microwave irradiation conditions,17 as
opposed to conventional heating, has the advantage to
shorten the reaction times because of the rapid core heating
associated with microwaves. However, this procedure is not
always applicable, as often the use of solvents suitable to the
microwave conditions represents a real limit, unless to carry
out the reaction in a pressure tube.
3. Conclusion
In conclusion, we have reported an effective and efficient
method to perform the formation and the reaction of nitrile
With the goal of reducing the reaction times, we have
therefore repeated all the runs under microwave irradiation,
using a self-tunable microwave synthesizer. The MW
experiments were performed in a self-tuning single mode
CEM DiscoverTM Focused Synthesizer apparatus. The
instrument continuously adjusts the applied wattage to
maintain the desired temperature.18 Reactions were per-
Table 1. Formation of isoxazolines 1 and isoxazoles 2 under conventional
or microwave conditions
Conventional reaction
MWI reaction
Time (min) Conv. (%)
Product
Time (h)
Conv. (%)
1a
1b
1c
2a
2b
2c
2d
2e
2f
6
12
6
6
8
10
6
6
10
10
73
87
45
75
65
80
84
68
72
86
3
3
3
3
3
3
3
3
3
3
99
99
99
100
98
95
99
97
92
2g
99
Scheme 3.

G. Giacomelli et al. / Tetrahedron 59 (2003) 5437–5440
5439
oxides from nitroalkanes, using a simple reagent such as
DMTMM, through microwave irradiation. Moreover, we
have verified that this approach can be also applied to solid-
phase synthesis.
J¼8 Hz), 2.80 (m, 1H, CH, J¼9.5 Hz), 2.03 (s, 3H, Me);
13C NMR d 166.9, 158.9, 150.2, 136.4, 128.9, 128.0, 126.7,
101.1, 50.3, 33.2.
4.2.2. 3-Methyl-4,5-dihydroisoxazole-5-carboxylic acid
ethyl ester (1b).8,24 From nitroethane and ethyl acrylate,
0.27 g (87%) [MWI 0.31 g (99%)], 1H NMR; d 4.35 (m, 1H,
CH, J¼5, 11 Hz)), 4.02 (q, 2H, O–CH2), 3.00 (m, 2H, CH2,
J¼5, 11 Hz), 2.08 (s, 3H, Me), 1.18 (t, 3H, O–C–Me); 13C
NMR d 172.0, 163.8, 79.1, 60.2, 23.4, 20.1, 13.2.
4. Experimental
4.1. General
All reagents and solvents employed were reagent grade
materials purified by standard methods and distilled before
use. Nitrocompounds were commercial products distilled
carefully before use and 4-(4,6-dimethoxy[1,3,5]triazin-2-
yl)-4-methylmorpholinium chloride (DMTMM) was pre-
pared as described.15 (R)-2,2-Dimethyl-3(tert-butoxycarbo-
nyl)-4-ethynyloxazolidine was obtained from L-serine
through a described sequence reaction.9 Elemental analyses
were performed on a Perkin–Elmer 420 B analyzer. The 1H
NMR (300 MHz) and 13C NMR (75.4 MHz) Fourier
transform spectra were obtained with a Varian VXR-300
spectrometer using CDCl3 solutions and TMS as an internal
standard. Chemical purity was established by HPLC-UV
measurements and the structure of known compounds were
further corroborated by comparing their 1H NMR data with
those of literature.
4.2.3. 3-Methylisoxazole-5-carboxylic acid ethyl ester
(2b).8 From nitroethane and propiolic acid ethyl ester, 0.20 g
(65%) [MWI0.31 g (98%)], 1H NMR;d6.78(s, 1H, CH), 4.22
(q, 2H, O–CH2), 2.35(s, 3H, Me), 1.30(t, 3H, O–C–Me);13
C
NMR d 167.2, 158.9, 150.2, 101.5, 59.1, 13.6, 12.4.
4.2.4. 3-Methyl-5-(2-methylbutyl)-4,5-dihydroisoxazole
(1c). From nitroethane and 4-methylhex-1-ene, 0.14 g
(45%) [MWI 0.31 g (99%)], 1H NMR (mixture of rotamers)
d 4.61 (m, 1H, CH), 2.95 (m, 1H, CH), 2.51 (m, 1H, CH),
1.96 (s, 3H, Me), 1.72 (m, 1H, CH), 1.62–1.42 (m, 2H,
CH2), 1.39–1.09 (m, 2H, CH2), 1.84 (m, 6H, Me); 13C NMR
(mixture of rotamers) d 155.0, 79.1, 78.6, 44.5, 44.2, 42.5,
42.1, 31.7, 31.4, 29.8, 29.2, 19.3, 18.8, 13.3, 11.1. C9H17NO
(155.24): calcd C, 69.63; H, 11.04; N, 9.02; found: C, 69.52;
H, 11.12; N, 9.02.
4.2. General procedure: 3-methyl-5-phenylisoxazole8,22
4.2.5. 3-Methyl-5-diethoxymethylisoxazole (2c). From
nitroethane and propiolaldehyde diethyl acetal, 0.30 g
(80%) [MWI 0.35 g (95%)], H NMR d 6.16 (s, 1H, CH),
5.59 (s, 1H, CH), 3.61 (q, 4H, O–CH2), 2.27 (s, 3H, Me),
1.21 (t, 6H, O–C–Me); 13C NMR d 174.2, 147.4, 104.2,
94.9, 61.8, 23.7, 14.9. C9H15NO3 (185.22): calcd C, 58.36;
H, 8.16; N, 7.56; found: C, 58.40; H, 8.09; N, 7.54.
(a) Conventional procedure. Acetonitrile (10 mL),
DMTMM (0.69 g, 2.5 mmol), 4-dimethylaminopyridine
(DMAP) (0.03 g, 0.2 mmol) and phenylacetylene
(1.07 mL, 10 mmol) were placed in a flask at room
temperature. After 10 min, nitroethane (0.14 mL, 2 mmol)
was added dropwise with stirring. The mixture as stirred at
room temperature (6 h), then H2O (10 mL) was added. The
mixture was then extracted with diethyl ether, the combined
organic layer washed with brine and dried (Na2SO4).
Removal of diethyl ether in vacuo, gave 0.24 g of
chemically pure 3-methyl-5-phenyl isoxazole, 2a (75%,),
1H NMR; d 7.75 (d, 2H, Ph), 7.44 (m, 3H, Ph), 6.45 (s, 1H,
CH), 2.35 (s, 3H, Me); 13C NMR d 157.9, 148.1, 136.4,
128.9, 128.0, 126.2, 98.4, 15.3.8
1
4.2.6. 5-Phenylisoxazole-3-carboxylic acid ethyl ester
(2d).20 From ethyl nitroacetate and phenylacetylene, 0.37 g
1
(84%) [MWI 0.44 g (99%)], H NMR d 7.78 (d, 2H. Ph),
7.45 (m, 3H, Ph), 6.59 (s, 1H, CH), 3.56 (q, 2H, O–CH2),
0.85 (t, 3H, O–C–Me); 13C NMR d 170.2, 161.9, 150.3,
136.0, 128.9, 126.7, 125.8, 99.1, 62.2. 30.5, 18.7.
4.2.7. (5-Phenylisoxazol-3-yl)acetic acid methyl ester
(2e). From 2-nitro methyl propionate and phenylacetalde-
hyde, 0.29 g (68%) [MWI 0.41 g (97%)], H NMR d 7.88
(d, 2H, Ph), 7.56 (m, 3H, Ph), 6.71 (s, 1H, CH), 3.91 (s, 2H,
CH2), 3.87 (s, 3H, O–CH3); 13C NMR d 167.4, 159.2,
149.9, 136.4, 128.9, 128.0, 127.6, 101.2, 49.8, 33.5.
C12H11NO3 (217.22): calcd C, 66.35; H, 5.10; N, 6.45:
found: C, 66.42; H, 5.23; N, 6.45.
(b) Microwave procedure. Acetonitrile (10 mL), DMTMM
(0.69 g, 2.5 mmol), 4-dimethylaminopyridine (DMAP)
(0.03 g, 0.2 mmol) and phenylacetylene (1.07 mL, 10 mmol)
were placed in a 100 mL flask at room temperature. After
10 min. nitroethane (0.14 mL, 2 mmol) was added dropwise.
The open flask was irradiated at 808C (by modulation of the
power) for 3 min in a self-tuning single mode CEM
Discovere Focused Synthesizer. The solution was cooled
rapidly at room temperature by passing compressed air
through the microwave cavity for 1 min, then H2O (10 mL)
was added. The mixture was extracted with diethyl ether, the
combined organic layer washed with brine and dried
(Na2SO4). Removal of diethyl ether in vacuo, gave 0.32 g of
chemically pure 3-methyl-5-phenyl isoxazole, 2a (100%).
1
4.2.8. 3-(But-3-enyl)-5-phenylisoxazole (2f). From 5-
nitropent-1-ene and phenylacetylene, 0.29 (72%) [MWI
1
0.37 g (92%)], H NMR d 7.75 (d, 2H, Ph), 7.43 (m, 3H,
Ph), 6.38 (s, 1H, CH), 5.88 (m, 1H, HCv, J¼9, 14.5 Hz),
5.07 (m, 2H, vCH2), 2.85 (m, 2H, CH2), 2.47 (m, 2H,
CH2); 13C NMR d 169.8, 162.0, 150.9, 130.2, 128.9, 127.4,
125.8, 113.0, 64.4, 19.8. C13H13NO (187.24): calcd C,
78.36; H, 6.58; N, 7.03: found: C, 78.24; H, 6.57; N, 7.03.
4.2.1. 3-Methyl-5-phenyl-4,5-dihydroisoxazole (1a).8,23
From nitroethane and styrene, 0.24 g (73%), [from micro-
wave procedure (MWI). 0.33 g (99%)], 1H NMR; d 7.33 (m,
5H, Ph), 5.55 (dd, 1H, CH, J¼8, 9.5 Hz), 3.36 (m, 1H, CH,
4.2.9. 3-(Tetrahydropyran-2-yloxymethyl)-5-phenylisox-
azole (2g).25 From 2-(2-nitroethoxy)tetra-hydropyran and

5440
G. Giacomelli et al. / Tetrahedron 59 (2003) 5437–5440
phenylacetylene, 0.44 (86%) [MWI 0.51 g (99%)],1H NMR
d 7.79 (d, 2H, Ph), 7.46 (m, 3H, Ph), 6.59 (s, 1H, CH), 4.82
(s, 2H, CH2–O), 4.76 (m, 1H, O–CH) 3.62–3.53 (m, 2H,
O–CH2), 1.74–1.68 (m, 2H, CH2), 1.55 (m, 4H, CH2–
CH2); 13C NMR d 170. 2, 161.9, 129.8, 128.8, 127.5, 126.3,
99.1, 98.4, 65.8, 62.0, 29.9, 25.0, 19.4.
References
1. Torssell, K. B. G. Nitrile Oxides, Nitrones and Nitronates in
Organic Synthesis; VCH: New York, 1988.
2. Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410.
3. (a) Just, G.; Dahl, L. Tetrahedron 1968, 24, 5251. (b)
Grundmann, C.; Dean, J. M. J. Org. Chem. 1965, 30, 2809.
(c) Hassner, H.; Rai, K. M. L. Synthesis 1989, 57.
4. (a) Grundmann, C.; Dean, J. M. J. Org. Chem. 1965, 30, 2809.
(b) Hassner, H.; Rai, K. M. L. Synthesis 1989, 57.
5. Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82,
5339.
4.2.10. (S)-3-Methyl-5-(2,2-dimethyl-3-tert-butoxycarbo-
nyl-oxazolidin-4-yl)isoxazole (4). From nitroethane and
(R)-2,2-dimethyl-3-(tert-butoxycarbonyl)-4-ethynyloxazo-
lidine, 3: from microwave procedure as reported above
(0.54 g, 96 %), [a]D20¼273.5 (c¼1, CHCl3),19 0.57 g (99%),
mp 538C, [a]2D5¼23.1 (c¼3, CHCl3), 1H NMR (mixture of
conformers) d 6.01 (s, 1H,CH), 5.01 (dd, 1H,CH), 4.04 (m,
2H, CH2), 2.28 (ps, 3H), 1.59 (s, 3H, Me), 1.52 (pd, 3H,
Me), 1.49 (s, 4H, C–Me), 1.40 (s, 5H, C–Me); 13C NMR
508C) d 159.3, 128.7, 120.4, 101.5, 80.3, 67.3, 59.9, 53.9,
28.8, 26.2, 13.9.
6. Falorni, M.; Giacomelli, G.; Spanu, E. Tetrahedron Lett. 1998,
39, 9241.
7. Shimizu, T.; Hayashi, Y.; Shibafuchi, H.; Teramura, K. Bull.
Chem. Soc. Jpn 1986, 59, 2827.
8. Basel, Y.; Hassner, A. Synthesis 1997, 309.
9. De Luca, L.; Giacomelli, G.; Porcheddu, A. J. Org. Chem.
2001, 66, 7907 and references therein.
4.3. Procedure for the solid-phase preparation of (3-
propylisoxazol-5-yl)methanol
10. De Luca, L.; Giacomelli, G.; Porcheddu, A. Org. Lett. 2002, 4,
553.
11. De Luca, L.; Giacomelli, G.; Riu, A. J. Org. Chem. 2001, 66,
6823.
The synthesis was carried out in a manual 20 mL reactor
equipped with a sintered glass and using a nitrogen flow for
agitation and filtration. A solution of propargyl alcohol 1
(0.41 g, 7.4 mmol) in dry pyridine (3.0 mL) was added
dropwise to chlorotrityl resin (0.35 g of a 1.24 mmol/g
Novabiochem sample, 0.43 mmol, swollen in CH2Cl2) in
7.0 mL of pyridine. The mixture was shaken at room
temperature for 48 h, filtered and washed several times with
pyridine and dry diethyl ether and dried to afford the
corresponding alkyne resin: FT IR (KBr): 3289 cm21. The
resin was then separated in some portions for repeated runs.
12. De Luca, L.; Giacomelli, G.; Porcheddu, A.; Spanedda, A. M.
G.; Falorni, M. Synthesis 2000, 1295.
13. Falorni, M.; Giacomelli, G.; Porcheddu, A.; Dettori, G. Eur.
J. Org. Chem. 2000, 3217.
14. The salt can be prepared in situ from 2-chloro-4,6-
dimethoxy[1,3,5]triazine and N-methylmorpholine with the
same results.
15. Kunishima, M.; Kawachi, C.; Morita, J.; Terao, K.; Iwasaki,
F.; Tani, S. Tetrahedron 1999, 55, 13159.
16. Probably also autocondensation of the nitrile oxide to furoxane
occurs under these conditions [Mukaiyama, T.; Hoshino, T.
J. Am. Chem. Soc. 1981, 22, 3371].
To the resin (0.16 mmol), swollen with CH2Cl2 and filtered
to remove the solvent, it was added MeCN (5.0 mL), THF
(2.5 mL), 1-nitrobutane (1.72 mmol) and DMTMM
(6.9 mmol): after 2 h, DMAP (0.2 mmol) was added
dropwise. Then the suspension was placed into an open
flask, the mixture irradiated as above for 5 min and
monitored for the disappearance of the alkyne stretch
(24 h). The resin was then filtered and washed several times
with CH2Cl2 affording polymeric isoxazole. Substrate
cleavage was accomplished by treating the resin with a
freshly prepared TFA–CH2Cl2 (5:95) solution at room
temperature (20 min). Filtration and resin washing with
CH2Cl2 gave an organic phase which was washed with
Na2CO3 aqueous 10% solution and dried (Na2SO4).8a
Removal of the solvent gave the target isoxazole 5 in 82%
17. Kuhnert, N. Angew. Chem. Int. Ed. 2002, 41, 1863.
18. In these conditions, the reaction temperature remained at
808C.
19. Falorni, M.; Giacomelli, G.; Spanu, E. Tetrahedron Lett. 1998,
39, 9241.
20. Reginato, G.; Mordini, A.; Caracciolo, M. J. Org. Chem. 1997,
62, 6187.
21. The enantiomeric purity of compound 4 (.98%) had been
previously determined19 by 19F NMR analyses of the
diastereomeric Mosher amides [Dole, J. A.; Mosher, H. S.
J. Am. Chem. Soc. 1973, 95, 512] prepared both from the same
compound and its racemic form after Boc-deprotection with
Amberlystw in MeOH/H2O at 258C.
1
22. Bunnelle, W. H.; Singam, P. R.; Narayanan, B. A.; Bradshaw,
C. W.; Liou, J. S. Synthesis 1997, 439.
yield, chemically pure at HPLC; H NMR, d 6.03 (s, 1H,
CH), 4.66 (s, 2H, CH2-O), 2.66 (m, 2H, CH2), 1.69–1.53
(m, 2H, CH2), 1.18 (bs, 1H, OH), 0.91 (t, 3H, Me).11
23. Moriya, O.; Takenaka, H.; Iyoda, M.; Urata, Y.; Endo, T.
J. Chem. Soc. Perkin Trans. 1 1994, 413.
24. Palmer, P. J.; Evans, D. E.; Brown, G.; King, G.; Shadbolt,
R. S.; Trigg, R. G.; Ward, R. J.; Ashford, A.; Ross, J. W.
J. Chem. Soc. Perkin Trans. 1 1972, 437.
Acknowledgements
25. Nakamura, N.; Yawara, T.; Kiyoshi, S. Heterocycles 1982, 17,
235.
The work was financially supported by the University of
Sassari and MIUR (Rome) within the project PRIN 2001.