A surprising new route to 4-nitro-3-phenylisoxazole

Article abstract of DOI:10.3762/bjoc.6.68

A one-pot synthesis of 4-nitro-3-phenylisoxazole has been carried out by treatment of cinnamyl alcohol dissolved in acetic acid with sodium nitrite; in addition, 4-phenyl-3-furoxanmethanol was obtained in 40% yield.

Full text of DOI:10.3762/bjoc.6.68

A surprising new route to 4-nitro-3-phenylisoxazole
Henning Hopf1, Aboul-fetouh E. Mourad*2 and Peter G. Jones3
Preliminary Communication
Open Access
Address:
Institut für Organische Chemie, Technische Universität
Braunschweig, Postfach 3329, D-38023 Braunschweig, Germany,
Chemistry Department, Faculty of Science, Minia University, 61519
Beilstein J. Org. Chem. 2010, 6, No. 68. doi:10.3762/bjoc.6.68
1
Received: 08 February 2010
Accepted: 01 June 2010
Published: 23 June 2010
2
El-Minia, Egypt and 3Institut für Anorganische und Analytische
Chemie, Technische Universität Braunschweig, Postfach 3329,
D-38023 Braunschweig, Germany
Associate Editor: J. Murphy
Email:
© 2010 Hopf et al; licensee Beilstein-Institut.
License and terms: see end of document.
Henning Hopf - h.hopf@tu-bs.de; Aboul-fetouh E. Mourad* -
mouradaboulf@yahoo.com; Peter G. Jones - p.jones@tu-bs.de
*
Corresponding author
Keywords:
cinnamyl alcohol; furoxan derivatives; isoxazole derivatives; X-ray
diffraction
Abstract
A one-pot synthesis of 4-nitro-3-phenylisoxazole has been carried out by treatment of cinnamyl alcohol dissolved in acetic acid
with sodium nitrite; in addition, 4-phenyl-3-furoxanmethanol was obtained in 40% yield.
Introduction
The isoxazole ring system, which can be easily obtained by the corresponding mesogenic phases, since isoxazoles display
[
3 + 2] cycloaddition of nitric oxides to alkynes, is of interest classical nematic and smetic mesophases associated with their
since it forms a part of various biodynamic agents. Isoxazole rod-like core structure [9].
derivatives that act as antithrombotic, hypolipidemic, nootropic,
antiviral, antiobesity, and CNS modulation agents have been The pioneering work on furoxans as nitric oxide donors by
described [1].
Gasco et al. has stimulated a large number of further studies.
One of these reports deals with a synthetic route and structural
On the other hand, derivatives having liquid crystalline prop- characterization of two isomeric phenylfuroxans 2 and 3 [10].
erties have received a great deal of attention as they have a wide According to the original report, 4-phenyl-3-furoxanmethanol
variety of applications, especially in flat-panel displays [2], (2) was obtained as the sole product in 40% yield, by treatment
light emitting diodes [3-5], anisotropic networks [6,7], and of cinnamyl alcohol (1) dissolved in acetic acid with concen-
semiconductor materials [8]. Incorporation of the isoxazole trated aqueous sodium nitrite at 70 °C (Scheme 1).
moiety into such materials can result in significant changes in
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Beilstein J. Org. Chem. 2010, 6, No. 68.
Scheme 1: Preparation of 2 and 4 by treatment of cinnamyl alcohol (1).
Results and Discussion
Application of this approach to the synthesis of 2 and purifica-
tion of the reaction product, as reported, by column chromato-
graphy with petroleum ether/ethyl acetate (4:1) as eluant
resulted, in our hands, not only in the isolation of the desired
reaction product 2 (40%), but surprisingly, also of compound 4
(
26% yield). Compound 4 (Rf = 0.65) was eluted before com-
pound 2 (Rf = 0.41). The structure of compound 4 was eluci-
dated on the basis of its spectral (see Experimental section) and
crystallographic data. The crystal structure of compound 4 is
shown in Figure 1. Bond lengths and angles (e.g. C3–N2
1
.3110(15), N2–O1 1.4283(13), O1–C5 1.2202(15) Å) may be
considered normal. The five-membered ring is planar within a
mean deviation of 0.002 Å, and subtends interplanar angles of
6
.5° with the nitro and (in the same sense) 58.4° with the phenyl
Figure 2: Packing diagram of compound 4 viewed perpendicular to
substituent. Molecules are connected to form broad ribbons in
(101). Hydrogen bonds are indicated by thick dashed bonds.
the (101) plane and parallel to the short y axis (Figure 2) by
“
weak” hydrogen bonds H12···O2 2.56 and H5···O3 2.39 Å.
We propose that the nitro compound 4 is generated via the
intermediate 6. This, in turn, could be generated by dehydration
of the precursor 5, an addition product of HNO2 to the substrate
1
by a formal hetero Alder-ene reaction. Isoxazole 6 could then
undergo electrophilic substitution via 7 to afford the nitroso
compound 8, which in a final step would be oxidized to 4 under
the reaction conditions.
Previously reported approaches to 4 include the reaction of
aromatic α,β-unsaturated aldehydes with dinitrogen trioxide
[
11,12], the nitration of 3-phenyl-isoxazole [13,14], and the
hydrolysis of methyl 4-nitro-3-phenyl-5-carboxylate, obtained
by reaction of α-nitroacetophenone oxime and methoxalyl
chloride [15].
Figure 1: The crystal structure of compound 4. Ellipsoids correspond
to 50% probability levels.
In conclusion, a very simple route to 4-nitro-3-phenylisoxazole
(
4), as well as the furoxan derivative 2, which constitutes a
A suggested mechanism for the formation of 4 is outlined in nitric oxide (NO) donor site in NO donor systems [16], is
Scheme 2. disclosed.
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Beilstein J. Org. Chem. 2010, 6, No. 68.
Scheme 2: Suggested mechanism for the formation of 4.
Experimental
X-Ray structure determination of 4: Crystal data: C9H6N2O3,
Melting points were measured on Büchi 350 apparatus and are Mr = 190.16, monoclinic, P21/c, T = −173 °C, a = 12.1621(7),
uncorrected. IR spectra were measured with Bruker Tensor 27 b = 5.6566(3), c = 12.0633(8) Å, β = 101.638(6)°,
instrument. 1H and 13C NMR spectra were recorded in CDCl3 V = 812.85 Å3, Z = 4, F(000) = 392, λ(Mo Kα) = 0.71073 Å,
with a Bruker DRX-400 instrument operating at 400 MHz and μ = 0.12 mm−1, Dx = 1.554 g cm−3. Data collection: A colour-
1
00 MHz, respectively. Silica gel 60 (Merck, 70–230 mesh) less prism ca. 0.3 × 0.15 × 0.1 mm was mounted in inert oil on a
was used for column chromatography. Macherey-Nagel poly- glass fibre and transferred to the cold gas stream of an Oxford
gram SilG/UV 254 was used for TLC. Petroleum ether refers to Diffraction Xcalibur E diffractometer. A total of 13,352 reflec-
the fraction of bp 40–60 °C. The mass spectrum was taken on a tions were recorded to 2Θ 57.2°, of which 2100 were inde-
Finnigan MAT 4515 spectrometer at 70 eV.
pendent (Rint 0.037). Structure refinement: The structure was
refined using SHELXL-97 [18]. Hydrogen atoms were included
Preparation of 4-phenyl-3-furoxanmethanol (2) and 4-nitro- using a riding model. The final R2 (all reflections) was 0.084
-phenylisoxazole (4): To a stirred solution of cinnamyl for all intensities and 127 parameters, with R1 (I>2σ(I)) 0.035;
3
alcohol (1, 4.08 g, 30 mmol) in glacial acetic acid (6 mL), was S 0.94, max. Δρ 0.25 e Å−3.
added saturated aqueous sodium nitrite (90 mmol) solution
dropwise so that the temperature did not exceed 70 °C. Stirring X-ray crystallographic data (excluding structure factors) were
was continued at room temperature for 1 h. The reaction mix- deposited under the number CCDC-763982 and can be obtained
ture was diluted with water, extracted with diethyl ether, free of charge from the Cambridge Crystallographic Data
washed with brine, dried with anhydrous sodium sulfate and Centre via http://www.ccdc.cam.ac.uk/data_request/cif.
concentrated in vacuo. The residue was purified by column
chromatography using petroleum ether/ethyl acetate (4:1) as Acknowledgements
eluent to give 4-phenyl-3-furoxanmethanol (2.29 g, 40%) and A. E. M. is indebted to the Institute of Organic Chemistry,
4
-nitro-3-phenylisoxazole (1.49 g, 26%), respectively.
Technical University of Braunschweig (Germany) for a summer
fellowship, and to Professor H. Hopf for providing working
4
-Phenyl-3-furoxanmethanol (2): mp 67 °C (benzene/petro- facilities.
leum ether); lit. mp 66–67 °C [10]; IR: ν = 3127, 1569, 1523,
449, 1404, 1372, 1195, 1130, 883, 767, 693 cm−1; 1H NMR: δ References
1
=
7.85–7.78 (m, 2H, Ar-H), 7.61–7.58 (m, 3H, Ar-H), 4.75 (s, 1. Barta, S.; Srinivasan, T.; Rastogi, S. K.; Kundu, B.; Parta, A.;
Bhaduri, A. P.; Dixit, M. Bioorg. Med. Chem. Lett. 2002, 12, 1905.
2
1
H, CH2), 2.75 (br. s, 1H, OH); MS (EI): m/z = 191 [M]+ (42),
doi:10.1016/S0960-894X(02)00333-5
74 (7), 145 (12), 129 (16), 103 (100), 93 (8), 76 (38).
And references cited therein.
2
.
Demus, D.; Goodby, J. W.; Gray, G. W.; Spiess, H. W.; Vill, L. Low
Molecular Weight Liquid Crystals I. Handbook of Liquid Crystals;
Wiley-VCH: Weinheim, 1998; Vol. 2a. doi:10.1002/9783527619276
Vlachos, P.; Mansoor, B.; Alfred, M. P.; O`Neil, M.; Kelly, S. M.
Chem. Commun. 2005, 2921. doi:10.1039/b501875g
Sonar, P.; Singh, S. P.; Sudhakar, S.; Dodabalapur, A.; Sellinger, A.
Chem. Mater. 2008, 20, 3184. doi:10.1021/cm800139q
4
-Nitro-3-phenylisoxazole (4): mp 113–114 °C (ethyl acetate);
lit. mp 114.5 °C [17]; 1H NMR: δ = 9.36 (s, 1H, H-5),
.70–7.67 (m, 2H, Ar-H), 7.59–7.49 (m, 3H, Ar-H); 13C NMR:
δ = 160.6 (C-5), 156.5 (C-3), 133.9 (C-4), 131.1, 129.5, 128.6,
24.7 (Ph).
3
.
.
7
4
1
Page 3 of 4
(page number not for citation purposes)

Beilstein J. Org. Chem. 2010, 6, No. 68.
5
.
.
Cristiano, R.; Ely, F.; Gallardo, H. Liq. Cryst. 2005, 32, 15.
doi:10.1080/02678290412331329279
6
Hsu, C.-S.; Chen, H.-L. J. Polym. Sci., Part A: Polym. Chem. 1999, 37,
3929.
doi:10.1002/(SICI)1099-0518(19991101)37:21<3929::AID-POLA8>3.0.
CO;2-9
7.
8.
9.
Cassano, R.; Dabrowski, R.; Dziaduszek, J.; Picci, C.; Chidichimo, G.;
De Filpo, G.; Muzzalupo, R.; Puoci, F. Tetrahedron Lett. 2007, 48,
1447. doi:10.1016/j.tetlet.2006.12.094
Melucci, M.; Favaretto, L.; Bettini, C.; Gazzano, M.; Camaioni, N.;
Fukazawa, P.; Ostoja, P.; Monari, M.; Barbarella, G. Chem.–Eur. J.
2007, 13, 10046. doi:10.1002/chem.200701368
Haino, T.; Tanaka, M.; Ideta, K.; Kubo, K.; Mori, A.; Maccagnani, Y.
Tetrahedron Lett. 2004, 45, 2277. doi:10.1016/j.tetlet.2004.01.116
And references cited therein.
1
0.Gasco, A. M.; Fruttero, R.; Sorba, G.; Gasco, A. Liebigs Ann. Chem.
991, 1211. doi:10.1002/jlac.1991199101207
1
1
1.Quilico, A. Isoxazoles. In Five- and Six-Membered Compounds with
Nitrogen and Oxygen (Excluding Oxazoles); Wiley, R. H.; Quilico, A.;
Speroni, G.; Behr, L. C.; McKee, R. L., Eds.; Chemistry of Heterocyclic
Compounds: A Series Of Monographs, Vol. 17; John Wiley & Sons,
1962; pp 5–94. doi:10.1002/9780470186787.ch1
1
2.Wieland, H. Justus Liebigs Ann. Chem. 1903, 328, 154.
doi:10.1002/jlac.19033280206
1
3.Langella, M. R.; Finzi, P. V. Chim. Ind. (Milan) 1965, 47, 996.
4.Sokolov, S. D.; Yudintseva, I. M.; Petrovskii, P. V.; Kaliuzhnaya, V. G.
J. Org. Chem. USSR 1971, 7, 2051.
1
1
1
1
1
5.Nesi, R.; Giomi, D.; Papaleo, S.; Turchi, S. J. Org. Chem. 1992, 57,
3
713. doi:10.1021/jo00039a037
6.Hwang, K.-J.; Jo, I.; Shin, Y. A.; Yoo, S.; Lee, J. H. Tetrahedron Lett.
995, 36, 3337. doi:10.1016/0040-4039(95)00535-K
7.Nesi, R.; Giomi, D.; Turchi, S.; Tedeschi, P. Gazz. Chim. Ital. 1993,
23, 633.
1
1
8.Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112.
doi:10.1107/S0108767307043930
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