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

Summary 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 [3 + 2] cycloaddition of nitric oxides to alkynes, is of interest since it forms a part of various biodynamic agents. Isoxazole derivatives that act as antithrombotic, hypolipidemic, nootropic, antiviral, antiobesity, and CNS modulation agents have been described [1].
On the other hand, derivatives having liquid crystalline properties have received a great deal of attention as they have a wide variety of applications, especially in flat-panel displays [2], light emitting diodes [3][4][5], anisotropic networks [6,7], and semiconductor materials [8]. Incorporation of the isoxazole moiety into such materials can result in significant changes in the corresponding mesogenic phases, since isoxazoles display classical nematic and smetic mesophases associated with their rod-like core structure [9].
The pioneering work on furoxans as nitric oxide donors by Gasco et al. has stimulated a large number of further studies. One of these reports deals with a synthetic route and structural characterization of two isomeric phenylfuroxans 2 and 3 [10]. According to the original report, 4-phenyl-3-furoxanmethanol (2) was obtained as the sole product in 40% yield, by treatment of cinnamyl alcohol (1) dissolved in acetic acid with concentrated aqueous sodium nitrite at 70 °C (Scheme 1).

Results and Discussion
Application of this approach to the synthesis of 2 and purification of the reaction product, as reported, by column chromatography 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 (R f = 0.65) was eluted before compound 2 (R f = 0.41). The structure of compound 4 was elucidated 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 substituent. Molecules are connected to form broad ribbons in 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. A suggested mechanism for the formation of 4 is outlined in Scheme 2. 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 HNO 2 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.
In conclusion, a very simple route to 4-nitro-3-phenylisoxazole (4), as well as the furoxan derivative 2, which constitutes a nitric oxide (NO) donor site in NO donor systems [16], is disclosed.