Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

4-Hydroxynaphtho[1,8-de][1,2]oxazine in the Synthesis of 1,2,8-Trisubstituted Naphthalenes. Novel Isoxazole 2-oxide to Nitrile oxide Isomerization

Version 1 : Received: 8 November 2023 / Approved: 8 November 2023 / Online: 9 November 2023 (07:15:57 CET)

A peer-reviewed article of this Preprint also exists.

Gerontitis, I.E.; Tsoungas, P.G.; Varvounis, G. Naphtho[1,8-de][1,2]Oxazin-4-ol: Precursor to 1,2,8-Trisubstituted Naphthalenes and 1-Unsubstituted Naphtho[1,2-d]isoxazole 2-Oxide: A Novel Isomerization of the N-Oxide to Nitrile Oxide en Route to Isoxazol(in)es. Molecules 2024, 29, 48. Gerontitis, I.E.; Tsoungas, P.G.; Varvounis, G. Naphtho[1,8-de][1,2]Oxazin-4-ol: Precursor to 1,2,8-Trisubstituted Naphthalenes and 1-Unsubstituted Naphtho[1,2-d]isoxazole 2-Oxide: A Novel Isomerization of the N-Oxide to Nitrile Oxide en Route to Isoxazol(in)es. Molecules 2024, 29, 48.

Abstract

Naphtho[1,8-de][1,2]oxazin-4-ol and its acyl or benzyl derivatives ring open to various 2,8-dihydroxy-1-naphthonitriles, that undergo methylation, reduction, demethylation and debenzylation reactions, to afford the target compound (E)-2-hydroxy-8-methoxy-1-naphthaldehyde. The best overall yield of the latter was 28.7%. This compound was converted to its corresponding (E)-2-hydroxy-8-methoxy-1-naphthaldehyde ox-ime, which was oxidatively o-cyclized with phenyliodine(III) diacetate (PIDA) to 9-methoxynaphtho[1,2-d]isoxazole 2-oxide. The latter in deuterated DMSO, at room temperature, rearranged to its isomer to 2-hydroxy-8-methoxy(naphthalen-1-yl)nitrile oxide. The isomeriza-tion was detected by a time-course plot 1H NMR spectroscopy and further identified from its13C NMR and HRMS spectra. The nitrile oxide was stable in (non)deuterated DMSO for at least 18 hours. A 3,4-bis(2-hydroxy-8-methoxynaphthalen-1-yl)-1,2,5-oxadiazole 2-oxide as a dimeriza-tion product or an isocyanate as a rearrangement isomer were both ruled out, the former by the absence of the relevant molecular ion in its HRMS spectrum while the latter by 1,3-dipolar cy-cloaddition reactions with various dipolarophiles that gave substituted isoxazoles, thus con-firming the nitrile oxide structure.

Keywords

naphthols, oxime, oxidation, isomerization, nitrile oxide, 1,3-dipolar cycloaddition, isoxazoles

Subject

Chemistry and Materials Science, Organic Chemistry

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