Synlett 2023; 34(11): 1253-1258
DOI: 10.1055/a-2028-9454
letter

Regioselective Synthesis of 3,4-Disubstituted Isoxazoles by Using a Chalcone-Rearrangement Strategy

,
Tohko Kine
,
Haruna Uenishi
,
Yuri Maki
,
Yasuhito Kase
,
Mayo Takagi
,
This work was financially supported by JSPS KAKENHI (Grants Numbers 19K16329 and 18K05132) and by 2021 Kindai University Research Enhancement Grants (KD2106 and SR09).


Abstract

We have developed a regioselective synthesis of 3,4-disubstituted isoxazoles by using a chalcone-rearrangement strategy. The reaction of β-ketoacetals with hydroxylamine hydrochloride and pyridine afforded the corresponding 3,4-disubstituted isoxazoles via isoxazolines or oximes. Depending on the substrate, another disubstituted isomer was also obtained under our optimized conditions, and a reaction mechanism for each transformation is proposed.

Supporting Information



Publikationsverlauf

Eingereicht: 07. Januar 2023

Angenommen nach Revision: 06. Februar 2023

Accepted Manuscript online:
06. Februar 2023

Artikel online veröffentlicht:
01. März 2023

© 2023. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References and Notes

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  • 13 The trans-relationship between the aromatic ring and the methoxy group was confirmed by X-ray crystallographic analysis of 4a. See the Supporting Information for the details of the X-ray analysis.
  • 14 Isoxazoles; General Procedure NaH (2.0 equiv) was added to a solution of the appropriate isoxazoline (1.0 equiv) in THF (0.1 M), and the mixture was stirred at r.t. until the reaction was complete. The reaction was then quenched with aq NH4Cl and the organic layer was extracted with EtOAc, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by column chromatography [silica gel, hexane–EtOAc (10:1)]. 3-(4-Methoxyphenyl)-4-(p-tolyl)isoxazole (2a) White solid; yield: 95%; mp 141–142 °C. 1H NMR (400 MHz, CDCl3): δ = 8.45 (s, 1 H), 8.45 (d, J = 8.8 Hz, 2 H), 7.16 (s, 4 H), 6.89 (d, J = 8.8 Hz, 2 H), 3.83 (s, 3 H), 2.37 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 160.8, 160.0, 156.2, 138.0, 130.2, 129.6, 128.9, 126.3, 121.1, 120.2, 114.2, 55.4, 21.3. HRMS (ESI): m/z [M + H]+ calcd for C17H16NO2: 266.1181; found: 266.1168.
  • 15 4,5-Disubstituted Isoxazoles; General Procedure NH2OH·HCl (1.5 equiv) and pyridine (3.0 equiv) were added to a solution of the appropriate β-ketoacetal 1 (1.0 equiv) in MeOH (0.5 M), and the mixture was stirred at 80 °C for 24 h, then cooled to r.t. The reaction was then quenched with aq NH4Cl, and the organic layer was extracted with EtOAc, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by column chromatography [silica gel, hexane–EtOAc (10:1)]. 5-(2-Methoxyphenyl)-4-(p-tolyl)isoxazole (3k) Pale-yellow oil; yield: 98%. 1H NMR (400 MHz, CDCl3): δ = 8.48 (s, 1 H), 7.48–7.43 (m, 2 H), 7.15 (d, J = 8.0 Hz, 2 H), 7.10 (d, J = 8.0 Hz, 2 H), 7.03 (t, J = 7.6 Hz, 1 H), 6.95 (d, J = 8.0 Hz, 1 H), 3.54 (s, 3 H), 2.33 (s, 3 H). 13C NMR (151 MHz, CDCl3): δ = 162.4, 157.2, 150.7, 137.2, 131.8, 131.1, 129.3, 127.8, 127.2, 120.8, 117.8, 117.4, 111.7, 55.4, 21.3. HRMS (ESI): m/z [M + H]+ calcd for C17H16NO2: 266.1176; found: 266.1174.