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

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.

Key words

isoxazoles - rearrangement - regioselectivity - isoxazolines - oximes

Publication History

Received: 07 January 2023

Accepted after revision: 06 February 2023

Accepted Manuscript online:
06 February 2023

Article published online:
01 March 2023

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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.