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

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  • References and Notes

  • 1 Arya GC, Kaur K, Jaitak V. Eur. J. Med. Chem. 2021; 221: 113511
    • 2a Morita T, Yugandar S, Fuse S, Nakamura H. Tetrahedron Lett. 2018; 59: 1159
    • 2b Bondarenko OB, Zyk NV. Chem. Heterocycl. Compd. 2020; 56: 1523
    • 3a Hu F, Szostak M. Adv. Synth. Catal. 2015; 357: 2583
    • 3b Das S, Chanda K. RSC Adv. 2021; 11: 32680
    • 4a Miki Y, Kobayashi S, Ogawa N, Hachiken H. Synlett 1994; 1001
    • 4b Miki Y, Fujita R, Matsushita K. J. Chem. Soc., Perkin Trans. 1 1998; 2533
    • 4c Nakamura A, Takane R, Tanaka J, Morimoto J, Maegawa T. Heterocycles 2018; 97: 785
  • 5 Moriarty RM, Khosrowshahi JS, Prakash O. Tetrahedron Lett. 1985; 26: 2961
  • 6 Nakamura A, Tanaka S, Imamiya A, Takane R, Ohta C, Fujimura K, Maegawa T, Miki Y. Org. Biomol. Chem. 2017; 15: 6702
  • 7 Nakamura A, Imamiya A, Ikegami Y, Rao F, Yuguchi H, Miki Y, Maegawa T. RSC Adv. 2022; 12: 30426
  • 8 Kamal R, Sharma D, Wadhwa D, Prakash O. Synlett 2012; 93
    • 9a Tsyganov DV, Semenova MN, Konyushkin LD, Ushkarov VI, Raihstat MM, Semenov VV. Mendeleev Commun. 2019; 29: 163
    • 9b Stroylov VS, Svitanko IV, Maksimenko AS, Kislyi VP, Semenova MN, Semenov VV. Bioorg. Med. Chem. Lett. 2020; 30: 127608
    • 9c Silyanova EA, Ushkarov VI, Samet AV, Maksimenko AS, Koblov IA, Kislyi VP, Semenovac MN, Semenov VV. Mendeleev Commun. 2022; 32: 120
    • 10a Kim HJ, Lee JH, Olmstead MM, Kurth MJ. J. Org. Chem. 1992; 57: 6513
    • 10b Grecian S, Fokin VV. Angew. Chem. Int. Ed. 2008; 47: 8285
    • 10c Brahma S, Ray JK. J. Heterocycl. Chem. 2008; 45: 311
    • 10d Schmitt DC, Lam L, Johnson JS. Org. Lett. 2011; 13: 5136
    • 10e Dissanayake AA, Odom AL. Tetrahedron 2012; 68: 807
    • 10f Jia Q, Benjamin PM. S, Huang J, Du Z, Zheng X, Zhang K, Conney AH, Wang J. Synlett 2013; 24: 79
  • 11 Chernysheva NB, Maksimenko AS, Andreyanov FA, Kislyi VP, Strelenko YA, Khrustalev VN, Semenova MN, Semenov VV. Eur. J. Med. Chem. 2018; 146: 511

    • For other reports on syntheses of disubstituted isoxazole from chalcones, see:
    • 12a Wei X, Fang J, Hu Y, Hu H. Synthesis 1992; 1205
    • 12b Desai VG, Tilve SG. Synth. Commun. 1999; 29: 3017
    • 12c Kurangi RF, Kawthankar R, Sawal S, Desai VG, Tilve SG. Synth. Commun. 2007; 37: 585
    • 12d Tang S, He J, Sun Y, He L, She X. Org. Lett. 2009; 11: 3982
    • 12e Bhatt A, Singh RK, Kant R. Synth. Commun. 2019; 49: 1083
    • 12f Bhatt A, Singh RK, Kant R. Tetrahedron Lett. 2019; 60: 1143
  • 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.