Isoxazoline Explained

Isoxazolines are a class of five-membered heterocyclic chemical compounds, containing one atom each of oxygen and nitrogen which are located adjacent to one another. The ring was named in-line with the Hantzsch–Widman nomenclature. They are structural isomers of the more common oxazolines and exist in three different isomers depending on the location of the double bond. The relatively weak N-O bond makes isoxazolines prone to ring-opening and rearrangement reactions.

Compounds containing an isoxazoline ring, sometimes referred to isoxazolyls, have a variety of uses with many being biologically active. A number of naturally occurring isoxazolines with possible anti-cancer activity are produced by marine sponges.^[1] Perhaps the most commonly encountered products containing isoxazolines are some veterinary medicines used to prevent flea infestations in dogs and cats e.g. Fluralaner, Afoxolaner and Sarolaner.

Examples

USA FDA approved for use in dogs and/or cats

SourceL^[2]

• Fluralaner
• Lotilaner
• Afoxalaner (approved for dogs only)
• Sarolaner (approved for dogs only)

Synthesis

2-Isoxazolines are generally produced by the 1,3-dipolar cycloaddition of nitrile oxides with alkenes.^[3] This has been applied in a diastereoselective manner in the synthesis of epothilones.^[4]

3-isoxazolines are prepared from 2-isoxazolines via their N-methylation to form 2-isoxazolinium salts, followed by nucleophilic attack and deprotonation.^[5]

4-Isoxazolines are most commonly produced by (3+2) cycloaddition between a nitrone and an alkyne.^[6] This can be considered an extension of the more common nitrone-olefin (3+2) cycloaddition used for creating isoxazolidines.

See also

• Isoxazole
• 1,2-Benzisoxazole

Notes and References

1. Kaur . Kamalneet . Kumar . Vinod . Sharma . Anil Kumar . Gupta . Girish Kumar . Isoxazoline containing natural products as anticancer agents: A review . European Journal of Medicinal Chemistry . April 2014 . 77 . 121–133 . 10.1016/j.ejmech.2014.02.063. 24631731 .
2. Zhou . Xueying . Hohman . Alexandra E. . Hsu . Walter H. . January 2022 . Current review of isoxazoline ectoparasiticides used in veterinary medicine . Journal of Veterinary Pharmacology and Therapeutics . en . 45 . 1 . 1–15 . 10.1111/jvp.12959 . 0140-7783. free .
3. Erik Larsen . Karl . Torssell . Kurt B.G. . An improved procedure for the preparation of 2-isoxazolines . Tetrahedron . January 1984 . 40 . 15 . 2985–2988 . 10.1016/S0040-4020(01)91313-4.
4. Stereoselective Syntheses of Epothilones A and B via Directed Nitrile Oxide Cycloaddition. . Jeffrey . Bode . Erick . Carreira . Journal of the American Chemical Society . 2011 . 3611–3612 . 10.1021/ja0155635 . 11472140 . 123 . 15.
5. Jäger . Volker . Frey . Wolfgang . Bathich . Yaser . Shiva . Sunitha . Ibrahim . Mohammad . Henneböhle . Marco . LeRoy . Pierre-Yves . Imerhasan . Mukhtar . 2-Isoxazolinium Salts and 3-Isoxazolines: Exploratory Chemistry and Uses for the Synthesis of Branched Amino Polyols and Amino Acids . Zeitschrift für Naturforschung B . 1 July 2010 . 65 . 7 . 821–832 . 10.1515/znb-2010-0708. 12345097 . free .
6. Freeman . Jeremiah P. . .DELTA.4-Isoxazolines (2,3-dihydroisoxazoles) . Chemical Reviews . June 1983 . 83 . 3 . 241–261 . 10.1021/cr00055a002.