Nitrile Oxide, Alkenes, Dipolar Cycloaddition, Isomerization and Metathesis Involved in the Syntheses of 2-Isoxazolines

Abstract

The involvement of 1,3-dipolar cycloaddition (1,3-DP), double bond migration, metathesis, and nitrile oxide (including in situ-generated nitrile oxide) as dipoles, together with the C=C bond containing dipolarophiles, in the syntheses of 2-isoxazolines is presented. Methods for synthesizing isoxazolines (other than 1,3-DP cycloaddition) were also presented briefly. Various methods of nitrile oxide preparation, especially in situ-generated procedures, are presented. Special attention was paid to the application of various combinations of 1,3-DP cycloaddition with double bond migration (DBM) and with alkene metathesis (AM) in the syntheses of trisubstituted isoxazolines. Allyl compounds of the type QCH2CH=CH2 (Q = ArO, ArS, Ar, and others) play the role of dipolarophile precursors in the combinations of DPC mentioned, DBM and AM. Mechanistic aspects of cycloadditions, i.e., concerted or stepwise reaction mechanism and their regio- and stereoselectivity are also discussed from experimental and theoretical points of view. Side reactions accompanying cycloaddition, especially nitrile oxide dimerization, are considered. 2-Isoxazoline applications in organic synthesis and their biological activity, broad utility in medicine, agriculture, and other fields were also raised. Some remaining challenges in the field of 1,3-DP cycloaddition in the syntheses of isoxazolines are finally discussed.

[3 + 2] Cycloaddition of nitrile oxides to dichloropropenes and 1,3‐dichlorobut‐2‐ene: A regioselectivity issue

“…Substituent in position 4 of the benzene ring of the reagents 2 did not affect the ratio of regioisomers: for NOs 2a, 2b, 2c, 2f fundamentally different in electronic nature (Table 1, entries [1][2][3]6), almost the same ratio of isomers was obtained. On the contrary, the steric factor had a more noticeable effect on this ratio: for NOs having substituents in positions 2,6 of the benzene ring 2d and 2e (entries 4, 5), the amount of isomers 5 was significantly higher.…”

“…IR spectra were registered on a Varian 3100 FTIR spectrometer in 4000-400 cm À1 range. 1 H and 13 C spectra were run in CDCl 3 at room temperature on Bruker DPX-400 spectrometer (400.13, 100.61 MHz, respectively). Chemical shifts were referred to residual signals of CDCl 3 (7.27 for 1 H, 77.160 for 13 C).…”

“…Cycloaddition of nitrile oxides (NOs) to alkenes [1] and alkynes [2,3] is a convenient way to obtain isoxazolines and isoxazoles in one preparative step. These compounds are well-known to possess wide-range biological activity, which applied in medicinal chemistry [4][5][6][7].…”

Trifluoromethyl‐β‐dicarbonyls as Versatile Synthons in Synthesis of Heterocycles

“…The most common and efficient approaches found in the literature for synthesis of isoxazole derivatives involve [3 + 2] dipolar cycloaddition between nitrile oxides and alkynes or alkenes, [159] and condensation of hydroxylamine with 1,3dicarbonyl compounds or its equivalents. [160] Sloop et al reported that the reaction of 1 with hydroxylamine 55 in presence of sulfuric acid leads to mixture of 3(5)trifluoromethylisoxazoles 235 and 236 (R=Me) or a single product, 3-trifluoromethylisoxazole 235 (R=Ph) (Scheme 74).…”

“…The most common and efficient approaches found in the literature for synthesis of isoxazole derivatives involve [3+2] dipolar cycloaddition between nitrile oxides and alkynes or alkenes, [159] and condensation of hydroxylamine with 1,3‐dicarbonyl compounds or its equivalents [160] …”