Synthesis of 3,5‐Disubstituted Isoxazoles through a 1,3‐Dipolar Cycloaddition Reaction between Alkynes and Nitrile Oxides Generated from O‐Silylated Hydroxamic Acids

Abstract

The Cover Feature shows a chemist who is juggling O‐silylated hydroxamic acids, in the presence of NEt3 and trifluoromethanesulfonic anhydride (Tf2O), to allow 1,3‐dipolar cycloaddition reaction with alkynyl dipolarophiles and regioselective formation of 3,5‐disubstituted isoxazole. Cycloaddition takes place between the alkyne and nitrile oxide, generated in‐situ from the O‐silylated hydroxamic acid previously developed by the Carreira group. Juggling has been selected for illustration considering the straightforward, practical and efficient strategy which we have applied and optimized towards the regioselective synthesis of 3,5‐disubstituted isoxazoles. More information can be found in the Full Paper by D. Bonifazi et al.

Mechanochemical Desymmetrization of Unbiased Bis- and Tris-alkynes to Access 3,5-Isoxazoles-Alkyne Adducts and Unsymmetrical Bis-3,5-isoxazoles

“…When ENR bis-alkyne (7a) was reacted with an hydroxyimidoyl chloride bearing electron-neutral groups (ENG) (8d), 3,5-isoxazole-alkyne adduct (9d) was desymmetrize with an excellent yield, where desymmetrization of bis-alkyne (7a) previously was reported to require at least 10 equivalents of bisalkyne substrate to achieve selectivity for the formation of the 3,5isoxazole-alkyne adduct. [5] In contrast, when ENR bis-alkynes (7a-b) reacted with hydroxyimidoyl chlorides bearing an electronwithdrawing groups (EWG) (8a-c), 3,5-isoxazole-alkyne adducts (9a-c), (9g), and (9m) were obtained in low yields. The opposite trend was observed for bis-alkynes on electron-rich rings (ERR) (7d) which showed higher reactivity for hydroxyimidoyl chlorides bearing EWG (8a).…”

“…[2,3] Desymmetrization of symmetrical bis-and trisalkyne via a controlled 1,3-dipolar cycloaddition with nitrile oxide dipoles (NOs) to form 3,5-isoxazole-alkyne adducts has not been thoroughly investigated, and only a few examples have been reported. [4][5][6] To date, desymmetrization of bis-and tris-alkyne focused on CuAAC (Copper Azide Alkyne Cycloaddition) to form 1,4-triazole-alkyne adducts. [1,[7][8][9][10][11][12] Current desymmetrization strategies to synthesize 3,5-isoxazole-alkyne or azide-alkyne adducts require protecting groups, specific dipoles, and an excess amount of the bis-or tris-alkyne.…”

Recent Advances in the Generation of Nitrilium Betaine 1,3-Dipoles

“…79 However, despite the apparent applicability of this methodology, no further reports of this approach towards NO formation appeared until 2019, when Bonifazi adapted the methodology to afford the regioselective preparation of 3,5disubstituted isoxazoles from an NO intermediate. 80 Quantitative generation of the 1,3-dipole has reportedly been accomplished in under 3 minutes when employing this protocol. K. Livingstone et al…”

Stereoselective synthesis of spirocyclic pyrrolidines/pyrrolizidines/pyrrolothiazolidines using l-proline functionalized manganese ferrite nanorods as a novel heterogeneous catalyst

“…[2][3][4][5][6] Azomethine ylides have four p electrons spread over the three-atom C-N-C unit, of which the most common representation has a positive charge located on the nitrogen atom and a negative charge distributed over the two carbon atoms. 7 The cycloaddition of an azomethine ylide with a p-system involves a total of six p electrons [p4s + p2s] and takes place by a thermally allowed, suprafacial process in which two carbon-carbon bonds are formed on the same face of the azomethine ylide and on the same face of the dipolarophile. 8 It is generally accepted that the cycloaddition involves both carbon-carbon p-bonds being formed at the same time, although not necessarily to the same extent.…”

“…Due to the constrained structure of spiro compounds, the existence of the chiral central spiro carbon and the indole core represents an interesting pharmacophore, and these compounds show a wide range of biological and pharmacological activities. 9 Furthermore, a broad range of natural alkaloids contain well-known spirooxindole moieties, such as formosanine, 4 pteropodine, 5 coerulescine, 6 strychnofoline, 7 rychnophyilline, 4 and alstonisine, 8 with highly pronounced proved pharmacological properties ( Fig. 1 ).…”