Iron-Mediated Synthesis of Isoxazoles from Alkynes: Using Iron(III) Nitrate as a Nitration and Cyclization Reagent

Abstract

A simple and direct method for the iron(III) nitrate-mediated synthesis of isoxazoles from alkynes has been developed; both self-coupling and cross-coupling products could be successfully prepared from alkynes. Meanwhile, for the cross-coupling and cyclizing of two different alkynes examined, the iron-mediated system shows a good chemoselectivity for the synthesis of corresponding isoxazoles. In our method, cheap and eco-friendly iron(III) nitrate is used as the nitration and cyclization reagent, and KI is used as the additive; they both play a positive role in this transformation. Furthermore, a different mechanism for the formation of isoxazoles from alkynes has been proposed.

A review of recent synthetic strategies and biological activities of isoxazole

“…Zhenzhen Lai and co‐authors have reported a simple and direct method for iron(III) nitrate‐mediated synthesis of isoxazoles from aromatic alkynes 1 . Both self‐coupling and cross‐coupling products could be successfully prepared from alkynes as depicted in Scheme 19 [41]. Compound 2 has been synthesized by using aromatic alkynes 1 , Fe(NO 3 ) 3 ·9H 2 O, KI, and THF under an N 2 atmosphere.…”

“…S C H E M E 1 9 Iron (III) nitrate mediated direct synthesis of isoxazoles from alkynes [41] S C H E M E 2 0 Synthesis of perfluroalkyl isoxazole and plausible mechanism for the synthetic route [42] S C H E M E 2 1 Synthesis of Isoxazoles via divergent [2 + 1 + 1 + 1] annulations of Sulfoxonium Ylides and using Cu(TFA) 2 as a catalyst [43]…”

Mechanochemistry Enabled Construction of Isoxazole Skeleton via CuO Nanoparticles Catalyzed Intermolecular Dehydrohalogenative Annulation

“…White solid; Yield: 247 mg (94%); mp:85-87 (5-(4-Fluorophenyl)isoxazol-3-yl)(phenyl) methanone (3 o) [46] White solid; Yield: 222 (83%); mp:144-146 °C; FT-IR (neat): υ = 1668, 1625, 1231 cm À 1 ; 1 H NMR (500 MHz, CDCl [49] White solid; Yield: 255 mg (92%); mp:108-110 °C; FT-IR (neat): υ = 1674, 1610, 1218 cm À 1 ; 1 H NMR (500 MHz, CDCl 3 ): δ (ppm) 8.26 (d, J = 8.0 Hz, 2H), 7.74 (d, J = 8.0 Hz, 2H), 7.34-7.29 (m, 4H), 6.97 (s, 1H), 2.45 (s, 3H), 2.42 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ): δ (ppm) 185.5, 170.9, 162.6, 145.2, 141. 1, 133.3, 130.9, 129.8, 129.3, 125.9, 124.1, 99.7, 21.8, 21.6.…”

Recent advances in metal catalyzed or mediated cyclization/functionalization of alkynes to construct isoxazoles

“…Furthermore, the observations of control experiments suggested that 2H-azirine Int- 44 In addition, the Xu group reported an iron-mediated cascade cyclization approach for the synthesis of diverse isoxazoles from alkynes with iron nitrate as the nitration reagent (Scheme 34). 54 Further optimization of the reaction conditions showed that the kinds of additives were indispensable for this type of transformation. With KI as the additive, the self-coupling of alkynes can smoothly proceed in the presence of 1.5 equiv.…”

“…Particularly interesting is the fact that when KI and t-BuCN were selected as the additives, the cross-coupling of terminal alkynes (76) with electron-deficient alkynes (77) were also perfectly accommodated under the similar reaction conditions (Scheme 35). 54 The substrate scopes and limitations of both terminal alkynes and electron-deficient alkynes were then comprehensively evaluated. Remarkably, propiolamide and alkynyl sulfonate were also tolerated well, albeit giving the corresponding isoxazole derivatives 78 in lower yields.…”