Synthesis of 4-Sulfenyl Isoxazoles through AlCl₃-Mediated Electrophilic Cyclization and Sulfenylation of 2-Alkyn-1-one O-Methyloximes

Abstract

An efficient method for the synthesis of 4-sulfenyl isoxazoles has been developed via AlCl3-mediated electrophilic cyclization/sulfenylation of 2-alkyn-1-one O-methyloximes. Remarkably, N-arylsulfanylsuccinimides are employed as electrophiles for the construction of 4-arylsulfanyl isoxazoles, and 4-alkylsulfanyl isoxazoles are accessed with dialkyl disulfides as electrophiles.

Synthesis of 4‐Chalcogenylated Isoxazoles Mediated by PhICl2 and Diorganyl Disulfides/Diselenides

“…Furthermore, dialkyl disulfides including dipropyl and dibenzyl disulfanes were also applicable for this conversion to access 4‐sulfenyl isoxazoles ( 3 i – j ) in 81% and 51% yields, respectively. However, owing to the lower reactivity of organosulfenyl chloride intermediates compared with organoselenenyl chlorides and the reversible formation of disulfides, [17c] the amount of PhICl 2 and disulfides had to be increased to 1.2 equiv. and 1.0 equiv, respectively, to ensure a full consumption of the substrates.…”

“…Zeni and co‐workers realized the incorporation of the organoselenyl groups into isoxazole scaffold through a FeCl 3 ‐mediated intramolecular electrophilic cyclization/selenylation of alkynone O ‐methyl oxime compounds by using diselenides as selenium source (Scheme 1b) [17b] . Gao and colleagues synthesized 4‐sulfenyl isoxazoles from the reaction between alkynone Z ‐ O ‐methyloximes and N ‐sulfanylsuccinimides or disulfides via an AlCl 3 ‐mediated intramolecular electrophilic cyclization (Scheme 1c) [17c] . Despite the advances of these protocols, it is still significant to develop alternative methods with high efficiency, mild reaction conditions and no participation of heavy metals.…”

Electrochemical Oxidative Cross‐Coupling of Enaminones and Thiophenols to Construct C−S Bonds

“…In 2017, our group reported an electrochemical dehydrogenative C−H/S−H cross‐coupling reaction of indoles and thiophenols [6a] . Zeng, [6b] Xu, [6c] Mei, [6d] and other groups [6e–k] also did related works, respectively. In 2019, Zan Yang et al reported electrochemically induced thiocyanation of enaminones [6l] .…”

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

“…Recently, Yang and co-workers described an elegant and practical AlCl 3 -mediated cascade cyclization/sulfenylation of alkynone O-methyloximes (97) with an electrophilic source for the synthesis of 4-sulfenyl isoxazoles (100) (Scheme 42). 64 In the presence of 1 equiv. AlCl 3 in MeNO 2 at 60°C for 3-7 h, a whole variety of functional groups of both alkynone O-methyloximes and N-arylsulfanylsuccinimides (98) such as alkyl, alkoxyl, halo, ester, nitro, trimethylsilyl, and thienyl were well tolerated, delivering the corresponding products in good yields.…”

“…And then, radical addition of the sulfonyl radical with 1,3enynes affords two resonant radical intermediates: alkyl radical Int-62 and allenyl radical Int-63. 74 Subsequently, the radical cross coupling of allenyl radical Int-63 with the NO radical generates the allenyl intermediate Int- 64, which undergoes successive isomerization and intramolecular nucleophilic cyclization to produce the desired products 119 in the presence of InBr 3 . The authors also demonstrated that InBr 3 plays an important role in this cascade pathway.…”