Synthesis of 3,4,5-Trisubstituted Isoxazoles through Gold-Catalyzed Cascade Cyclization-Oxidative Alkynylation and Cyclization-Fluorination of 2-Alkynone O-Methyloximes

Abstract

Gold-catalyzed tandem cyclization−oxidative alkynylation and cyclization-fluorination reactions of 2-alkynone O-methyloximes are described. The reactions proceed smoothly at room temperature in the presence of 10 mol % of (PPh 3 )AuNTf 2 , 2.5 equivalents of selectfluor, and 2 equivalents of K 3 PO 4 . 2-Alkynone Omethyloximes undergo intramolecular oxyauration/cyclization and ensuing oxidative cross-coupling and fluorination process to afford the corresponding 3,4,5-trisubstituted isoxazoles in a cascade manner.

Gold-Catalyzed Reactions of Specially Activated Alkynes, Allenes, and Alkenes

“…In this case, mechanistic studies suggested that only a redox Au­(I)/Au­(III) catalytic cycle could account for the formation of fluoroisoxazoles. Furthermore, the group of Ryu studied the possibility to perform a gold-catalyzed oxidative cross-coupling reaction using phenylacetylene derivatives 874 as coupling partners (Scheme , part C) . After a thorough investigation of the reaction conditions, a series of alkynylisoxazoles 875 could be obtained from alkynyloxime dervatives 873 in moderate yields (30–47%) and under relatively mild conditions.…”

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

“…Recently, Jurberg and co-workers developed a palladiumcatalyzed cross-coupling strategy for the synthesis of 3,5-disubstituted isoxazoles using 5-( pseudo)halogenated isoxazoles as the platform molecule (Scheme 21). 40 With triflate substituted isoxazoles (42) as the optimal substrate, the well-known Sonogashira and Suzuki cross-coupling can be easily achieved, thus generating the corresponding alkynylation products (44) and arylation (46) products in moderate to good yields.…”

“…In 2014, Ryu and co-workers developed a gold-catalyzed cascade cyclization-oxidative alkynylation and cyclizationfluorination of alkynyl O-methyl oximes (54) (Scheme 26). 44 Further screening of the reaction conditions revealed that both (PPh 3 )AuNTf 2 and K 3 PO 4 were indispensable for this protocol. The authors also explained that the role of K 3 PO 4 is to abstract the acetylenic proton of the terminal alkyne and produce a gold-acetylide species.…”

“…53 Using FeCl 2 as an inexpensive, nontoxic, and efficient catalyst, a wide range of functional groups such as methoxyl, nitro, and benzyl were well tolerated under this catalytic system, giving the desired products 73 in satisfactory yields. 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.…”

Palladium-Catalyzed Cascade Annulation/Allylation of Alkynyl Oxime Ethers with Allyl Halides: Rapid Access to Fully Substituted Isoxazoles

“…Among them, cyclization of alkynyl oxime ether has aroused much attention which is summarized in Scheme . Ryu, Larock, and Ruchirawat et al utilized electrophilic cyclization of alkynyl- O -methyl oximes for the synthesis of 4-haloisoxazoles, respectively (Scheme a). Chen and our group developed palladium-catalyzed coupling between alkynyl- O -methyl oximes with activated alkenes/alkynes for the construction of 4-alkeny/alkyny isoxazoles (Scheme b,c).…”