Copper-Catalyzed Reductive Ring-Cleavage of Isoxazoles: Synthesis of Fluoroalkylated Enaminones and Application for the Preparation of Celecoxib, Deracoxib, and Mavacoxib

Abstract

We have identified a new reactivity of copper/diamine catalysis for the reductive ring-cleavage of isoxazoles to yield fluoroalkylated enaminones. This protocol has the advantage of using commercially available reagents, ease of setting up, broad tolerance of functionality, and is regiospecific and free of defluorination and reduction of reducible functional groups. The utility was demonstrated by a one-step, regioselective synthesis of fluoroalkylated pyrazole-based drugs such as celecoxib, deracoxib, and mavacoxib.

Recent Advances in Transition Metal Catalyzed Synthesis of β‐Enaminones and β‐Enaminoesters

“…Subsequently, nucleophilic addition of the formyl group of 101 to the electrophilic carbene center occurred and zwitterionic intermediate 105 was generated, which released an electron pair to induce the imino nitrogen to attack the carbon of the iminium ion, ylated isoxazoles 109 to yield CF 2 -and CF 3 -substituted enaminones 110 (Scheme 20). [44] Polyfluorinated enaminones (products 111-112) and nonfluorinated enaminones (products 113-114) were also prepared from viable isoxazole substrates in high yields. The wide range of application, using commercially available reagents, ease of setting up, broad tolerance of functionality, regiospecific and free of defluorination and reduction of reducible functional groups were advantages worth mentioning.…”

Bismuth‐Mediated α‐Arylation of Acidic Diketones with ortho‐Substituted Boronic Acids

“…In contrast, α-arylated fluoroalkyl diones are valued as key precursors to biologically relevant heterocycles, including pyrazoles, isoxazoles and pyrimidines (Scheme 1B). [22][23][24][25] Together, these arylated fluoroalkyl heterocycles account for over 4 500 patented compounds with indications including obesity, inflammation, cancer and Huntington's disease.…”

“…Notably, nearly 10 000 (60 %) of the compounds claimed in >120 agrochemical patents bear at least one ortho substituent on the aryl moiety (Scheme 1A), a feature which significantly hinders cross‐coupling approaches to this motif (see below). In contrast, α‐arylated fluoroalkyl diones are valued as key precursors to biologically relevant heterocycles, including pyrazoles, isoxazoles and pyrimidines (Scheme 1B) [22–25] . Together, these arylated fluoroalkyl heterocycles account for over 4 500 patented compounds with indications including obesity, inflammation, cancer and Huntington's disease.…”

An Approach to Vinylidenequinazolines from Isoxazoles and Dioxazolones

“…In the field of C–H activation, isoxazole rings working as the popular directing groups were reacted with various coupling partners such as alkynes, aldehydes, and alkenes to deliver functionalized heterocycles . In addition, isoxazoles have also emerged as susceptible sources in cascade reactions because the N–O bond of the isoxazole ring is easy to cleave . Considering the high attraction of isoxazole cores, we wondered if it would be possible to first introduce an amide group in the ortho -position of isoxazoles through C–H activation, then use the ring-opening of isoxazole rings to generate β-enaminones that would subsequently undergo intramolecular annulation to synthesize the desired vinylidenequinazolines.…”