Step-by-Step Multifunctionalization of Isoxazoles Based On SEAr Reactions and C–H Direct Arylations

Abstract

Functionalized isoxazoles are important as pharmaceuticals and agrochemicals. Generally, electrophilic aromatic substitution or generation of carbanions/electrophilic trapping approach is used to introduce functional groups into unsubstituted heteroaromatics. However, these approaches have not been simple to apply to unsubstituted isoxazoles due to their poor nucleophilicity and instability under basic conditions. Recently several approaches have been reported to overcome these problems. This review summarizes the functionalization of isoxazoles, including SEAr reactions and C–H direct arylations, towards the step-by-step multifunctionalization of isoxazoles.1 Introduction2 SEAr Reaction of Isoxazoles3 Preparation of Isoxazolyl Anions and Their Use for the Synthesis of Functionalized Isoxazoles4 Other C–C and C–N Bond Formations of Isoxazoles5 Transition-Metal-Catalyzed C–H Direct Functionalization of Isoxazoles6 Step-by-Step Multifunctionalization of Isoxazoles7 Summary and Outlook

Synthesis of 3-Hydroxy-4-Substituted Picolinonitriles from 4-Propargylaminoisoxazoles via Stepwise and One-Pot Isoxazolopyridine Formation/N–O Bond Cleavage Sequence

“…It is known that 3- and/or 5-unsubstituted isoxazoles readily occur by N–O bond cleavage under mild basic conditions. , De Munno and co-workers reported the mechanism of hydroxide-ion-mediated ring opening of 3-unsubstituted isoxazoles . Houk and co-workers elucidated the mechanism of formate-mediated ring opening of 3-unsubstituted isoxazoles on the basis of theoretical calculations .…”

Transition Metal‐Mediated Functionalization of Isoxazoles: A Review

“…Functionalization of isoxazoles by electrophilic aromatic substitution (S E Ar) is challenging due to their poor nucleophilicity. [42] In 2018, Nakamura and co-workers reported an intramolecular S E Ar reaction of C4-substituted isoxazole derivatives to produce isoxazole-containing fused heterocycles such as isoxazolopyridines and isoxazolopyrans, under cationic gold(I) catalysis (Scheme 32). [43] The reaction was initiated by the activation of isoxazole-tethered alkyne derivative by the cationic gold(I) catalyst to generate intermediate I followed by catalyst.…”

Photochemical Conversion of Isoxazoles to 5-Hydroxyimidazolines

“…Conventional synthetic approaches of functionalized isoxazoles are based on ring construction with prefunctionalized linear components . However, several direct functionalization approaches that employ isoxazolyl anion species, S E Ar reactions, and C–H activation using catalysts , have recently been reported. Interestingly, isoxazoles also undergo photolysis under UV light irradiation (Scheme a) .…”