Transition Metal‐Mediated Functionalization of Isoxazoles: A Review

Abstract

Isoxazoles are an important class of heterocycles with nitrogen and oxygen in a 1,2-relationship. They find wide applications in synthetic organic chemistry and are part of several drug molecules. Since the last two decades, great progress has been achieved in the synthesis and functionalization of isoxazoles, in which transition metal catalysis played a pivotal role towards achieving this goal. In particular, the transition metal (TM)-mediated site-selective functionalizations of isoxazoles which retain the pharmacologically and synthetically valuable isoxazole skeleton, are highly appealing. This comprehensive review is solely dedicated to the TM-mediated functionalization of isoxazoles, wherein we have included isoxazoles as directing groups (DG) for TM-catalyzed CÀ H functionalization reactions, TM-catalyzed direct CÀ H functionalization, along with cross-coupling reactions of isoxazoles, TM-catalyzed annulation reactions of isoxazoles and finally ring-opening reactions of isoxazoles under TMcatalysis are also discussed. Also, incorporated are discussions on reaction designs, their advantages and limitations, mechanistic details and challenges that need to be addressed to inspire synthetic organic and medicinal chemists to explore new reaction arenas and make use of this key scaffold.Scheme 1. Synthetic approaches for functionalized isoxazoles.Scheme 2. Functionalization of isoxazoles via the 4-isoxazolyl anion species.

Structural Evidence for Aromatic Heterocycle N–O Bond Activation via Oxidative Addition

“…3,8−10 There are many examples of reactions in which the N−O bond of isoxazoles, benzisoxazoles, or anthranils is functionalized, either under thermal, 11,12 Brønsted basic, 13−15 Lewis acidic, 16 or transition-metalcatalyzed conditions. 17−19 Isoxazoles are also known to decompose under basic conditions, for example, in the Kemp elimination 18 or the Boulton−Katritzky rearrangement. 13,14,20 These transformations provide information on possible decomposition pathways during attempted cross-coupling.…”

Synthesis of acridinesviacopper-catalyzed amination/annulation cascades between arylboronic acids and anthranils

“…In this context, the easily accessible anthranil (2,1-benzisoxazole) derivatives have been extensively investigated recently. 1 They are found to be not only bioactive units, but also competent amination reagents in diverse (transition-metal-catalyzed) transformations, such as C–N cross-couplings and C–H aminations, thus providing approaches for constructing various C–N bonds.…”

Structural Evidence for Aromatic Heterocycle N–O Bond Activation via Oxidative Addition

“…3,[8][9][10] There are many examples of reactions in which the N-O bond of isoxazoles, benzisoxazoles or anthranils is functionalized, either under thermal, 11,12 Bronsted basic, [13][14][15] Lewis acidic 16 or transition-metal catalyzed conditions. [17][18][19] Isoxazoles are also known to decompose under basic conditions, for example in the Kemp elimination 18 or the Boulton-Katritzky rearrangement. 13,14,20 These transformations provide information on possible decomposition pathways during attempted cross-coupling.…”