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.

Herein, we disclose a catalyst-controlled chemodivergent approach to access C2-substituted indoles and diverse aniline derivatives with good chemo-and stereoselectivity by employing vinylcyclopropanes (VCPs) as coupling partners via a tandem C−H/C−C activation/annulation strategy. The key feature of this work is the divergent reactivity profile showcased by VCPs, going beyond allylation under a high-valent Rh-/MPAA catalyst system.I n the last few decades, transition-metal (TM) catalysis has brought about a paradigm shift in organic synthesis by emerging as a key player in atom-and step-economical C−C and C−heteroatom bond forming reactions. 1 To achieve the challenging site-selective direct C−H functionalization of nonbiased C−H bonds, various strategies have been adopted which include utilization of different Lewis basic directing groups (DGs) or by changing the steric/electronic nature of the substrates as well as employing a catalyst and/or reagent control (solvent/additives). 2 Meanwhile, considerable efforts have been invested in merging C−H activation with the challenging C−C bond activation approach by employing small ring systems as substrates which are driven by their innate high strain release energy. 3 Vinyl cyclopropanes (VCPs) belong to a class of reactive coupling partners, and have been extensively used by synthetic organic chemists owing to their multifold reactivity in the presence of different catalytic systems. 4 Utilizing the metallacycle formed via sequential C−H activation/alkene insertion of VCP with DG-containing arenes under TM-catalysis and subsequent chelation assisted β-carbon elimination results in a C−C bond cleavage, which makes VCPs valuable coupling partners for C−H functionalizations (Scheme 1a). In 2015, the Wang group reported a sequential C−H/C−C activation using VCPs, yielding allylated arenes and skipped dienes under Rhcatalysis with good (E)-stereoselectivity (Scheme 1b). 5 In 2016, Ackermann and co-workers utilized VCPs as a masked allyl source for the Co(III)-catalyzed C2-allylation of indoles, achieving unique diastereoselectivity toward the thermodynamically less stable Z-alkenes (Scheme 1b). 6 Thereafter, a modified allylation protocol using VCPs was reported, under low-valent Mn-catalysis, to give allylated (hetero)arenes 7 and indoles. 8 Recently, Gooβen and co-workers used Ru-catalysts for the C− H allylation of benzoic acids using VCPs. 9 Matsunaga and co-workers reported a Co(III)-catalyzed arene allylation with the help of imidates as the DG. 10

A convenient, “one-pot” synthesis of trisubstituted pyrroles via a Ru(II)-catalyzed and Cu(II)-mediated reaction of substituted isoxazoles with sulfonylhydrazones has been developed. A series of highly functionalized pyrroles are obtained via...