Catalyst-Controlled Chemodivergent Reactivity of Vinyl Cyclopropanes: A Selective Approach toward Indoles and Aniline Derivatives

Abstract

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

Predicting success in Cu-catalyzed C–N coupling reactions using data science

“…Having established the workflow, we sought to additionally validate the workflow using two molecules of synthetic interest: P300 , a delta opioid agonist precursor ( 42 , 43 ) ( Fig. 5A ), and P301 , an indoline precursor ( 44 – 46 ) ( Fig. 5B ).…”

Recent updates on vinyl cyclopropanes, aziridines and oxiranes: access to heterocyclic scaffolds

“…Recently, Kapur and co-workers 87 reported the chemodivergent activity of vinyl cyclopropanes 11 to accomplish substituted indole derivatives 121 (Scheme 42). The Rh/Cu-assisted catalytic pathway involves C-H activation, which undergoes sole allylation to accomplish highly functionalized anilines.…”

Metal‐Catalysed Synthesis of Benzofused Five‐Membered N/O/S‐Heterocycles, a Progressive Area in Synthetic Organic Chemistry

“…catalytic system (Scheme 15). [70] The authors claimed that the efficacy of this Rh-catalysed reaction was significantly affected by the oxidants and their loading, while the use of MPAA ligands effectively facilitated the reaction, owing to their potency to form MPAA-bridged binuclear metal complexes to form MPAA-bridged binuclear metal complexes which enhance the CÀ H bond cleavage. On the basis of several performed control experiments, they proposed a plausible reaction mechanism for the indole formation.…”

“…Following this strategy, in 2022, Kapur and co‐workers reported Rh‐catalysed chemo‐ and stereo‐selective synthesis of C2‐substituted indoles 46 by coordinating N ‐Pyrimidyl anilines 44 with vinylcyclopropanes (VCPs) 45 as coupling partners under the high‐valent Rh‐/MPAA catalytic system (Scheme 15). [70] The authors claimed that the efficacy of this Rh‐catalysed reaction was significantly affected by the oxidants and their loading, while the use of MPAA ligands effectively facilitated the reaction, owing to their potency to form MPAA‐bridged binuclear metal complexes to form MPAA‐bridged binuclear metal complexes which enhance the C−H bond cleavage. On the basis of several performed control experiments, they proposed a plausible reaction mechanism for the indole formation.…”