Mechanism-Driven Approach To Develop a Mild and Versatile C-H Amidation through Ir-III Catalysis

Described herein is a mechanism-based approach to develop a versatile C-H amidation protocol under Ir-III catalysis. Reaction kinetics of a key C-N coupling step with acyl azide and 1,4,2-dioxazol-5-one led us to conclude that dioxazolones are much more efficient in mediating the formation of a carbon-nitrogen bond from an iridacyclic intermediate. Computational analysis revealed that the origin of higher reactivity is asynchronous decarboxylation motion, which may facilitate the formation of Ir-imido species. Importantly, stoichiometric reactivity was successfully translated into catalytic activity with a broad range of substrates (18 different types), many of which are regarded as challenging to functionalize. Application of the new method enables late-stage functionalization of drug molecules (c) 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim1561sciescopu

Mechanism-Guided Development of Transition-Metal-Catalyzed C–N Bond-Forming Reactions Using Dioxazolones as the Versatile Amidating Source

© XXXX American Chemical Society.ConspectusCatalytic reactions that construct carbon-nitrogen bonds are one of central themes in both synthetic and medicinal chemistry since the obtainable nitrogen-containing motifs are commonly encountered in natural products and have also seen a growing prominence as key structural features in marketed drugs and preclinical candidates. Pd-catalyzed cross-couplings, such as Buchwald-Hartwig amination, are at the forefront of such synthetic methods in practical settings. However, they require prefunctionalized substrates such as (hetero)aryl halides that must be prepared independently, often by multiple operations. One emerging way to circumvent these preparatory steps and directly convert ubiquitous C-H bonds into valuable C-N bonds is catalytic C-H amination, which allows synthetic chemists to devise shorter and more efficient retrosynthetic schemes. The past two decades have witnessed considerable progress in expanding the repertoire of this strategy, especially by identifying effective amino group precursors. In this context, dioxazolones have experienced a dramatic resurgence in recent years as a versatile nitrogen source in combination with transition-metal catalyst systems that facilitate decarboxylation to access key metal-acylnitrenoid intermediates. In addition to their high robustness and easy accessibility from abundant carboxylic acids, the unique reactivity of the transient intermediates in the amido group transfer has led to a fruitful journey for mild and efficient C-H amidation reactions.This Account summarizes our recent contributions to the development of C-N bond-forming reactions using dioxazolones as effective nitrenoid precursors, which are categorized into two subsets according to their mechanistic differences: inner- versus outer-sphere pathways. The first section describes how we could unveil the synthetic potential of dioxazolones in the realm of the inner-sphere C-H amidation, where we demonstrated that dioxazolones serve not only as manageable alternatives to acyl azides but also as highly efficient reagents to significantly reduce the catalyst loading and temperature. Taking advantage of the mild conditions in combination with group 9 Cp*M complexes (M = Rh, Ir, Co) or isoelectronic Ru species, we have dramatically expanded the accessible synthetic scope. Mechanistic investigations revealed that the putative metal-nitrenoid species is involved as a key intermediate during catalysis, which leads to facile C-N bond formation. On the basis of the mechanistic underpinning, we have succeeded in developing novel catalytic platforms that harness the intermediacy of metal-nitrenoids to explore C-H insertion chemistry via an outer-sphere pathway. Indeed, the tailored catalysts were capable of suppressing the competitive Curtius-type decomposition, thus granting access to versatile lactam products. We have further repurposed the catalytic systems upon modification of chelating ligands and also the identity of the transition metal to achieve three goals: (i) addressing selectivity issues to control the regio-, chemo-, and enantioselectivities, (ii) developing sustainable catalysis by first-low metals, and (iii) navigating chemical space for (di)functionalization of alkenes/alkynes. Together with our own research efforts, highlighted herein are some important relevant advances by other groups. We finally conclude with a brief overview with an eye toward further developments.11Nsciescopu

Mechanism-Guided Development of Transition-Metal-Catalyzed C-N Bond-Forming Reactions Using Dioxazolones as the Versatile Amidating Source

© XXXX American Chemical Society.ConspectusCatalytic reactions that construct carbon-nitrogen bonds are one of central themes in both synthetic and medicinal chemistry since the obtainable nitrogen-containing motifs are commonly encountered in natural products and have also seen a growing prominence as key structural features in marketed drugs and preclinical candidates. Pd-catalyzed cross-couplings, such as Buchwald-Hartwig amination, are at the forefront of such synthetic methods in practical settings. However, they require prefunctionalized substrates such as (hetero)aryl halides that must be prepared independently, often by multiple operations. One emerging way to circumvent these preparatory steps and directly convert ubiquitous C-H bonds into valuable C-N bonds is catalytic C-H amination, which allows synthetic chemists to devise shorter and more efficient retrosynthetic schemes. The past two decades have witnessed considerable progress in expanding the repertoire of this strategy, especially by identifying effective amino group precursors. In this context, dioxazolones have experienced a dramatic resurgence in recent years as a versatile nitrogen source in combination with transition-metal catalyst systems that facilitate decarboxylation to access key metal-acylnitrenoid intermediates. In addition to their high robustness and easy accessibility from abundant carboxylic acids, the unique reactivity of the transient intermediates in the amido group transfer has led to a fruitful journey for mild and efficient C-H amidation reactions.This Account summarizes our recent contributions to the development of C-N bond-forming reactions using dioxazolones as effective nitrenoid precursors, which are categorized into two subsets according to their mechanistic differences: inner- versus outer-sphere pathways. The first section describes how we could unveil the synthetic potential of dioxazolones in the realm of the inner-sphere C-H amidation, where we demonstrated that dioxazolones serve not only as manageable alternatives to acyl azides but also as highly efficient reagents to significantly reduce the catalyst loading and temperature. Taking advantage of the mild conditions in combination with group 9 Cp*M complexes (M = Rh, Ir, Co) or isoelectronic Ru species, we have dramatically expanded the accessible synthetic scope. Mechanistic investigations revealed that the putative metal-nitrenoid species is involved as a key intermediate during catalysis, which leads to facile C-N bond formation. On the basis of the mechanistic underpinning, we have succeeded in developing novel catalytic platforms that harness the intermediacy of metal-nitrenoids to explore C-H insertion chemistry via an outer-sphere pathway. Indeed, the tailored catalysts were capable of suppressing the competitive Curtius-type decomposition, thus granting access to versatile lactam products. We have further repurposed the catalytic systems upon modification of chelating ligands and also the identity of the transition metal to achieve three goals: (i) addressing selectivity issues to control the regio-, chemo-, and enantioselectivities, (ii) developing sustainable catalysis by first-low metals, and (iii) navigating chemical space for (di)functionalization of alkenes/alkynes. Together with our own research efforts, highlighted herein are some important relevant advances by other groups. We finally conclude with a brief overview with an eye toward further developments.11Nsciescopu

Quantitative Analysis on Two-Point Ligand Modulation of Iridium Catalysts for Chemodivergent C-H Amidation

The transition-metal-catalyzed nitrenoid transfer reaction is one of the most attractive methods for installing a new C-N bond into diverse reactive units. While numerous selective aminations are known, understanding complex structural effects of the key intermediates on the observed chemoselectivity is still elusive in most cases. Herein, we report a designing approach to enable selective nitrenoid transfer leading to sp(2) spirocyclization and sp(3) C-H insertion by cooperative two-point modulation of ligands in the (CpIr)-Ir-X(III)(kappa(2)-chelate) catalyst system. Computational analysis led us to interrogate structural motifs that can be attributed to the desired mechanistic dichotomy. Multivariate linear regression analysis on the perturbation on the eta(5)-cyclopentadienyl ancillary (Cp-X) and LX coligand, wherein we prepared over than 40 new catalysts for screening, allowed for construction of an intuitive yet robust statistical model that predicts a large set of chemoselective outcomes, implying that the catalysts' structural effects play a critical role on the chemoselective nitrenoid transfer. On the basis of this quantitative analysis, a new catalytic platform is now established for the unique lactam formation, leading to the unprecedented chemoselective reactivity (up to >20:1) toward a diverse array of competing sites, such as tertiary, secondary, benzylic, allylic C-H bonds, and aromatic pi system.© 2020 American Chemical Society11Nsciescopu

Chain Walking as a Strategy for Iridium-Catalyzed Migratory Amidation of Alkenyl Alcohols to Access α-Amino Ketones

© 2022 American Chemical Society.Catalytic carbon-nitrogen bond formation in hydrocarbons is an appealing synthetic tool to access valuable nitrogen-containing compounds. Although a number of synthetic approaches have been developed to construct a bifunctional α-amino carbonyl scaffold in this realm, installation of an amino functionality at the remote and unfunctionalized aliphatic sites remains underdeveloped. Here we present a tandem iridium catalysis that enables the redox-relay amidation of alkenyl alcohols via chain walking and metal-nitrenoid transfer, which eventually offers a new route to various α-amino ketones with excellent regioselectivity. The virtue of this transformation is that an unrefined isomeric mixture of alkenyl alcohols can be utilized as the readily available starting materials to lead to the regioconvergent amidation. Mechanistic investigations revealed that the reaction proceeds via a tandem process involving two key components of redox-relay chain walking and intermolecular nitrenoid transfer with the assistance of hydrogen bonding, thus representing the competence of Ir catalysis for the olefin migratory C-N coupling with high efficiency and exquisite selectivity.11Nsciescopu

Revisiting Arene C(sp2)−H Amidation by Intramolecular Transfer of Iridium Nitrenoids: Evidence for a Spirocyclization Pathway

Two mechanistic pathways, that is, electrocyclization and electrophilic aromatic substitution, are operative in most intramolecular C−H amination reactions proceeding by metal nitrenoid catalysis. Reported here is an alternative mechanistic scaffold leading to benzofused δ-lactams selectively. Integrated experimental and computational analysis revealed that the reaction proceeds by a key spirocyclization step followed by a skeletal rearrangement. Based on this mechanistic insight, a new synthetic route to spirolactams has been developed. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinhe

Enantioselective Access to Spirolactams via Nitrenoid Transfer Enabled by Enhanced Noncovalent Interactions

Described herein is the Ir-catalyzed enantioselective access to chiral spirolactam products via the nitrenoid transfer to aromatic ipso-carbons. The key strategy for precise stereocontrol is to enhance the secondary attractive and repulsive interactions between the chiral catalyst and substrates by the introduction of a traceless O-silyl achiral auxiliary, thus effectively differentiating two prochiral faces of arenol-derived 1,4,2-dioxazol-5-one substrates.11Nsciescopu

Selective formation of gamma-lactams via C-H amidation enabled by tailored iridium catalysts

Intramolecular insertion of metal nitrenes into carbon-hydrogen bonds to form gamma-lactam rings has traditionally been hindered bycompeting isocyanate formation. We report the application of theory and mechanism studies to optimize a class of pentamethylcyclopentadienyl iridium(III) catalysts for suppression of this competing pathway. Modulation of the stereoelectronic properties of the auxiliary bidentate ligands to be more electron-donating was suggested by density functional theory calculations to lower the C-H insertion barrier favoring the desired reaction. These catalysts transform a wide range of 1,4,2-dioxazol-5-ones, carbonylnitrene precursors easily accessible from carboxylic acids, into the corresponding gamma-lactams via sp(3) and sp(2) C-H amidation with exceptional selectivity. The power of this method was further demonstrated by the successful late-stage functionalization of amino acid derivatives and other bioactive molecules.N

Selective formation of g-lactams via C–H amidation enabled by tailored iridium catalysts

Intramolecular insertion of metal nitrenes into carbon-hydrogen bonds to form g-lactam rings has traditionally been hindered bycompeting isocyanate formation.We report the application of theory and mechanism studies to optimize a class of pentamethylcyclopentadienyl iridium(III) catalysts for suppression of this competing pathway. Modulation of the stereoelectronic properties of the auxiliary bidentate ligands to be more electron-donating was suggested by density functional theory calculations to lower the C–H insertion barrier favoring the desired reaction. These catalysts transform a wide range of 1,4,2-dioxazol-5-ones, carbonylnitrene precursors easily accessible from carboxylic acids, into the corresponding g-lactams via sp3 and sp2 C–H amidation with exceptional selectivity. The power of this method was further demonstrated by the successful late-stage functionalization of amino acid derivatives and other bioactive molecules