C−H Functionalization—Prediction of Selectivity in Iridium(I)-Catalyzed Hydrogen Isotope Exchange Competition Reactions

An assessment of the C−H activation catalyst [(COD)Ir(IMes)(PPh₃)]PF₆ (COD=1,5-cyclooctadiene, IMes=1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene) in the deuteration of phenyl rings containing different functional directing groups is divulged. Competition experiments have revealed a clear order of the directing groups in the hydrogen isotope exchange (HIE) with an iridium (I) catalyst. Through DFT calculations the iridium–substrate coordination complex has been identified to be the main trigger for reactivity and selectivity in the competition situation with two or more directing groups. We postulate that the competition concept found in this HIE reaction can be used to explain regioselectivities in other transition-metal-catalyzed functionalization reactions of complex drug-type molecules as long as a C−H activation mechanism is involved.     

Enantioselective Synthesis of N−N Biaryl Atropisomers through Iridium(I)-Catalyzed C−H Alkylation with Acrylates

Enantioselective synthesis of N−N biaryl atropisomers is an emerging area but remains underexplored. The development of efficient synthesis of N−N biaryl atropisomers is in great demand. Herein, the construction of N−N biaryl atropisomers through iridium-catalyzed asymmetric C−H alkylation is reported for the first time. In the presence of readily available Ir precursor and Xyl-BINAP, a variety of axially chiral molecules based on indole-pyrrole skeleton were obtained in good yields (up to 98 %) with excellent enantioselectivity (up to 99 % ee). In addition, N−N bispyrrole atropisomers could also be synthesized in excellent yields and enantioselectivity. This method features perfect atom economy, wide substrate scope, and multifunctionalized products allowing diverse transformations.     

C−H Bond Activation by Iridium(III) and Iridium(IV) Oxo Complexes

Oxidation of an iridium(III) oxo precursor enabled the structural, spectroscopic, and quantum-chemical characterization of the first well-defined iridium(IV) oxo complex. Side-by-side examination of the proton-coupled electron transfer thermochemistry revealed similar driving forces for the isostructural oxo complexes in two redox states due to compensating contributions from H⁺ and e⁻ transfer. However, C−H activation of dihydroanthracene revealed significant hydrogen tunneling for the distinctly more basic iridium(III) oxo complex. Our findings complement the growing body of data that relate tunneling to ground state properties as predictors for the selectivity of C−H bond activation.     

Metal-Free C−H Borylation of N-Heteroarenes by Boron Trifluoride

Organoboron compounds are essential reagents in modern C−C coupling reactions. Their synthesis via catalytic C−H borylation by main group elements is emerging as a powerful tool alternative to transition metal based catalysis. Herein, a straightforward metal-free synthesis of aryldifluoroboranes from BF₃ and heteroarenes is reported. The reaction is assisted by sterically hindered amines and catalytic amounts of thioureas. According to computational studies the reaction proceeds via frustrated Lewis pair (FLP) mechanism. The obtained aryldifluoroboranes are further stabilized against destructive protodeborylation by converting them to the corresponding air stable tetramethylammonium organotrifluoroborates.     

Simple Ether-Directed Enantioselective C(sp3)−H Borylation of Cyclopropanes Enabled by Iridium Catalysis

Reported here is an efficient and simple ether-directed iridium-catalyzed enantioselective C(sp³)−H borylation of cyclopropanes. Various functional groups were well-tolerated, affording a vast array of chiral cyclopropanes with high enantioselectivities. We also demonstrated that the turnover numbers of the current reaction could be up to 335.     

meta-Nitration of Arenes Bearing ortho/para Directing Group(s) Using C−H Borylation

Herein, we report the meta-nitration of arenes bearing ortho/para directing group(s) using the iridium-catalyzed C−H borylation reaction followed by a newly developed copper(II)-catalyzed transformation of the crude aryl pinacol boronate esters into the corresponding nitroarenes in a one-pot fashion. This protocol allows the synthesis of meta-nitrated arenes that are tedious to prepare or require multistep synthesis using the existing methods. The reaction tolerates a wide array of ortho/para-directing groups, such as −F, −Cl, −Br, −CH₃, −Et, −iPr −OCH₃, and −OCF₃. It also provides regioselective access to the nitro derivatives of π-electron-deficient heterocycles, such as pyridine and quinoline derivatives. The application of this method is demonstrated in the late-stage modification of complex molecules and also in the gram-scale preparation of an intermediate en route to the FDA-approved drug Nilotinib. Finally, we have shown that the nitro product obtained by this strategy can also be directly converted to the aniline or hindered amine through Baran's amination protocol.     

Selective Labeling of Peptides with o-Carboranes via Manganese(I)-Catalyzed C−H Activation

A robust method for the selective labeling of peptides via manganese(I) catalysis was devised to achieve the C-2 alkenylation of tryptophan containing peptides with 1-ethynyl-o-carboranes. The manganese-catalyzed C−H activation was accomplished with high catalytic efficiency, and featured low toxicity, high functional group tolerance and excellent E-stereoselectivity. This approach unravels a promising tool for the assembly of o-carborane with structurally complex peptides of relevance to applications in boron neutron capture therapy.     

Site- and Stereoselective C(sp3)−H Borylation of Strained (Hetero)Cycloalkanols Enabled by Iridium Catalysis

Transition metal-catalyzed site- and stereoselective C−H activation of strained (hetero)cycloalkanes remains a formidable challenge. We herein report a carbamate-directed iridium-catalyzed asymmetric β−C(sp³)−H borylation of cyclopropanol derivatives. A variety of densely functionalized cyclopropanols were obtained in good enantioselectivities via desymmetrization and kinetic resolution. In addition, site-selective C(sp³)−H borylation of methine groups furnished α-borylated (hetero)cycloalkanols in moderate to good yields. The synthetic utility of the method was further shown in a gram-scale synthesis and diverse downstream transformations of borylated products.     

Rhodium(III)-Catalyzed C−H/N−H Functionalization with Hydrogen Evolution

A rhodium(III)-catalyzed C−H/N−H bond functionalization of benzimidates with α-chloroaldehydes to afford isoquinolin-3-ol derivatives is reported. No external oxidants are needed in this process, and interestingly, evolution of hydrogen gas is observed.     

Manganese(I)-Catalyzed Regioselective C−H Allenylation: Direct Access to 2-Allenylindoles

A Mn^I-catalyzed regioselective C−H allenylation is reported that allows a broad range of 2-allenylindoles to be synthesized regioselectively on a gram scale under simple conditions. Notably, a highly efficient chirality transfer was observed (up to 93 % ee) in this transformation. This procedure was further found to allow, for the first time, the direct preparation of ketones by Mn^I-catalyzed C−H activation. Mechanistic investigations revealed that the precoordination of the oxygen atom to the manganese center as well as the congested tertiary carbon atom in the propargylic carbonates play a crucial role.     

Metal-Free Stereoconvergent C−H Borylation of Enamides

Enamides, functional derivatives of enamines, play a significant role as synthetic targets. However, the stereoselective synthesis of these molecules has posed a longstanding challenge in organic chemistry, particularly for acyclic enamides that are less thermodynamically stable. In this study, we present a general strategy for constructing β-borylenamides by C−H borylation, which provides a versatile platform for generating the stereodefined enamides. Our approach involves the utilization of metalloid borenium cation, generated through the reaction of BBr₃ and enamides in the presence of two different additives, avoiding any exogenous catalyst. Importantly, the stereoconvergent nature of this methodology allows for the use of starting materials with mixed E/Z configurations, thus highlighting the unique advantage of this chemistry. Mechanistic investigations have shed light on the pivotal roles played by the two additives, the reactive boron species, and the phenomenon of stereoconvergence.     

Gold(I)-Catalyzed Intramolecular C(sp3)−H Insertion by Decarbenation of Cycloheptatrienes

A novel synthesis of indanes and dihydronaphtalenes based on the intramolecular insertion into C(sp³)−H bonds of gold(I) carbenes generated by retro-Buchner reaction (decarbenation) has been developed. Deuterium-labeling and kinetic isotope effect experiments, DFT calculations, and generation of the proposed carbene intermediate from a well-characterized gold(I) carbenoid support the involvement of a three-center concerted mechanism for the C(sp³)−H functionalization process.     

Insights into Ruthenium(II/IV)-Catalyzed Distal C−H Oxygenation by Weak Coordination

C−H hydroxylation of aryl acetamides and alkyl phenylacetyl esters was accomplished via challenging distal weak O-coordination by versatile ruthenium(II/IV) catalysis. The ruthenium(II)-catalyzed C−H oxygenation of aryl acetamides proceeded through C−H activation, ruthenium(II/IV) oxidation and reductive elimination, thus providing step-economical access to valuable phenols. The p-cymene-ruthenium(II/IV) manifold was established by detailed experimental and DFT-computational studies.     

Rhodium(I)-Catalyzed Tertiary Phosphine Directed C−H Arylation: Rapid Construction of Ligand Libraries

Modification of commercially available monophosphine ligands with either aryl bromides or chlorides by rhodium(I)-catalyzed, tertiary phosphine directed C−H activation is described. A series of ligand libraries containing mono- and diaryl-substituted groups, having different steric and electronic properties, were obtained in high yields. Based on the outstanding properties of their parent scaffolds, the modified ligands have been found to be powerful in organic reactions.     

C−H Activation of Unbiased C(sp3)−H Bonds: Gold(I)-Catalyzed Cycloisomerization of 1-Bromoalkynes**

Selective functionalization of non-activated C(sp³)−H bonds is a major challenge in chemistry, so functional groups are often used to enhance reactivity. Here, we present a gold(I)-catalyzed C(sp³)−H activation of 1-bromoalkynes without any sort of electronic, or conformational bias. The reaction proceeds regiospecifically and stereospecifically to the corresponding bromocyclopentene derivatives. The latter can be readily modified, comprising an excellent library of diverse 3D scaffolds for medicinal chemistry. In addition, a mechanistic study has shown that the reaction proceeds via a so far unknown mechanism: a concerted [1,5]-H shift / C−C bond formation involving a gold-stabilized vinylcation-like transition state.     

Glycopeptides by Linch-Pin C−H Activations for Peptide-Carbohydrate Conjugation by Manganese(I)-Catalysis

Late-stage C−H glycosylations of structurally complex amino acids and peptides were accomplished by means of racemization-free manganese(I)-catalyzed C−H activation. Thus, glycosylative modifications proved to be viable by a linch-pin approach, featuring chemo- and site-selective C−H transformations. The peptide–saccharide conjugation provided modular access to structurally complex glycopeptides, likewise enabling the assembly of fluorescent-labelled glycopeptides.     

BBr3-Mediated P(III)-Directed C−H Borylation of Phosphines

Transition-metal-catalyzed C−H borylation has been widely used in the preparation of organoboron compounds. Here, we developed a general protocol on metal-free P(III)-directed C−H borylation of phosphines mediated by BBr₃, resulting in the formation of products bearing both phosphorus and boron. The development of the metal-free strategy to mimic previous metallic processes has shown low cost, superior practicality, and environmental friendliness. Density functional theory (DFT) calculations demonstrate the preferred pathway for this metal-free directed C−H borylation process.     

Transition Metal-Free Aromatic C−H,C−N,C−S and C−O Borylation

Aromatic organoboron compounds are highly valuable building blocks in organic chemistry. They were mainly synthesized through aromatic C−H and C−Het borylation, in which transition metal-catalysis dominate. In the past decade, with increasing attention to sustainable chemistry, numerous transition metal-free C−H and C−Het borylation transformations have been developed and emerged as efficient methods towards the synthesis of aromatic organoboron compounds. This account mainly focuses on recent advances in transition metal-free aromatic C−H, C−N, C−S, and C−O borylation transformations and provides insights to where further developments are required.     

Base-Controlled Completely Selective Linear or Branched Rhodium(I)-Catalyzed C−H ortho-Alkylation of Azines without Preactivation

A [Rh^I]/bisphosphine/base catalytic system for the ortho-selective C−H alkylation of azines by acrylates and acrylamides is reported. This catalytic system features an unprecedented complete linear or branched selectivity that is solely dependent on the catalytic base that is used. Complete branched selectivity is even achieved for ethyl methacrylate, which enables the introduction of a quaternary carbon center. Excellent functional group compatibility is demonstrated for both linear and branched alkylations. The operational simplicity and broad scope of this transformation allow for rapid access to functionalized azines of direct pharmaceutical and agrochemical relevance.     

Manganese(I)-Catalyzed β-Methylation of Alcohols Using Methanol as C1 Source

Highly selective β-methylation of alcohols was achieved using an earth-abundant first row transition metal in the air stable molecular manganese complex [Mn(CO)₂Br[HN(C₂H₄PⁱPr₂)₂]] 1 ([HN(C₂H₄PⁱPr₂)₂]=MACHO-ⁱPr). The reaction requires only low loadings of 1 (0.5 mol %), methanolate as base and MeOH as methylation reagent as well as solvent. Various alcohols were β-methylated with very good selectivity (>99 %) and excellent yield (up to 94 %). Biomass derived aliphatic alcohols and diols were also selectively methylated on the β-position, opening a pathway to “biohybrid” molecules constructed entirely from non-fossil carbon. Mechanistic studies indicate that the reaction proceeds through a borrowing hydrogen pathway involving metal–ligand cooperation at the Mn-pincer complex. This transformation provides a convenient, economical, and environmentally benign pathway for the selective C−C bond formation with potential applications for the preparation of advanced biofuels, fine chemicals, and biologically active molecules