Sterically Controlled Lewis Acid-Base Interaction Toward para-Selective Borylation of Aromatic Aldimines and Benzylamines.

Site-selective C-H bond functionalization of arenes at the para position remains extremely challenging primarily due to its relative inaccessibility from the catalytic site. As a consequence, it is significantly restricted to limited molecular scaffolds. Herein, we report a method for the para-C-H borylation of aromatic aldimines and benzylamines using commercially available ligands under iridium catalysis.

A tautomerized ligand enabled meta selective C-H borylation of phenol.

Remote meta selective C-H functionalization of aromatic compounds remains a challenging problem in chemical synthesis. Here, we report an iridium catalyst bearing a bidentate pyridine-pyridone (PY-PYRI) ligand framework that efficiently catalyzes this meta selective borylation reaction. We demonstrate that the developed concept can be employed to introduce a boron functionality at the remote meta position of phenols, phenol containing bioactive and drug molecules, which was an extraordinary challenge.

Iron-Catalyzed Intermolecular C-N Cross-Coupling Reactions via Radical Activation Mechanism.

A concept for intermolecular C-N cross-coupling amination has been discovered using tetrazoles and aromatic and aliphatic azides with boronic acids under iron-catalyzed conditions. The amination follows an unprecedented metalloradical activation mechanism that is different from traditional metal-catalyzed C-N cross-coupling reactions. The scope of the reaction has been demonstrated by the employment of a large number of tetrazoles, azides, and boronic acids.

Transition metal-catalyzed remote C─H borylation: An emerging synthetic tool.

Transition metal-catalyzed C─H bond activation and borylation is a powerful synthetic method that offers versatile synthetic transformation from organoboron compounds to virtually all other functional groups. Compared to the ortho-borylation, remote borylation remains more challenging owing to the inaccessibility of these C─H bonds. Enforcing the metal catalyst toward the remote C─H bonds needs well-judged catalyst design through proper ligand development.

Iron-Catalyzed Intermolecular Amination of Benzylic C(sp)-H Bonds.

A catalytic system for intermolecular benzylic C(sp)-H amination is developed utilizing 1,2,3,4-tetrazole as a nitrene precursor via iron catalysis. This method enables direct installation of 2-aminopyridine into the benzylic and heterobenzylic position. The method selectively aminates 2° benzylic C(sp)-H bond over the 3° and 1° benzylic C(sp)-H bonds.

An iron(ii)-based metalloradical system for intramolecular amination of C(sp)-H and C(sp)-H bonds: synthetic applications and mechanistic studies.

A catalytic system for intramolecular C(sp)-H and C(sp)-H amination of substituted tetrazolopyridines has been successfully developed. The amination reactions are developed using an iron-porphyrin based catalytic system. It has been demonstrated that the same iron-porphyrin based catalytic system efficiently activates both the C(sp)-H and C(sp)-H bonds of the tetrazole as well as azide-featuring substrates with a high level of regioselectivity.

Ligand- and Substrate-Controlled C-H Borylation of Anilines at Room Temperature.

A new catalytic method for borylation of unprotected anilines is described. The catalytic method is developed by designing a new type of ligand framework that enables borylation at room temperature. We showed that whereas previously reported borylation of 2-substituted anilines required multistep protection/deprotection sequences and a high reaction temperature, our method gives a straightforward solution for achieving borylation without such protection/deprotection chemistry at room temperature.

Transition-Metal-Catalyzed Denitrogenative Annulation to Access High-Valued N-Heterocycles.

Over the past few years, the development of efficient methods to construct high-valued N-heterocyclic molecules have received massive attention owing to their extensive application in the areas of medicinal chemistry, drug discovery, natural product synthesis and so on. To access those high-valued N-heterocycles, many methods have been developed. In this context, transition-metal-catalyzed denitrogenative annulation of 1,2,3-triazoles and 1,2,3,4-tetrazoles has appeared as a powerful synthetic tool because it offers a step- and atom-economical route for the preparation of the nitrogen-rich molecules.

Metal-catalysed C-H bond activation and borylation.

Transition metal-catalysed direct borylation of hydrocarbons C-H bond activation has received a remarkable level of attention as a popular reaction in the synthesis of organoboron compounds owing to their synthetic versatility. While controlling the site-selectivity was one of the most challenging issues in these C-H borylation reactions, enormous efforts of several research groups proved instrumental in dealing with selectivity issues that presently reached an impressive level for both proximal and distal C-H bond borylation reactions. For example, in the case of C-H bond borylation reactions, innovative methodologies have been developed either by the modification of the directing groups attached with the substrates or by creating new catalytic systems the design of new ligand frameworks.

Iridium-Catalyzed Ligand-Controlled Remote para-Selective C-H Activation and Borylation of Twisted Aromatic Amides.

A method of para-selective borylation of aromatic amides is described. The borylation proceeded via an unprecedented substrate-ligand distortion between the twisted aromatic amides and a newly designed ligand framework (defa) that is different from the traditionally used ligand (dtbpy) for the C-H borylation reactions. The designed ligand framework (defa) has led to the development of a new type of catalytic system that shows excellent para selectivity for a range of aromatic amides.

Ir-Catalyzed Ligand-Free Directed C-H Borylation of Arenes and Pharmaceuticals: Detailed Mechanistic Understanding.

An efficient method for Ir-catalyzed ligand free ortho borylation of arenes (such as, 2-phenoxypyridines, 2-anilinopyridines, benzylamines, benzylpiperazines, benzylmorpholines, benzylpyrrolidine, benzylpiperidines, benzylazepanes, α-amino acid derivatives, aminophenylethane derivatives, and other important scaffolds) and pharmaceuticals has been developed. The reaction underwent via an interesting mechanistic pathway, as revealed by the detailed mechanistic investigations by using kinetic isotope studies and DFT calculations. The catalytic cycle is found to involve the intermediacy of an Ir-boryl complex where the substrate C-H activation is the turnover determining step, intriguingly without any appreciable primary KIE.

Ir-catalyzed proximal and distal C-H borylation of arenes.

Over the past two decades, the C-H bond activation and functionalization reaction has been known as a prevailing method for the construction of carbon-carbon and carbon-heteroatom bonds using various transition metal catalysts. In this context, the iridium-catalyzed C-H bond activation and borylation reaction is one of the most valued methods. However, the major challenge in these borylation reactions is how to control the proximal () and distal ( and ) selectivity.

Road Map for the Construction of High-Valued -Heterocycles via Denitrogenative Annulation.

The pursuit for the discovery of new and powerful synthetic methods to access high-value -heterocycles has been at the forefront of organic chemistry research for more than a century. Considering the importance of N-scaffolds in modern science, over the past few decades, great research efforts have been made to develop efficient synthetic methods for the construction of nitrogen-rich molecules. Among many efforts, transition metal catalyzed denitrogenative annulation reaction has emerged as a cornerstone due to its innate versatility and wider scope of application.

Meta Selective C-H Borylation of Sterically Biased and Unbiased Substrates Directed by Electrostatic Interaction.

An electrostatically directed meta borylation of sterically biased and unbiased substrates is described. The borylation follows an electrostatic interaction between the partially positive and negative charges between the ligand and substrate. With this strategy, it has been demonstrated that a wide number of challenging substrates, especially 4-substituted substrates, can selectively be borylated at the meta position.

Remarkably Efficient Iridium Catalysts for Directed C(sp)-H and C(sp)-H Borylation of Diverse Classes of Substrates.

Here we describe the discovery of a new class of C-H borylation catalysts and their use for regioselective C-H borylation of aromatic, heteroaromatic, and aliphatic systems. The new catalysts have Ir-C(thienyl) or Ir-C(furyl) anionic ligands instead of the diamine-type neutral chelating ligands used in the standard C-H borylation conditions. It is reported that the employment of these newly discovered catalysts show excellent reactivity and -selectivity for diverse classes of aromatic substrates with high isolated yields.

Iron-Catalyzed Radical Activation Mechanism for Denitrogenative Rearrangement Over C(sp )-H Amination.

An iron-catalyzed denitrogenative rearrangement of 1,2,3,4-tetrazole is developed over the competitive C(sp )-H amination. This catalytic rearrangement reaction follows an unprecedented metalloradical activation mechanism. Employing the developed method, a wide number of complex-N-heterocyclic product classes have been accessed.

Dual Reactivity of 1,2,3,4-Tetrazole: Manganese-Catalyzed Click Reaction and Denitrogenative Annulation.

A general catalytic method using a Mn-porphyrin-based catalytic system is reported that enables two different reactions (click reaction and denitrogenative annulation) and affords two different classes of nitrogen heterocycles, 1,5-disubstituted 1,2,3-triazoles (with a pyridyl motif) and 1,2,4-triazolo-pyridines. Mechanistic investigations suggest that although the click reaction likely proceeds through an ionic mechanism, which is different from the traditional click reaction, the denitrogenative annulation reaction likely proceeds via an electrophilic metallonitrene intermediate rather than a metalloradical intermediate. Collectively, this method is highly efficient and offers several advantages over other methods.

Iron-Catalyzed Amination of Strong Aliphatic C(sp)-H Bonds.

A concept for intramolecular denitrogenative C(sp)-H amination of 1,2,3,4-tetrazoles bearing unactivated primary, secondary, and tertiary C-H bonds is discovered. This catalytic amination follows an unprecedented metalloradical activation mechanism. The utility of the method is showcased with the short synthesis of a bioactive molecule.

C-H Borylation Catalysts that Distinguish Between Similarly Sized Substituents Like Fluorine and Hydrogen.

By modifying ligand steric and electronic profiles it is possible to C-H borylate ortho or meta to substituents in aromatic and heteroaromatic compounds, where steric differences between accessible C-H sites are small. Dramatic effects on selectivities between reactions using Bpin or 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (HBpin) are described for the first time. Judicious ligand and borane combinations give highly regioselective C-H borylations on substrates where typical borylation protocols afford poor selectivities.

Double-Fold Ortho and Remote C-H Bond Activation/Borylation of BINOL: A Unified Strategy for Arylation of BINOL.

A double-fold ortho and remote C-H borylation of BINOL is described. The proposed mechanisms involved electrostatically and sterically directed ortho and remote C-H activation processes, respectively. While Beg (eg = ethylene glycolate) directs the C-H activation at ortho positions, a combination of HBpin and Bpin activates remote C-H bonds.

Iron(II)-Based Metalloradical Activation: Switch from Traditional Click Chemistry to Denitrogenative Annulation.

A unique concept for the intermolecular denitrogenative annulation of 1,2,3,4-tetrazoles and alkynes was discovered by using a catalytic amount of Fe(TPP)Cl and Zn dust. The reaction precludes the traditional, more favored click reaction between an organic azide and alkynes, and instead proceeds by an unprecedented metalloradical activation. The method is anticipated to advance access to the construction of important basic nitrogen heterocycles, which will in turn enable discoveries of new drug candidates.

Amide Effects in C-H Activation: Noncovalent Interactions with L-Shaped Ligand for meta Borylation of Aromatic Amides.

A new concept for the meta-selective borylation of aromatic amides is described. It has been demonstrated that while esters gave para borylations, amides lead to meta borylations. For achieving high meta selectivity, an L-shaped bifunctional ligand has been employed and engages in an O⋅⋅⋅K noncovalent interaction with the oxygen atom of the moderately distorted amide carbonyl group.

Achieving High Ortho Selectivity in Aniline C-H Borylations by Modifying Boron Substituents.

High ortho selectivity for Ir-catalyzed C-H borylations (CHBs) of anilines results when Beg (eg = ethylene glycolate) is used as the borylating reagent in lieu of Bpin, which is known to give isomeric mixtures with anilines lacking a blocking group at the 4-position. With this modification, high selectivities and good yields are now possible for various anilines, including those with groups at the 2- and 3-positions. Experiments indicate that ArylN(H)Beg species are generated prior to CHB and support the improved ortho selectivity relative to Bpin reactions arising from smaller Beg ligands on the Ir catalyst.

Ir-Catalyzed Intramolecular Transannulation/C(sp)-H Amination of 1,2,3,4-Tetrazoles by Electrocyclization.

An efficient strategy for the intramolecular denitrogenative transannulation/C(sp)-H amination of 1,2,3,4-tetrazoles bearing C8-substituted arenes, heteroarenes, and alkenes is described. The process involves the generation of the metal-nitrene intermediate from tetrazole by the combination of [Cp*IrCl] and AgSbF. It has been shown that the reaction proceeds via an unprecedented electrocyclization process.

Cobalt(II)-based Metalloradical Activation of 2-(Diazomethyl)pyridines for Radical Transannulation and Cyclopropanation.

A new catalytic method for the denitrogenative transannulation/cyclopropanation of in-situ-generated 2-(diazomethyl)pyridines is described using a cobalt-catalyzed radical-activation mechanism. The method takes advantage of the inherent properties of a Co -carbene radical intermediate and is the first report of denitrogenative transannulation/cyclopropanation by a radical-activation mechanism, which is supported by various control experiments. The synthetic benefits of the metalloradical approach are showcased with a short total synthesis of (±)-monomorine.