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. Moreover, we have demonstrated that the method can also be applied for the remote C6 borylation of indole derivatives including tryptophan that was the key synthetic precursor for the total synthesis of Verruculogen and Fumitremorgin A alkaloids. The inspiration of this catalytic concept was started from the O-Si secondary interaction, which by means of several more detailed control experiments and detailed computational investigations revealed that an unprecedented Bpin shift occurs during the transformation of iridium bis(boryl) complex to iridium tris(boryl) complex, which eventually control the remote meta selectivity by means of the dispersion between the designed ligand and steering silane group.

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. Moreover, several late-stage aminations and a short synthesis of a drug candidate have been showcased for further synthetic utility. Collectively, this iron-catalyzed C-N cross-coupling should have wide applications in the context of medicinal chemistry, drug discovery, and pharmaceutical industries.

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. This review article aims to summarize the recent discoveries for the remote C─H borylation by the employment of new catalyst/ligand design with the help of steric of the ligand, noncovalent interactions. It has been found that C─H borylation now takes part in the total synthesis of natural products in a shorter route. Whereas, Ir-catalyzed C─H borylation is predominant, cobalt catalyst has also started to affect this field for sustainable and cost-effective development.

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. Compared with the denitrogenative annulation of various 1,2,3-triazole frameworks, annulation of 1,2,3,4-tetrazole remains more challenging due to the inertness of the tetrazole moiety. This Review summarizes the significant achievements made in the field of denitrogenative annulation of various 1,2,3-triazoles and 1,2,3,4-tetrazoles including some pioneering examples in this area of research. We anticipate that this denitrogenative annulation reaction will find broad applications in the pharmaceutical industry, drug discovery and other fields of medicinal chemistry.

An iron(ii)-based metalloradical system for intramolecular amination of C(sp2)-H and C(sp3)-H bonds: synthetic applications and mechanistic studies.

A catalytic system for intramolecular C(sp2)-H and C(sp3)-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(sp2)-H and C(sp3)-H bonds of the tetrazole as well as azide-featuring substrates with a high level of regioselectivity. The method exhibited an excellent functional group tolerance. The method affords three different classes of high-value N-heterocyclic scaffolds. A number of important late-stage C-H aminations have been performed to access important classes of molecules. Detailed studies (experimental and computational) showed that both the C(sp2)-H and C(sp3)-H amination reactions involve a metalloradical activation mechanism, which is different from the previously reported electro-cyclization mechanism. Collectively, this study reports the discovery of a new class of metalloradical activation modes using a base metal catalyst that should find wide application in the context of medicinal chemistry, drug discovery and industrial applications.

Iron-Catalyzed Intermolecular Amination of Benzylic C(sp3)-H Bonds.

A catalytic system for intermolecular benzylic C(sp3)-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(sp3)-H bond over the 3° and 1° benzylic C(sp3)-H bonds. Experimental studies reveal that the C(sp3)-H amination undergoes via the formation of a benzylic radical intermediate. This study reports the discovery of new method for 2-pyridine substituted benzylamine synthesis using inexpensive, biocompatible base metal catalysis that should have wide application in the context of medicinal chemistry and drug discovery.

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

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

Metal-catalysed C-H bond activation and borylation.

Transition metal-catalysed direct borylation of hydrocarbons via 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 ortho 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 via the design of new ligand frameworks. Whereas meta and para selective C-H borylations remained a formidable challenge, numerous innovative concepts have been developed within a very short period of time by the development of new catalytic systems with the employment of various noncovalent interactions. Moreover, significant advancements have occurred for aliphatic C(sp3)-H borylations as well as enantioselective borylations. In this review article, we aim to discuss and summarize the different approaches and findings related to the development of directed proximal ortho, distal meta/para, aliphatic (racemic and enantioselective) borylation reactions since 2014. Additionally, considering the C-H borylation reaction as one of the most important mainstream reactions, various applications of this C-H borylation reaction toward the synthesis of natural products, therapeutics, and applications in materials chemistry will be summarized in the last part of this review article.

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. Moreover, the designed ligand has shown excellent reactivity and selectivity for a range of heterocyclic aromatic amides. The identification of key transition states and intermediates using the DFT computations associated with the three regio-isomeric pathways revealed that the most efficient catalytic pathway with the defa ligand leads to the para borylation while in the case of bpy the borylation at the para and meta sites compete.

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. The method displays a broad range of substrate scope and functional group tolerance. Numerous late-stage borylation of various important molecules and drugs were achieved using this developed strategy. The borylated compounds were further converted into more valuable functionalities. Moreover, utilizing the benefit of the B-N intramolecular interaction of the mono borylated compounds, an operationally simple method has been developed for the selective diborylation of 2-phenoxypyridines and numerous functionalized arenes. Furthermore, the synthetic utility has been showcased with the removal of the pyridyl directing group from the borylated product to achieve ortho borylated phenol along with the ipso-borylation for the preparation of 1,2-diborylated benzene.

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

The pursuit for the discovery of new and powerful synthetic methods to access high-value N-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.The denitrogenative annulation approach offers clear advantages over many existing methods, as it enables effective, single-step interconversion of easily available feedstocks into a variety of other important N-containing heterocyclic frameworks. Recently, transition metal catalyzed denitrogenative annulation reaction of the 1,2,3-triazole via a metal carbene intermediate sparked significant interest in the application of various important heterocycle syntheses. Denitrogenative annulation reaction of 1,2,3-triazoles proceeds via an ionic mechanism. Recently, we demonstrated a new concept for the denitrogenative reaction of triazoles with alkenes and alkynes via in situ generated 2-(diazomethyl)pyridines. The method takes advantage of the inherent properties of a Co(III)-carbene radical intermediate and is the first report of the denitrogenative annulation/cyclopropanation by a radical-activation mechanism.On the other hand, in contrast to the denitrogenative annulation of 1,2,3-triazole, annulation reaction of 1,2,3,4-tetrazole (a surrogate of azide having an important pyridyl unit) via metal nitrene remains a big challenge. Previously, flash vacuum pyrolysis studies had been used for nitrene-nitrene rearrangement of 1,2,3,4-tetrazole at high temperature. This Account summarizes our recent efforts in developing transition metal catalyzed denitrogenative annulation of 1,2,3-triazoles via a radical mechanism and 1,2,3,4-tetrazoles via metal nitrene to access important nitrogen-rich molecules. We demonstrated that the 1,2,3,4-tetrazole under Ir-catalyzed reaction conditions can produce a productive Ir-nitrene intermediate that can successfully be employed for the construction of a wide number of α-carbolines and 7-azaindoles. Moreover, we developed an iron-based unique strategy for the intermolecular denitrogenative annulation reaction between tetrazoles and alkynes. The reaction overcomes the traditional click reaction and proceeds via an unprecedented metalloradical activation mechanism. Furthermore, we used our understanding of tetrazole reactivity to design an iron-catalyzed intramolecular denitrogenative C(sp3)-H amination reaction of primary, secondary, and tertiary centers by using a metalloradical activation concept. At the same time, we also developed a general catalytic method to enable two distinct reactions (1,3-cycloaddition and denitrogenative annulation) using Mn(TPP)Cl that afforded two different classes of nitrogen heterocycles. Mechanistic studies showed that although the click reaction likely proceeds through an ionic mechanism and the denitrogenative annulation reaction likely proceeds via an electrophilic metallonitrene intermediate rather than a metallonitrene radical intermediate. Finally, we report an iron-catalyzed rearrangement reaction (ring expansion/migration) that proceeded with an unprecedented level of selectivity, reactivity, and functional group tolerance offering rapid access to numerous complex N-heterocycles. We believe that our continuous efforts in this field would be beneficial for pharmaceutical industries, drug discovery, and other fields of medicinal chemistry.

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 (ortho) and distal (meta and para) selectivity. Interestingly, while so many approaches are now available for the proximal ortho selective borylation of arenes, borylation at the distal meta and or para position of arenes remains still challenging. Only a few approaches have been reported so far in the literature employing iridium catalysis. In this feature article, we have demonstrated some of the recent discoveries from our laboratories for the proximal (ortho) and distal (meta and para) selective borylation reactions. Moreover, some of the recent catalyst engineering discoveries for the selective proximal ortho borylation reactions for a diverse class of substrates have also been discussed. The discussion part of several other pioneering reports is limited due to the lack of scope of this feature article.

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. Moreover, unsubstituted substrates also displayed excellent meta selectivity. The reaction employs a bench-stable ligand and proceeds at a milder temperature, precluding the need to synthesize a bulky and sophisticated ligand/template.

Remarkably Efficient Iridium Catalysts for Directed C(sp2)-H and C(sp3)-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 ortho-selectivity for diverse classes of aromatic substrates with high isolated yields. Moreover, the catalysts proved to be efficient for a wide number of aliphatic substrates for selective C(sp3)-H bond borylations. Heterocyclic molecules are selectively borylated using the inherently elevated reactivity of the C-H bonds. A number of late-stage C-H functionalization have been described using the same catalysts. Furthermore, we show that one of the catalysts could be used even in open air for the C(sp2)-H and C(sp3)-H borylations enabling the method more general. Preliminary mechanistic studies suggest that the active catalytic intermediate is the Ir(bis)boryl complex, and the attached ligand acts as bidentate ligand. Collectively, this study underlines the discovery of new class of C-H borylation catalysts that should find wide application in the context of C-H functionalization chemistry.

Iron-Catalyzed Radical Activation Mechanism for Denitrogenative Rearrangement Over C(sp3 )-H Amination.

An iron-catalyzed denitrogenative rearrangement of 1,2,3,4-tetrazole is developed over the competitive C(sp3 )-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. The synthetic utility of this radical activation method is showcased with the short synthesis of a bioactive molecule. Collectively, this discovery underlines the progress of radical activation strategy that should find wide application in the perspective of medicinal chemistry, drug discovery and natural product synthesis research.

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. For example, this method excludes a multi-step synthesis of the N-heterocyclic molecules described and produces only environmentally benign N2 gas a by-product.

Iron-Catalyzed Amination of Strong Aliphatic C(sp3)-H Bonds.

A concept for intramolecular denitrogenative C(sp3)-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. Moreover, an initial effort has been embarked on for the enantioselective C(sp3)-H amination through the catalyst design. Collectively, this study underlines the development of C(sp3)-H bond functionalization chemistry that should find wide application in the context of drug discovery and natural product synthesis.

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 B2pin2 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 B2eg2 (eg = ethylene glycolate) directs the C-H activation at ortho positions, a combination of HBpin and B2pin2 activates remote C-H bonds. The strategy was combined with Suzuki arylation as a one-pot protocol for the rapid synthesis of BINOL derivatives with retention of chirality.

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.