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.

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.

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.

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 B2eg2 (eg = ethylene glycolate) is used as the borylating reagent in lieu of B2pin2, 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 B2pin2 reactions arising from smaller Beg ligands on the Ir catalyst. The lowest-energy transition states (TSs) from density functional theory computational analyses have N-H···O hydrogen-bonding interactions between PhN(H)Beg and O atoms in Beg ligands. Ir-catalyzed CHB of PhN(H)Me with B2eg2 is also highly ortho-selective. 1H NMR experiments show that N-borylation fully generates PhN(Me)Beg prior to CHB. The TS with the lowest Gibbs energy was the ortho TS, in which the Beg unit is oriented anti to the bipyridine ligand.

Noncovalent Interactions in Ir-Catalyzed C-H Activation: L-Shaped Ligand for Para-Selective Borylation of Aromatic Esters.

An efficient strategy for the para-selective borylation of aromatic esters is described. For achieving high para-selectivity, a new catalytic system has been developed modifying the core structure of the bipyridine. It has been proposed that the L-shaped ligand is essential to recognize the functionality of the oxygen atom of the ester carbonyl group via noncovalent interaction, which provides an unprecedented controlling factor for para-selective C-H activation/borylation.