Metal-Free Arylation of Benzothiophenes at C4 by Activation as their Benzothiophene S-Oxides.

Benzothiophenes, activated by oxidation to the corresponding S-oxides, undergo C-H/C-H-type coupling with phenols to give C4 arylation products. While an electron-withdrawing group at C3 of the benzothiophene is important, the process operates without a directing group and a metal catalyst, thus rendering it compatible with sensitive functionalities-e.g. halides and formyl groups. Quantum chemical calculations suggest a formal stepwise mechanism involving heterolytic cleavage of an aryloxysulfur species to give a π-complex of the corresponding benzothiophene and a phenoxonium cation. Subsequent addition of the phenoxonium cation to the C4 position of the benzothiophene is favored over the addition to C3; Fukui functions predict that the major regioisomer is formed at the more electron-rich position between C3 and C4. Varied selective manipulation of the benzothiophene products showcase the synthetic utility of the metal-free arylation process.

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.

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.

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.

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. This interaction provides exceptional control for meta C-H activation/borylation.

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.

Formal Ir-Catalyzed Ligand-Enabled Ortho and Meta Borylation of Aromatic Aldehydes via in Situ-Generated Imines.

The ligand-enabled development of ortho and meta C-H borylation of aromatic aldehydes is reported. It was envisaged that while ortho borylation could be achieved using tert-butylamine as the traceless protecting/directing group, meta borylation proceeds via an electrostatic interaction and a secondary interaction between the ligand of the catalyst and the substrate. These ligand-substrate electrostatic interactions and secondary B-N interactions provide an unprecedented controlling factor for meta-selective C-H activation/borylation.