Iridium‐Catalyzed Silylation of Five‐Membered Heteroarenes: High Sterically Derived Selectivity from a Pyridyl‐Imidazoline Ligand

The steric effects of substituents on five‐membered rings are less pronounced than those on six‐membered rings because of the difference in bond angles. Thus, the regioselectivities of reactions of five‐membered heteroarenes that occur with selectivities dictated by steric effects, such as the borylation of C?H bonds, have been poor in many cases. We report that the silylation of five‐membered‐ring heteroarenes occurs with high sterically derived regioselectivity when catalyzed by the combination of [Ir(cod)(OMe)]₂ (cod=1,5‐cyclooctadiene) and a phenanthroline ligand or a new pyridyl‐imidazoline ligand that further increases the regioselectivity. The silylation reactions with these catalysts produce high yields of heteroarylsilanes from functionalization at the most sterically accessible C?H bonds of these rings under conditions that the borylation of C?H bonds with previously reported catalysts formed mixtures of products or products that are unstable. The heteroarylsilane products undergo cross‐coupling reactions and substitution reactions with ipso selectivity to generate heteroarenes that bear halogen, aryl, and perfluoroalkyl substituents.     

Catalytic C−H Borylation Using Iron Complexes Bearing 4,5,6,7‐Tetrahydroisoindol‐2‐ide‐Based PNP‐Type Pincer Ligand

Catalytic C?H borylation has been reported using newly designed iron complexes bearing a 4,5,6,7‐tetrahydroisoindol‐2‐ide‐based PNP pincer ligand. The reaction tolerated various five‐membered heteroarenes, such as pyrrole derivatives, as well as six‐membered aromatic compounds, such as toluene. Successful examples of the iron‐catalyzed sp³ C?H borylation of anisole derivatives were also presented.     

Iridium-Catalyzed Silylation of Five-Membered Heteroarenes: High Sterically Derived Selectivity from a Pyridyl-Imidazoline Ligand

The steric effects of substituents on five-membered rings are less pronounced than those on six-membered rings because of the difference in bond angles. Thus, the regioselectivities of reactions of five-membered heteroarenes that occur with selectivities dictated by steric effects, such as the borylation of C−H bonds, have been poor in many cases. We report that the silylation of five-membered-ring heteroarenes occurs with high sterically derived regioselectivity when catalyzed by the combination of [Ir(cod)(OMe)]₂ (cod=1,5-cyclooctadiene) and a phenanthroline ligand or a new pyridyl-imidazoline ligand that further increases the regioselectivity. The silylation reactions with these catalysts produce high yields of heteroarylsilanes from functionalization at the most sterically accessible C−H bonds of these rings under conditions that the borylation of C−H bonds with previously reported catalysts formed mixtures of products or products that are unstable. The heteroarylsilane products undergo cross-coupling reactions and substitution reactions with ipso selectivity to generate heteroarenes that bear halogen, aryl, and perfluoroalkyl substituents.     

AgONO‐Assisted Direct CH Arylation of Heteroarenes with Anilines

A novel copper‐catalyzed C?H arylation of heteroarenes with anilines by an in situ diazonium reaction is established by using silver nitrite (AgONO) as an unconventional nitrosating reagent under acid‐free conditions. It provides a complementary approach for the C?H arylation of electron‐rich heteroarenes with aromatic amines affording a variety of heterobiaryls in moderate to good yields.     

Iron‐Catalyzed Aminative Cyclization/Intermolecular Homolytic Aromatic Substitution Using Oxime Esters and Simple Arenes

Intermolecular C?H alkylation of simple arenes in the presence of an iron catalyst has been achieved in a cascade manner with an aminative cyclization triggered by N?O bond cleavage of an alkene‐tethered oxime ester. Various arenes, including electron‐rich and electron‐poor arenes, and heteroarenes can be employed in the reaction system. Regioselectivity and radical trapping experiments support the involvement of alkyl radical species, which undergo a homolytic aromatic substitution (HAS) to afford the arylation products.     

Iridium‐Catalyzed Intermolecular Dehydrogenative Silylation of Polycyclic Aromatic Compounds without Directing Groups

This study describes the iridium‐catalyzed intermolecular dehydrogenative silylation of C(sp²)?H bonds of polycyclic aromatic compounds without directing groups. The reaction produced various arylsilanes through both Si?H and C?H bond activation, with hydrogen as the sole byproduct. Reactivity was affected by the electronic nature of the aromatic compounds, and silylation of electron‐deficient and polycyclic aromatic compounds proceeded efficiently. Site‐selectivity was controlled predominantly by steric factors. Therefore, the current functionalization proceeded with opposite chemo‐ and site‐selectivity compared to that observed for general electrophilic functionalization of aromatic compounds.     

A Chiral Nitrogen Ligand for Enantioselective,Iridium‐Catalyzed Silylation of Aromatic C−H Bonds

Iridium catalysts containing dative nitrogen ligands are highly active for the borylation and silylation of C−H bonds, but chiral analogs of these catalysts for enantioselective silylation reactions have not been developed. We report a new chiral pyridinyloxazoline ligand for enantioselective, intramolecular silylation of symmetrical diarylmethoxy diethylsilanes. Regioselective and enantioselective silylation of unsymmetrical substrates was also achieved in the presence of this newly developed system. Preliminary mechanistic studies imply that C−H bond cleavage is irreversible, but not the rate‐determining step.     

A Chiral Nitrogen Ligand for Enantioselective,Iridium‐Catalyzed Silylation of Aromatic C−H Bonds

Iridium catalysts containing dative nitrogen ligands are highly active for the borylation and silylation of C−H bonds, but chiral analogs of these catalysts for enantioselective silylation reactions have not been developed. We report a new chiral pyridinyloxazoline ligand for enantioselective, intramolecular silylation of symmetrical diarylmethoxy diethylsilanes. Regioselective and enantioselective silylation of unsymmetrical substrates was also achieved in the presence of this newly developed system. Preliminary mechanistic studies imply that C−H bond cleavage is irreversible, but not the rate‐determining step.     

Cobalt‐Catalyzed Oxidative C−H/C−H Cross‐Coupling between Two Heteroarenes

The first example of cobalt‐catalyzed oxidative C?H/C?H cross‐coupling between two heteroarenes is reported, which exhibits a broad substrate scope and a high tolerance level for sensitive functional groups. When the amount of Co(OAc)₂?4 H₂O is reduced from 6.0 to 0.5 mol %, an excellent yield is still obtained at an elevated temperature with a prolonged reaction time. The method can be extended to the reaction between an arene and a heteroarene. It is worth noting that the Ag₂CO₃ oxidant is renewable. Preliminary mechanistic studies by radical trapping experiments, hydrogen/deuterium exchange experiments, kinetic isotope effect, electron paramagnetic resonance (EPR), and high resolution mass spectrometry (HRMS) suggest that a single electron transfer (SET) pathway is operative, which is distinctly different from the dual C?H bond activation pathway that the well‐described oxidative C?H/C?H cross‐coupling reactions between two heteroarenes typically undergo.     

Stereoselective CH Borylations of Cyclopropanes and Cyclobutanes with Silica‐Supported Monophosphane–Ir Catalysts

Heteroatom‐directed C?H borylation of cyclopropanes and cyclobutanes was achieved with silica‐supported monophosphane–Ir catalysts. Borylation occurred at the C?H bonds located γ to the directing N or O atoms with exceptional cis stereoselectivity relative to the directing groups. This protocol was applied to the borylation of a tertiary C?H bond of a ring‐fused cyclopropane.     

Direct Introduction of a Dimesitylboryl Group Using Base‐Mediated Substitution of Aryl Halides with Silyldimesitylborane

The first dimesitylboryl substitution of aryl halides with a silylborane bearing a dimesitylboryl group in the presence of alkali‐metal alkoxides is described. The reactions of aryl bromides or iodides with Ph₂MeSi?BMes₂ and Na(OtBu) afforded the desired aryl dimesitylboranes in good to high yields and with high borylation/silylation ratios. Selective reaction of the sterically less‐hindered C?Br bond of dibromoarenes provided monoborylated products. This reaction was used to rapidly construct a D‐π‐A aryl dimesityl borane with a non‐symmetrical biphenyl spacer.     

Trifluoromethylation of Arylsilanes with [(phen)CuCF3]

A method for the trifluoromethylation of arylsilanes is reported. The reaction proceeds with [(phen)CuCF₃] as the CF₃ source under mild, oxidative conditions with high functional‐group compatibility. This transformation complements prior trifluoromethylation of arenes in several ways. Most important, this method converts arylsilanes formed by the silylation of aryl C?H bonds to trifluoromethylarenes, thereby allowing the conversion of arenes to trifluoromethylarenes. The unique capabilities of the reported method are demonstrated by the conversion of a C?H bond into a C?CF₃ bond in active pharmaceutical ingredients which do not undergo this overall transformation by alternative functionalization processes, including a combination of borylation and trifluoromethylation.     

Cobalt‐Catalyzed C?H Bond Functionalizations with Aryl and Alkyl Chlorides

Inexpensive cobalt catalysts derived from N‐heterocylic carbenes (NHC) allowed efficient catalytic C? H bond arylations on heteroaryl‐substituted arenes with widely available aryl chlorides, which set the stage for the preparation of sterically hindered tri‐ortho‐substituted biaryls. Likewise, challenging direct alkylations with β‐hydrogen‐containing primary and even secondary alkyl chlorides proceeded on pyridyl‐ and pyrimidyl‐substituted arenes and heteroarenes. The cobalt‐catalyzed C? H bond functionalizations occurred efficiently at ambient reaction temperature with excellent levels of site‐selectivities and ample scope. Mechanistic studies highlighted that electron‐deficient aryl chlorides reacted preferentially, while the arenes kinetic C? H bond acidity was found to largely govern their reactivity.     

Rhodium(III)/Copper(II)‐Promoted trans‐Selective Heteroaryl Acyloxylation of Alkynes: Stereodefined Access to trans‐Enol Esters

Enol esters are versatile synthetic building blocks which can be elaborated by a wide variety of transformations. The classical synthesis by O‐selective enolate acylation often hampers control of the E/Z selectivity with highly substituted substrates. A rhodium(III)/copper(II)‐mediated process is reported to provide tetrasubstituted enol esters in a trans‐selective fashion. Overall, the reaction consists of a heteroaryl acyloxylation of alkynes. The process is initiated by a rhodium(III)‐catalyzed C2‐selective activation of electron‐rich heteroarenes, such as benzofuran, furan, and thiophene. Upon addition across an alkyne, a transmetalation to copper(II) enables reductive C? O bond formation. The transformation allows the three‐component couplings of heteroarenes, alkynes, and carboxylic acids. Application of the method in the functionalization of bioactive furocoumarin natural products is also described.     

Catalytic Electrophilic CH Silylation of Pyridines Enabled by Temporary Dearomatization

A C? H silylation of pyridines that seemingly proceeds through electrophilic aromatic substitution (S_EAr) is reported. Reactions of 2‐ and 3‐substituted pyridines with hydrosilanes in the presence of a catalyst that splits the Si? H bond into a hydride and a silicon electrophile yield the corresponding 5‐silylated pyridines. This formal silylation of an aromatic C? H bond is the result of a three‐step sequence, consisting of a pyridine hydrosilylation, a dehydrogenative C? H silylation of the intermediate enamine, and a 1,4‐dihydropyridine retro‐hydrosilylation. The key intermediates were detected by ¹H NMR spectroscopy and prepared through the individual steps. This complex interplay of electrophilic silylation, hydride transfer, and proton abstraction is promoted by a single catalyst.     

Increasing Catalyst Efficiency in C−H Activation Catalysis

C?H activation reactions with high catalyst turnover numbers are still very rare in the literature and 10 mol % is a common catalyst loading in this field. We offer a representative overview of efficient C?H activation catalysis to highlight this neglected aspect of catalysis development and inspire future effort towards more efficient C?H activation. Examples ranging from palladium catalysis, Cp*Rh^III‐ and Cp*Co^III‐catalysis, the C?H borylation and silylation to methane C?H activation are presented. In these reactions, up to tens of thousands of catalyst turnovers have been observed.     

Catalyst‐Controlled Regiodivergent CH Borylation of Multifunctionalized Heteroarenes by Using Iridium Complexes

The regiodivergent C?H borylation of 2,5‐disubstituted heteroarenes with bis(pinacolato)diboron was achieved by using iridium catalysts formed in situ from [Ir(OMe)(cod)]₂/dtbpy (cod=1,5‐cyclooctadiene, dtbpy: 4,4′‐di‐tert‐butyl‐2,2′‐bipyridine) or [Ir(OMe)(cod)]₂/2 AsPh₃. When [Ir(OMe)(cod)]₂/dtbpy was used as the catalyst, borylation at the 4‐position proceeded selectively to afford 4‐borylated products in high yields (dtbpy system A). The regioselectivity changed when the [Ir(OMe)(cod)]₂/2 AsPh₃ catalyst was used; 3‐borylated products were obtained in high yields with high regioselectivity (AsPh₃ system B). The regioselectivity of borylation was easily controlled by changing the ligands. This reaction was used in the syntheses of two different bioactive compound analogues by using the same starting material.     

Hydrogen Bond Directed ortho‐Selective C−H Borylation of Secondary Aromatic Amides

Reported is an iridium catalyst for ortho‐selective C?H borylation of challenging secondary aromatic amide substrates, and the regioselectivity is controlled by hydrogen‐bond interactions. The BAIPy ‐Ir catalyst forms three hydrogen bonds with the substrate during the crucial activation step, and allows ortho‐C?H borylation with high selectivity. The catalyst displays unprecedented ortho selectivities for a wide variety of substrates that differ in electronic and steric properties, and the catalyst tolerates various functional groups. The regioselective C?H borylation catalyst is readily accessible and converts substrates on gram scale with high selectivity and conversion.     

Site‐Selective CH Borylation of Quinolines at the C8 Position Catalyzed by a Silica‐Supported Phosphane–Iridium System

Site‐selective C? H borylation of quinoline derivatives at the C8 position has been achieved by using a heterogeneous Ir catalyst system based on a silica‐supported cage‐type monophosphane ligand SMAP. The efficient synthesis of a corticotropin‐releasing factor₁ (CRF₁) receptor antagonist based on a late‐stage C? H borylation strategy demonstrates the utility of the C8 borylation reaction.     

Iridium‐Catalyzed Regioselective Silylation of Aromatic and Benzylic CH Bonds Directed by a Secondary Amine

Reported herein is an iridium‐catalyzed, regioselective silylation of the aromatic C? H bonds of benzylamines and the benzylic C? H bonds of 2,N‐dialkylanilines. In this process, (hydrido)silyl amines, generated in situ by dehydrogenative coupling of benzylamine or aniline with diethylsilane, undergo selective silylation at the C? H bond γ to the amino group. The products of this silylation are suitable for subsequent oxidation, halogenation, and cross‐coupling reactions to deliver benzylamine and arylamine derivatives.