Asymmetric C(sp2)?H Activation

A “niche” topic in the past decade, the asymmetric C? H bond activation has been attracting growing interest over the last few years. Particularly significant advances have been achieved in the field of direct, stereoselective transformations of C(sp²)? H bonds. This Concept article intends to showcase different types of asymmetric C(sp²)? H bond activation reactions, emphasising both the nature of the stereo‐discriminating step and the variability of valuable scaffolds that could be rapidly constructed by means of such strategies.     

Rhodium(I)‐Catalyzed Sequential C(sp)?C(sp3) and C(sp3)?C(sp3) Bond Formation through Migratory Carbene Insertion

A Rh^I‐catalyzed three‐component reaction of tert‐propargyl alcohol, diazoester, and alkyl halide has been developed. This reaction can be considered as a carbene‐involving sequential alkyl and alkynyl coupling, in which C(sp) C(sp³) and C(sp³) C(sp³) bonds are built successively on the carbenic carbon atom. The Rh^I‐carbene migratory insertion of an alkynyl moiety and subsequent alkylation are proposed to account for the two separate C C bond formations. This reaction provides an efficient and tunable method for the construction of all‐carbon quaternary center.     

Catalytic Functionalization of C(sp2)?H and C(sp3)?H Bonds by Using Bidentate Directing Groups

C? H bonds are ubiquitous in organic compounds. It would, therefore, appear that direct functionalization of substrates by activation of C? H bonds would eliminate the multiple steps and limitations associated with the preparation of functionalized starting materials. Regioselectivity is an important issue because organic molecules can contain a wide variety of C? H bonds. The use of a directing group can largely overcome the issue of regiocontrol by allowing the catalyst to come into proximity with the targeted C? H bonds. A wide variety of functional groups have been evaluated for use as directing groups in the transformation of C? H bonds. In 2005, Daugulis reported the arylation of unactivated C(sp³)? H bonds by using 8‐aminoquinoline and picolinamide as bidentate directing groups, with Pd(OAc)₂ as the catalyst. Encouraged by these promising results, a number of transformations of C? H bonds have since been developed by using systems based on bidentate directing groups. In this Review, recent advances in this area are discussed.     

C−H Bond Activation by Iridium(III) and Iridium(IV) Oxo Complexes

Oxidation of an iridium(III) oxo precursor enabled the structural, spectroscopic, and quantum-chemical characterization of the first well-defined iridium(IV) oxo complex. Side-by-side examination of the proton-coupled electron transfer thermochemistry revealed similar driving forces for the isostructural oxo complexes in two redox states due to compensating contributions from H⁺ and e⁻ transfer. However, C−H activation of dihydroanthracene revealed significant hydrogen tunneling for the distinctly more basic iridium(III) oxo complex. Our findings complement the growing body of data that relate tunneling to ground state properties as predictors for the selectivity of C−H bond activation.     

Copper‐Catalyzed Intramolecular C(sp3)?H and C(sp2)?H Amidation by Oxidative Cyclization

The first copper‐catalyzed intramolecular C(sp³) H and C(sp²) H oxidative amidation has been developed. Using a Cu(OAc)₂ catalyst and an Ag₂CO₃ oxidant in dichloroethane solvent, C(sp³) H amidation proceeded at a terminal methyl group, as well as at the internal benzylic position of an alkyl chain. This reaction has a broad substrate scope, and various β‐lactams were obtained in excellent yield, even on gram scale. Use of CuCl₂ and Ag₂CO₃ under an O₂ atmosphere in dimethyl sulfoxide, however, leads to 2‐indolinone selectively by C(sp²) H amidation. Kinetic isotope effect (KIE) studies indicated that C H bond activation is the rate‐determining step. The 5‐methoxyquinolyl directing group could be removed by oxidation.     

Terminal Phosphanido Rhodium Complexes Mediating Catalytic P?P and P?C Bond Formation

Complexes with terminal phosphanido (M PR₂) functionalities are believed to be crucial intermediates in new catalytic processes involving the formation of P P and P C bonds. We showcase here the isolation and characterization of mononuclear phosphanide rhodium complexes ([RhTp(H)(PR₂)L]) that result from the oxidative addition of secondary phosphanes, a reaction that was also explored computationally. These compounds are active catalysts for the dehydrocoupling of PHPh₂ to Ph₂P PPh₂. The hydrophosphination of dimethyl maleate and the unactivated olefin ethylene is also reported. Reliable evidence for the prominent role of mononuclear phosphanido rhodium species in these reactions is also provided.     

Rhodium(III)‐Catalyzed Amidation of Unactivated C(sp3)?H Bonds

Nitrogenation by direct functionalization of C H bonds represents an important strategy for constructing C N bonds. Rhodium(III)‐catalyzed direct amidation of unactivated C(sp³) H bonds is rare, especially under mild reaction conditions. Herein, a broad scope of C(sp³) H bonds are amidated under rhodium catalysis in high efficiency using 3‐substituted 1,4,2‐dioxazol‐5‐ones as the amide source. The protocol broadens the scope of rhodium(III)‐catalyzed C(sp³) H activation chemistry, and is applicable to the late‐stage functionalization of natural products.     

Rhodium(III)‐Catalyzed Amidation of Unactivated C(sp3)?H Bonds

Nitrogenation by direct functionalization of C H bonds represents an important strategy for constructing C N bonds. Rhodium(III)‐catalyzed direct amidation of unactivated C(sp³) H bonds is rare, especially under mild reaction conditions. Herein, a broad scope of C(sp³) H bonds are amidated under rhodium catalysis in high efficiency using 3‐substituted 1,4,2‐dioxazol‐5‐ones as the amide source. The protocol broadens the scope of rhodium(III)‐catalyzed C(sp³) H activation chemistry, and is applicable to the late‐stage functionalization of natural products.     

B?H,C?H,and B?C Bond Activation: The Role of Two Adjacent Agostic Interactions

Tuning the nature of the linker in a L∼BHR phosphinoborane compound led to the isolation of a ruthenium complex stabilized by two adjacent, δ‐C H and ε‐B_sp2 H, agostic interactions. Such a unique coordination mode stabilizes a 14‐electron “RuH₂P₂” fragment through connected σ‐bonds of different polarity, and affords selective B H, C H, and B C bond activation as illustrated by reactivity studies with H₂ and boranes.     

Rhodium(I)‐Catalyzed Enantioselective C?C Bond Activation

Relieving the strain : The rhodium(I)‐catalyzed activation of C C bonds in functionalized cyclobutanes opens a novel route to highly substituted carbo‐ and heterocycles. Particularly intriguing is the differentiation of enantiotopic C C bonds, which leads to the formation of highly enantiomerically enriched lactones, cyclopentanones, and cyclohexenones (see scheme).

     

Oxygen‐Promoted C?H Bond Activation at Palladium

[Pd(P(Ar)(tBu)₂)₂] ( 1 , Ar=naphthyl) reacts with molecular oxygen to form Pd^II hydroxide dimers in which the naphthyl ring is cyclometalated and one equivalent of phosphine per palladium atom is released. This reaction involves the cleavage of both C H and O O bonds, two transformations central to catalytic aerobic oxidizations of hydrocarbons. Observations at low temperature suggest the initial formation of a superoxo complex, which then generates a peroxo complex prior to the C H activation step. A transition state for energetically viable C H activation across a Pd peroxo bond was located computationally.     

Ligand‐Promoted Borylation of C(sp3)?H Bonds with Palladium(II) Catalysts

A quinoline‐based ligand effectively promotes the palladium‐catalyzed borylation of C(sp³) H bonds. Primary β‐C(sp³) H bonds in carboxylic acid derivatives as well as secondary C(sp³) H bonds in a variety of carbocyclic rings, including cyclopropanes, cyclobutanes, cyclopentanes, cyclohexanes, and cycloheptanes, can thus be borylated. This directed borylation method complements existing iridium(I)‐ and rhodium(I)‐catalyzed C H borylation reactions in terms of scope and operational conditions.     

Reversible Double C?H Bond Activation of Linear and Cyclic Ethers To Form Iridium Carbenes

The double C? H bond activation of a series of linear and cyclic ethers by the iridium complex [Tp^tol′Ir(C₆H₅)(N₂)] ( 2? N₂), which features a cyclometalated hydrotris(3‐p‐tolylpyrazol‐1‐yl)borate ligand (Tp^tol′) coordinated in a κ⁴‐N,N′,N′′,C manner, has been studied. Two methyl ethers, namely, Me₂O and MeOtBu, along with diethyl ether and the cyclic ethers tetrahydrofuran, tetrahydropyran (THP), and 1,4‐dioxane have been investigated with formation in every case of the corresponding hydride carbene complexes 3 – 8 , which are stabilized by κ⁴‐coordination of the ancillary Tp^tol′ ligand. Five of the compounds have been structurally authenticated by X‐ray crystallography. A remarkable feature of these rearrangements is the reversibility of the double C? H bond activation of Me₂O, MeOtBu, Et₂O, and THP. This has permitted catalytic deuterium incorporation into the methyl groups of the two methyl ethers, although in a rather inefficient manner (for synthetic purposes). Although possible in all cases, C? C coupling by migratory insertion of the carbene into the Ir? C σ bond of the metalated linkage has only been observed for complex 8 that contains a cyclic carbene that results from α,α‐C? H activation of 1,4‐dioxane. Computational studies on the formation of iridium carbenes are also reported, which show a role for metalated Tp ligands in the double C? H activation and account for the reversibility of the reaction in terms of the relative stability of the reagents and the products of the reaction.     

Entschuldigung: Readily Removable Directing Group Assisted Chemo‐ and Regioselective C(sp3)?H Activation by Palladium Catalysis

Currently used directing groups for selective aliphatic β‐functionalization of carbonyl compounds show excellent reactivity and selectivity with an amide as a linker. Described herein is 2‐piconimide, used for the first time with commercially available 2‐picolinamide/2‐picolic acid as precursors, to direct C H arylation/alkenylation by palladium catalysis. The directing group is essential for promoting the sequnetial primary and secondary C(sp³) H arylation with different aryl iodides in one substrate. The directing group was easily removed under simple reaction conditions at room temperature.     

C?NH2 Bond Formation Mediated by Iridium Complexes

In the presence of phosphanes (PR₃), the amido‐bridged trinuclear complex [{Ir(μ‐NH₂)(tfbb)}₃] (tfbb=tetrafluorobenzobarrelene) transforms into mononuclear discrete compounds [Ir(1,2‐η²‐4‐κ‐C₁₂H₈F₄N)(PR₃)₃], which are the products of the C N coupling between the amido moiety and a vinylic carbon of the diolefin. An alternative synthetic approach to these species involves the reaction of the 18 e⁻ complex [Ir(Cl)(tfbb)(PMePh₂)₂] with gaseous ammonia and additional phosphane. DFT studies show that both transformations occur through nucleophilic attack. In the first case the amido moiety attacks a diolefin coordinated to a neighboring molecule following a bimolecular mechanism induced by the highly basic NH₂ moiety; the second pathway involves a direct nucleophilic attack of ammonia to a coordinated tfbb molecule.     

Intermolecular C?H Bond Activation by a Cationic Iridium(III) Dichloride Phenanthroline Complex

It is demonstrated that a cationic iridium(III) dichloride phenanthroline complex is capable of C H activation and H/D exchange. It can cleave benzylic and unactivated secondary C H bonds, but exhibits unique selectivity when compared to similar systems that have been studied in the condensed phase. Gas‐phase rate constants and kinetic isotope effects are reported for a variety of substrates and the analysis is supported by DFT calculations at the M06/QZVP level.