Rollover‐Assisted C(sp2)C(sp3) Bond Formation

Rollover cyclometalation involves bidentate heterocyclic donors, unusually acting as cyclometalated ligands. The resulting products, possessing a free donor atom, react differently from the classical cyclometalated complexes. Taking advantage of a “rollover”/“retro‐rollover” reaction sequence, a succession of oxidative addition and reductive elimination in a series of platinum(II) complexes [Pt(N,C)(Me)(PR₃)] resulted in a rare C(sp²)?C(sp³) bond formation to give the bidentate nitrogen ligands 3‐methyl‐2,2′‐bipyridine, 3,6‐dimethyl‐2,2′‐bipyridine, and 3‐methyl‐2‐(2′‐pyridyl)‐quinoline, which were isolated and characterized. The nature of the phosphane PR₃ is essential to the outcome of the reaction. This route constitutes a new method for the activation and functionalization of C?H bond in the C(3) position of bidentate heterocyclic compounds, a position usually difficult to functionalize.     

Impact of Oxidation State on Reactivity and Selectivity Differences between Nickel(III) and Nickel(IV) Alkyl Complexes

Described is a systematic comparison of factors impacting the relative rates and selectivities of C(sp³)?C and C(sp³)?O bond‐forming reactions at high‐valent Ni as a function of oxidation state. Two Ni complexes are compared: a cationic octahedral Ni^IV complex ligated by tris(pyrazolyl)borate and a cationic octahedral Ni^III complex ligated by tris(pyrazolyl)methane. Key features of reactivity/selectivity are revealed: 1) C(sp³)?C(sp²) bond‐forming reductive elimination occurs from both centers, but the Ni^III complex reacts up to 300‐fold faster than the Ni^IV, depending on the reaction conditions. The relative reactivity is proposed to derive from ligand dissociation kinetics, which vary as a function of oxidation state and the presence/absence of visible light. 2) Upon the addition of acetate (AcO^?), the Ni^IV complex exclusively undergoes C(sp³)?OAc bond formation, while the Ni^III analogue forms the C(sp³)?C(sp²) coupled product selectively. This difference is rationalized based on the electrophilicity of the respective M?C(sp³) bonds, and thus their relative reactivity towards outer‐sphere S_N2‐type bond‐forming reactions.     

Access to β‐Lactams by Enantioselective Palladium(0)‐Catalyzed C(sp3)H Alkylation

β‐Lactams are very important structural motifs because of their broad biological activities as well as their propensity to engage in ring‐opening reactions. Transition‐metal‐catalyzed C? H functionalizations have emerged as strategy enabling yet uncommon highly efficient disconnections. In contrast to the significant progress of Pd⁰‐catalyzed C? H functionalization for aryl–aryl couplings, related reactions involving the formation of saturated C(sp³)? C(sp³) bonds are elusive. Reported here is an asymmetric C? H functionalization approach to β‐lactams using readily accessible chloroacetamide substrates. Important aspects of this transformation are challenging C(sp³)? C(sp³) and strain‐building reductive eliminations to for the four‐membered ring. In general, the β‐lactams are formed in excellent yields and enantioselectivities using a bulky taddol phosphoramidite ligand in combination with adamantyl carboxylic acid as cocatalyst.     

Mechanistic Insights into C(sp2)−C(sp)N Reductive Elimination from Gold(III) Cyanide Complexes

A new family of phosphine‐ligated dicyanoarylgold(III) complexes has been prepared and their reactivity towards reductive elimination has been studied in detail. Both, a highly positive entropy of activation and a primary ^12/13C KIE suggest a late concerted transition state while Hammett analysis and DFT calculations indicate that the process is asynchronous. As a result, a distinct mechanism involving an asynchronous concerted reductive elimination for the overall C(sp²)?C(sp)N bond forming reaction is characterized herein, for the first time, complementing previous studies reported for C(sp³)?C(sp³), C(sp²)?C(sp²), and C(sp³)?C(sp²) bond formation processes taking place on gold(III) species.     

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.     

Synthesis,Structures and Properties of C(sp2)‐Centered Homo‐ and Hetero‐Nuclear Gold Complexes

C(sp²)‐centered homo‐ and hetero‐nuclear gold complexes have attracted widespread interests in recent decades. Studies of this type of complexes may deepen the understandings of the intermediates in Au‐catalyzed organic reactions and explore new applications in catalytic and material science. The focuses of this review include the synthesis, structural characteristics, properties and applications of C(sp²)‐centered homo‐ and hetero‐nuclear gold complexes according to different structural classifications.     

Decarboxylative C(sp3)−O Cross‐Coupling

Alkyl aryl ethers are an important class of compounds in medicinal and agricultural chemistry. Catalytic C(sp³)?O cross‐coupling of alkyl electrophiles with phenols is an unexplored disconnection strategy to the synthesis of alkyl aryl ethers, with the potential to overcome some of the major limitations of existing methods such as C(sp²)?O cross‐coupling and S_N2 reactions. Reported here is a tandem photoredox and copper catalysis to achieve decarboxylative C(sp³)?O coupling of alkyl N‐hydroxyphthalimide (NHPI) esters with phenols under mild reaction conditions. This method was used to synthesize a diverse set of alkyl aryl ethers using readily available alkyl carboxylic acids, including many natural products and drug molecules. Complementarity in scope and functional‐group tolerance to existing methods was demonstrated.     

Palladium(II)-catalyzed arylation of unactivated C(sp3)-H bonds by using 2,1,3-benzoselenadiazole-4-amine as directing ligand

A modified bidentate directing ligand derived from 2,1,3-benzoselenadiazole (BSeD) was designed and synthesized. It exhibited high regioselectivity in the catalytic activation of unactivated C(sp³)-H bonds with aryl iodides in the presence of palladium catalyst in yields up to 94%.     

A Key Intermediate in Copper‐Mediated Arene Trifluoromethylation, [nBu4N][Cu(Ar)(CF3)3]: Synthesis,Characterization, and C(sp2)−CF3 Reductive Elimination

The synthesis, characterization, and C(sp²)?CF₃ reductive elimination of stable aryl[tris(trifluoromethyl)]cuprate(III) complexes [nBu₄N][Cu(Ar)(CF₃)₃] are described. Mechanistic investigations, including kinetic studies, studies of the effect of temperature, solvent, and the para substituent of the aryl group, as well as DFT calculations, suggest that the C(sp²)?CF₃ reductive elimination proceeds through a concerted carbon–carbon bond‐forming pathway.     

A Key Intermediate in Copper‐Mediated Arene Trifluoromethylation, [nBu4N][Cu(Ar)(CF3)3]: Synthesis,Characterization, and C(sp2)−CF3 Reductive Elimination

The synthesis, characterization, and C(sp²)?CF₃ reductive elimination of stable aryl[tris(trifluoromethyl)]cuprate(III) complexes [nBu₄N][Cu(Ar)(CF₃)₃] are described. Mechanistic investigations, including kinetic studies, studies of the effect of temperature, solvent, and the para substituent of the aryl group, as well as DFT calculations, suggest that the C(sp²)?CF₃ reductive elimination proceeds through a concerted carbon–carbon bond‐forming pathway.     

Visible Light Activation of Boronic Esters Enables Efficient Photoredox C(sp2)–C(sp3) Cross‐Couplings in Flow

We report herein a new method for the photoredox activation of boronic esters. Using these reagents, an efficient and high‐throughput continuous flow process was developed to perform a dual iridium‐ and nickel‐catalyzed C(sp²)–C(sp³) coupling by circumventing solubility issues associated with potassium trifluoroborate salts. Formation of an adduct with a pyridine‐derived Lewis base was found to be essential for the photoredox activation of the boronic esters. Based on these results we were able to develop a further simplified visible light mediated C(sp²)–C(sp³) coupling method using boronic esters and cyano heteroarenes under flow conditions.     

Benzylic C(sp3)–C(sp2) cross-coupling of indoles enabled by oxidative radical generation and nickel catalysis

A mechanistically unique functionalization strategy for a benzylic C(sp³)–H bond has been developed based on the facile oxidation event of indole substrates. This novel pathway was initiated by efficient radical generation at the benzylic position of the substrate, with subsequent transition metal catalysis to complete the overall transformation. Ultimately, an aryl or an acyl group could be effectively delivered from an aryl (pseudo)halide or an acid anhydride coupling partner, respectively. The developed method utilizes mild conditions and exhibits a wide substrate scope for both substituted indoles and C(sp²)-based reaction counterparts. Mechanistic studies have shown that competitive hydrogen atom transfer (HAT) processes, which are frequently encountered in conventional methods, are not involved in the product formation process of the developed strategy.

A mechanistically distinct Ni-catalysed benzylic functionalization of indoles is developed by the facile oxidation of arenes. The method exhibits a wide substrate scope and pronounced chemoselectivity that cannot be accessed via known protocols.     

Iron and Manganese Catalysts for the Selective Functionalization of Arene C(sp2)−H Bonds by Carbene Insertion

The first examples of the direct functionalization of non‐activated aryl sp² C?H bonds with ethyl diazoacetate (N₂CHCO₂Et) catalyzed by Mn‐ or Fe‐based complexes in a completely selective manner are reported, with no formation of the frequently observed cycloheptatriene derivatives through competing Buchner reaction. The best catalysts are Fe^II or Mn^II complexes bearing the tetradentate pytacn ligand (pytacn= 1‐(2‐pyridylmethyl)‐4,7‐dimethyl‐1,4,7‐triazacyclononane). When using alkylbenzenes, the alkylic C(sp³)?H bonds of the substituents remained unmodified, thus the reaction being also selective toward functionalization of sp² C?H bonds.     

Direct Acylation of C(sp3)−H Bonds Enabled by Nickel and Photoredox Catalysis

Using nickel and photoredox catalysis, the direct functionalization of C(sp³)?H bonds of N‐aryl amines by acyl electrophiles is described. The method affords a diverse range of α‐amino ketones at room temperature and is amenable to late‐stage coupling of complex and biologically relevant groups. C(sp³)?H activation occurs by photoredox‐mediated oxidation to generate α‐amino radicals which are intercepted by nickel in catalytic C(sp³)?C coupling. The merger of these two modes of catalysis leverages nickel's unique properties in alkyl cross‐coupling while avoiding limitations commonly associated with transition‐metal‐mediated C(sp³)?H activation, including requirements for chelating directing groups and high reaction temperatures.     

Tritopic NHC Precursors: Unusual Nickel Reactivity and Ethylene Insertion into a C(sp3)–H Bond

The imidazolium chloride [C₃H₃N(C₃H₆NMe₂)N{C(Me)(=NDipp)}]Cl ( 1 ; Dipp=2,6‐diisopropyl phenyl), a potential precursor to a tritopic N^imineC^NHCN^amine pincer‐type ligand, reacted with [Ni(cod)₂] to give the Ni^I‐Ni^I complex 2 , which contains a rare cod‐derived η³‐allyl‐type bridging ligand. The implied intermediate formation of a nickel hydride through oxidative addition of the imidazolium C−H bond did not occur with the symmetrical imidazolium chloride [C₃H₃N₂{C(Me)(=NDipp)}₂]Cl ( 3 ). Instead, a Ni−C(sp³) bond was formed, leading to the neutral N^imineCHN^imine pincer‐type complex Ni[C₃H₃N₂{C(Me)(=NDipp)}₂]Cl ( 4 ). Theoretical studies showed that this highly unusual feature in nickel NHC chemistry is due to steric constraints induced by the N substituents, which prevent Ni−H bond formation. Remarkably, ethylene inserted into the C(sp³)−H bond of 4 without nickel hydride formation, thus suggesting new pathways for the alkylation of non‐activated C−H bonds.     

Synthesis of α-Quaternary β-Lactams via Copper-Catalyzed Enantioconvergent Radical C(sp3)−C(sp2) Cross-Coupling with Organoboronate Esters

The copper-catalyzed enantioconvergent radical C(sp³)−C(sp²) cross-coupling of tertiary α-bromo-β-lactams with organoboronate esters could provide the synthetically valuable α-quaternary β-lactams. The challenge arises mainly from the construction of sterically congested quaternary stereocenters between the tertiary alkyl radicals and chiral copper(II) species. Herein, we describe our success in achieving such transformations through the utilization of a copper/hemilabile N,N,N-ligand catalyst to forge the sterically congested chiral C(sp³)−C(sp²) bond via a single-electron reduction/transmetalation/bond formation catalytic cycle. The synthetic potential of this approach is shown in the straightforward conversion of the corresponding products into many valuable building blocks. We hope that the developed catalytic cycle would open up new vistas for more enantioconvergent cross-coupling reactions.     

Steric Effect of Carboxylate Ligands on Pd‐Catalyzed Intramolecular C(sp2)–H and C(sp3)–H Arylation Reactions

A bulky carboxylic acid bearing three cyclohexylmethyl substituents at the α‐position, namely, tri(cyclohexylmethyl)acetic acid, is demonstrated to act as an efficient ligand source in Pd‐catalyzed intramolecular C(sp²)?H and C(sp³)?H arylation reactions. The reactions proceed smoothly under mild reaction conditions, even at room temperature due to the steric bulk of the carboxylate ligands, which accelerates the rate‐determining C?H bond activation step in the catalytic cycle.     

Mechanistic Insights into C(sp2)−C(sp)N Reductive Elimination from Gold(III) Cyanide Complexes

A new family of phosphine-ligated dicyanoarylgold(III) complexes has been prepared and their reactivity towards reductive elimination has been studied in detail. Both, a highly positive entropy of activation and a primary ^12/13C KIE suggest a late concerted transition state while Hammett analysis and DFT calculations indicate that the process is asynchronous. As a result, a distinct mechanism involving an asynchronous concerted reductive elimination for the overall C(sp²)−C(sp)N bond forming reaction is characterized herein, for the first time, complementing previous studies reported for C(sp³)−C(sp³), C(sp²)−C(sp²), and C(sp³)−C(sp²) bond formation processes taking place on gold(III) species.     

Photoactive electron donor–acceptor complex platform for Ni-mediated C(sp3)–C(sp2) bond formation

A dual photochemical/nickel-mediated decarboxylative strategy for the assembly of C(sp³)–C(sp²) linkages is disclosed. Under light irradiation at 390 nm, commercially available and inexpensive Hantzsch ester (HE) functions as a potent organic photoreductant to deliver catalytically active Ni(0) species through single-electron transfer (SET) manifolds. As part of its dual role, the Hantzsch ester effects a decarboxylative-based radical generation through electron donor–acceptor (EDA) complex activation. This homogeneous, net-reductive platform bypasses the need for exogenous photocatalysts, stoichiometric metal reductants, and additives. Under this cross-electrophile paradigm, the coupling of diverse C(sp³)-centered radical architectures (including primary, secondary, stabilized benzylic, α-oxy, and α-amino systems) with (hetero)aryl bromides has been accomplished. The protocol proceeds under mild reaction conditions in the presence of sensitive functional groups and pharmaceutically relevant cores.

This works demonstrates the implementation of an electron donor–acceptor (EDA) complex platform toward Ni-catalyzed C(sp³)–C(sp²) bond formation, circumventing the need for exogenous photocatalysts, additives, and stoichiometric metal reductants.     

B(C6F5)3‐Catalyzed sp3 C—Si Bond Forming Consecutive Reactions

Transition metal‐catalyzed hydrosilylation is one of the most widely utilized reduction methods as an alternative to hydrogenation in academia and industry. One feature distinct from hydrogenation would be able to install sp³ C—Si bond(s) onto substrates skeleton via hydrosilylation of alkenes. Recently, B(C₆F₅)₃ with hydrosilanes has been demonstrated to be an efficient, metal‐free catalyst system for the consecutive transformation of heteroatom‐containing substrates accompanied by the formation of sp³ C—Si bond(s), which has not been realized thus far under the transition metal‐catalyzed hydrosilylative conditions. In this review, I outline the B(C₆F₅)₃‐mediated consecutive hydrosilylations of heteroarenes containing quinolines, pyridines, and furans, and of conjugated nitriles/imines to provide a new family of compounds having sp³ C—Si bond(s) with high chemo‐, regio‐ and/or stereoselectivities. The silylative cascade conversion of unactivated N‐aryl piperidines to sila‐N‐heterocycles catalyzed by B(C₆F₅)₃ involving consecutive dehydrogenation, hydrosilylation, and intramolecular C(sp²)—H silylation, is presented in another section. Chemical selectivity and mechanism of the boron catalysis focused on the sp³ C—Si bond formation are highlighted.