Divergent CH Insertion–Cyclization Cascades of N‐Allyl Ynamides

Gold carbene reactivity patterns were accessed by ynamide insertion into a C(sp³)? H bond. A substantial increase in molecular complexity occurred through the cascade polycyclization of N‐allyl ynamides to form fused nitrogen‐heterocycle scaffolds. Exquisite selectivity was observed despite several competing pathways in an efficient gold‐catalyzed synthesis of densely functionalized C(sp³)‐rich polycycles and a copper‐catalyzed synthesis of fused pyridine derivatives. The respective gold–keteniminium and ketenimine activation pathways have been explored through a structure–reactivity study, and isotopic labeling identified turnover‐limiting C? H bond‐cleavage in both processes.     

Palladium‐Catalyzed Intramolecular Carbene Insertion into C(sp3)−H Bonds

A palladium‐catalyzed carbene insertion into C(sp³)?H bonds leading to pyrrolidines was developed. The coupling reaction can be catalyzed by both Pd⁰ and Pd^II, is regioselective, and shows a broad functional group tolerance. This reaction is the first example of palladium‐catalyzed C(sp³)?C(sp³) bond assembly starting from diazocarbonyl compounds. DFT calculations revealed that this direct C(sp³)?H bond functionalization reaction involves an unprecedented concerted metalation–deprotonation step.     

Redox‐Neutral Coupling between Two C(sp3)−H Bonds Enabled by 1,4‐Palladium Shift for the Synthesis of Fused Heterocycles

The intramolecular coupling of two C(sp³)?H bonds to forge a C(sp³)?C(sp³) bond is enabled by 1,4‐Pd shift from a trisubstituted aryl bromide. Contrary to most C(sp³)?C(sp³) cross‐dehydrogenative couplings, this reaction operates under redox‐neutral conditions, with the C?Br bond acting as an internal oxidant. Furthermore, it allows the coupling between two moderately acidic primary or secondary C?H bonds, which are adjacent to an oxygen or nitrogen atom on one side, and benzylic or adjacent to a carbonyl group on the other side. A variety of valuable fused heterocycles were obtained from easily accessible ortho‐bromophenol and aniline precursors. The second C?H bond cleavage was successfully replaced with carbonyl insertion to generate other types of C(sp³)‐C(sp³) bonds.     

Copper(I)‐Catalyzed Alkylation of Polyfluoroarenes through Direct CH Bond Functionalization

The copper(I)‐catalyzed alkylation of electron‐deficient polyfluoroarenes with N‐tosylhydrazones and diazo compounds has been developed. This reaction uses readily available starting materials and is operationally simple, thus representing a practical method for the construction of C(sp²)? C(sp³) bonds with polyfluoroarenes through direct C? H bond functionalization. Mechanistically, copper(I) carbene formation and subsequent migratory insertion are proposed as the key steps in the reaction pathway.     

Divergent C?H Insertion–Cyclization Cascades of N‐Allyl Ynamides

Gold carbene reactivity patterns were accessed by ynamide insertion into a C(sp³) H bond. A substantial increase in molecular complexity occurred through the cascade polycyclization of N‐allyl ynamides to form fused nitrogen‐heterocycle scaffolds. Exquisite selectivity was observed despite several competing pathways in an efficient gold‐catalyzed synthesis of densely functionalized C(sp³)‐rich polycycles and a copper‐catalyzed synthesis of fused pyridine derivatives. The respective gold–keteniminium and ketenimine activation pathways have been explored through a structure–reactivity study, and isotopic labeling identified turnover‐limiting C H bond‐cleavage in both processes.     

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.     

Ruthenium–Porphyrin‐Catalyzed Diastereoselective Intramolecular Alkyl Carbene Insertion into CH Bonds of Alkyl Diazomethanes Generated In Situ from N‐Tosylhydrazones

With a ruthenium–porphyrin catalyst, alkyl diazomethanes generated in situ from N‐tosylhydrazones efficiently underwent intramolecular C(sp³)? H insertion of an alkyl carbene to give substituted tetrahydrofurans and pyrrolidines in up to 99 % yield and with up to 99:1 cis selectivity. The reaction displays good tolerance of many functionalities, and the procedure is simple without the need for slow addition with a syringe pump. From a synthetic point of view, the C? H insertion of N‐tosylhydrazones can be viewed as reductive coupling between a C?O bond and a C? H bond to form a new C? C bond, since N‐tosylhydrazones can be readily prepared from carbonyl compounds. This reaction was successfully applied in a concise synthesis of (±)‐pseudoheliotridane.     

N‐Heterocyclic Carbene Ligand‐Enabled C(sp3)−H Arylation of Piperidine and Tetrahydropyran Derivatives

Pd^II‐catalyzed C(sp³)?H arylation of saturated heterocycles with a wide range of aryl iodides is enabled by an N‐heterocyclic carbene (NHC) ligand. A C(sp³)?H insertion step by the Pd^II/NHC complex in the absence of ArI is demonstrated experimentally for the first time. Experimental data suggests that the previously established NHC‐mediated Pd⁰/Pd^II catalytic manifold does not operate in this reaction. This transformation provides a new approach for diversifying pharmaceutically relevant piperidine and tetrahydropyran ring systems.     

C(sp3)H Activation without a Directing Group: Regioselective Synthesis of N‐Ylide or N‐Heterocyclic Carbene Complexes Controlled by the Choice of Metal and Ligand

N‐Ylide complexes of Ir have been generated by C(sp³)?H activation of α‐pyridinium or α‐imidazolium esters in reactions with [Cp*IrCl₂]₂ and NaOAc. These reactions are rare examples of C(sp³)?H activation without a covalent directing group, which—even more unusually—occur α to a carbonyl group. For the reaction of the α‐imidazolium ester [ 3 H]Cl, the site selectivity of C?H activation could be controlled by the choice of metal and ligand: with [Cp*IrCl₂]₂ and NaOAc, C(sp³)?H activation gave the N‐ylide complex 4 ; in contrast, with Ag₂O followed by [Cp*IrCl₂]₂, C(sp²)?H activation gave the N‐heterocyclic carbene complex 5 . DFT calculations revealed that the N‐ylide complex 4 was the kinetic product of an ambiphilic C?H activation. Examination of the computed transition state for the reaction to give 4 indicated that unlike in related reactions, the acetate ligand appears to play the dominant role in C?H bond cleavage.     

Palladium/Norbornene‐Catalyzed C−H Alkylation/Alkyne Insertion/Indole Dearomatization Domino Reaction: Assembly of Spiroindolenine‐Containing Pentacyclic Frameworks

Reported is a highly chemoselective intermolecular annulation of indole‐based biaryls with bromoalkyl alkynes by using palladium/norbornene (Pd/NBE) cooperative catalysis. This reaction is realized through a sequence of Catellani‐type C?H alkylation, alkyne insertion, and indole dearomatization, by forming two C(sp²)?C(sp³) and one C(sp²)?C(sp²) bonds in a single chemical operation, thus providing a diverse range of pentacyclic molecules, containing a spiroindolenine fragment, in good yields with excellent functional‐group tolerance. Preliminary mechanistic studies reveal that C?H bond cleavage is likely involved in the rate‐determining step, and the indole dearomatization might take place through an olefin coordination/insertion and β‐hydride elimination Heck‐type pathway.     

Electrophilic Iron Catalyst Paired with a Lithium Cation Enables Selective Functionalization of Non‐Activated Aliphatic C−H Bonds via Metallocarbene Intermediates

Combining an electrophilic iron complex [Fe(^Fpda)(THF)]₂ ( 3 ) [^Fpda=N,N′‐bis(pentafluorophenyl)‐o‐phenylenediamide] with the pre‐activation of α‐alkyl‐substituted α‐diazoesters reagents by LiAl(OR^F)₄ [OR^F=(OC(CF₃)₃] provides unprecedented access to selective iron‐catalyzed intramolecular functionalization of strong alkyl C(sp³)?H bonds. Reactions occur at 25 °C via α‐alkyl‐metallocarbene intermediates, and with activity/selectivity levels similar to those of rhodium carboxylate catalysts. Mechanistic investigations reveal a crucial role of the lithium cation in the rate‐determining formation of the electrophilic iron‐carbene intermediate, which then proceeds by concerted insertion into the C?H bond.     

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.     

Dehydrogenative N‐Incorporation: A Direct Approach to Quinoxaline N‐Oxides under Mild Conditions

An efficient method for the synthesis of quinoxaline N‐oxides proceeds by the dehydrogenative N‐incorporation of simple imines by C(sp²)? H and C(sp³)? H bond functionalization. The overall transformation involves the cleavage of three C? H bonds. The reaction is easily handled and proceeds under mild conditions. Simple and readily available tert‐butyl nitrite (TBN) was employed as the NO source.     

Rhodium(II)‐ or Copper(I)‐Catalyzed Formal Intramolecular Carbene Insertion into Vinylic C(sp2)−H Bonds: Access to Substituted 1H‐Indenes

A rhodium(II)‐ or copper(I)‐catalyzed formal intramolecular carbene insertion into vinylic C(sp²)−H bonds is reported herein. This method provides straightforward access to 1H ‐indenes with high efficiency and excellent functional‐group compatibility. Mechanistically, the reaction is proposed to involve the following sequence: metal carbene formation, intramolecular nucleophilic addition of the double bond to the electron‐deficient carbene carbon atom, dearomatization, and finally a 1,5‐H shift.     

Theoretical investigation toward organophosphine‐catalyzed [3 + 3] annulation of Morita–Baylis–Hillman carbonates with azomethine imines: Mechanism,origin of stereoselectivity,and role of catalyst

A computational study on the detailed mechanism and stereoselectivity of the chiral phosphine‐catalyzed C(sp²)? H activation/[3 + 3] annulation between Morita–Baylis–Hillman (MBH) carbonates and C,N‐cyclic azomethine imines has been performed. Generally, the catalytic cycle consists of two stages, that is, C(sp²)? H activation companied by the dissociation of the t‐BuO group forming phosphonium enolate, and [3 + 3] cycloaddition process followed by regeneration of the catalyst. The calculated results indicate that C(sp²)? H activation is rate‐determining while [3 + 3] cycloaddition is stereoselectivity‐determining. Furthermore, the advantageous hydrogen bond interactions and less steric hindrance in the RR configurational C? C bond forming transition states should be responsible for the favorability of RR‐configured product among the four possible products. The special role of the organocatalyst was also identified by natural bond orbital (NBO) and global reactivity index (GRI) analyses. The mechanistic insights obtained in the present study should be useful for understanding the novel organocatalytic C(sp²)? H activation and cycloaddition cascade reaction of MBH carbonates, and thus provide valuable clues on rational design of efficient organocatalysts for the C(sp²)? H activation/functionalizations.     

Cp*RhIII‐Catalyzed Arylation of C(sp3)H Bonds

The first Cp*Rh^III‐catalyzed arylation of unactivated C(sp³)? H bonds is presented. The unactivated primary C(sp³)? H bond of 2‐alkylpyridines can be activated by Rh^III and further reacts with triarylboroxines to efficiently build new C(sp³)? aryl bonds. The methodology also provides a facile and efficient synthesis of unsymmetrical triarylmethanes by Rh^III‐catalyzed C(sp³)? H arylation of diarylmethanes.     

Internal Peptide Late‐Stage Diversification: Peptide‐Isosteric Triazoles for Primary and Secondary C(sp3)−H Activation

Secondary C(sp³)?H arylations were accomplished by palladium catalysis with triazoles as peptide bond isosteres. The unique power of this approach is highlighted by the possibility of achieving secondary C(sp³)?H functionalizations on terminal peptides as well as the unprecedented positional‐selective C(sp³)?H functionalization of internal peptide positions, setting the stage for modular peptide late‐stage diversification.     

Intramolecular Interception of the Remote Position of Vinylcarbene Silver Complex Intermediates by C(sp3)−H Bond Insertion

The trapping of the elusive vinylogous position of a vinyl carbene with an aliphatic C(sp³)−H bond has been achieved for the first time during a silver-catalyzed carbene/alkyne metathesis (CAM) process. A Tp^x-containing silver complex first promotes the generation of a donor-acceptor silver carbene which triggers CAM, generating a subsequent donor-donor vinyl silver carbene species, which then undergoes a selective vinylogous C(sp³)−H bond insertion, leading to the synthesis of a new family of benzoazepines. Density functional theory (DFT) calculations unveil the reaction mechanism, which allows proposing that the C−H bond insertion reaction takes place in a stepwise manner, with the hydrogen shift being the rate determining step.     

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.     

Construction of Hexahydrophenanthrenes By Rhodium(I)‐Catalyzed Cycloisomerization of Benzylallene‐Substituted Internal Alkynes through C−H Activation

The treatment of benzylallene‐substituted internal alkynes with [RhCl(CO)₂]₂ effects a novel cycloisomerization by C(sp²)?H bond activation to produce hexahydrophenanthrene derivatives. The reaction likely proceeds through consecutive formation of a rhodabicyclo[4.3.0] intermediate, σ‐bond metathesis between the C(sp²)?H bond on the benzene ring and the C(sp²)?Rh^III bond, and isomerization between three σ‐, π‐, and σ‐allylrhodium(III) species, which was proposed based on experiments with deuterated substrates.