Palladium‐Catalyzed Spirocyclization through C−H Activation and Regioselective Alkyne Insertion

A Pd‐catalyzed spirocyclization involving a sequential carbopalladation, intramolecular C−H activation, and a highly regioselective alkyne insertion to afford spirooxindoles and spirodihydrobenzofurans has been achieved. The spirocyclic products were generated in good to excellent yields with complete regiocontrol in a readily scalable procedure.     

Nucleophile Coordination Enabled Regioselectivity in Palladium‐Catalyzed Asymmetric Allylic C−H Alkylation

Branched selectivity in asymmetric allylic C?H alkylation is enabled by using 2‐acylimidazoles as nucleophiles in the presence of a chiral phosphoramidite‐palladium catalyst. A wide range of terminal alkenes, including 1,4‐dienes and allylarenes, are nicely tolerated and provide chiral 2‐acylimidazoles in moderate to high yields and with high levels of regio‐, and enantio‐, and E/Z‐selectivities. Mechanistic studies using density‐functional theory calculations suggest a nucleophile‐coordination‐enabled inner‐sphere attack mode for the enantioselective carbon–carbon bond‐forming event.     

Palladium‐Catalyzed Directed meta‐Selective C−H Allylation of Arenes: Unactivated Internal Olefins as Allyl Surrogates

Palladium(II)‐catalyzed meta‐selective C?H allylation of arenes has been developed utilizing synthetically inert unactivated acyclic internal olefins as allylic surrogates. The strong σ‐donating and π‐accepting ability of pyrimidine‐based directing group facilitates the olefin insertion by overcoming inertness of the typical unactivated internal olefins. Exclusive allyl over styrenyl product selectivity as well as E stereoselectivity were achieved with broad substrate scope, wide functional‐group tolerance, and good to excellent yields. Late‐stage functionalisations of pharmaceuticals were demonstrated. Experimental and computational studies shed light on the mechanism and point to key steric control in the palladacycle, thus determining product selectivities.     

Methylenecyclopropane Annulation by Manganese(I)‐Catalyzed Stereoselective C−H/C−C Activation

C−H/C−C functionalizations with methylenecyclopropanes (MCPs) were accomplished with a versatile base‐metal catalyst. A robust manganese(I) complex enabled the expedient annulation of MCPs by synthetically meaningful ketimines to deliver, upon one‐pot hydroarylation, densely substituted polycylic anilines in a step‐economical fashion. Mechanistic studies provided strong support for a facile organometallic C−H manganation, while typical cobalt, ruthenium, rhodium, and palladium catalysts were found completely ineffective.     

Bifurcated Nickel‐Catalyzed Functionalizations: Heteroarene C−H Activation with Allenes

A unified strategy for nickel(0)‐catalyzed C−H allylations, alkenylations, and dienylations has been realized through versatile hydroarylations of allenes with ample scope. Thus, an inexpensive nickel catalyst modified with a N ‐heterocyclic carbene ligand enabled the direct transformation of C−H bonds of biologically relevant imidazole and purine derivatives with full control of regio‐ and chemoselectivity.     

Rhodium‐Catalyzed meta‐C−H Functionalization of Arenes

Rhodium‐catalyzed ortho ‐C−H functionalization is well known in the literature. Described herein is the Xphos‐supported rhodium catalysis of meta ‐C−H olefination of benzylsulfonic acid and phenyl acetic acid frameworks with the assistance of a para ‐methoxy‐substituted cyano phenol as the directing group. Complete mono‐selectivity is observed for both scaffolds. A wide range of olefins and functional groups attached to arene are tolerated in this protocol.     

Catalytic Enantioselective Double Carbopalladation/C−H Functionalization with Statistical Amplification of Product Enantiopurity: A Convertible Linker Approach

Combining a catalytic enantioselective reaction with dimerization in a single operation is an efficient way to upgrade the enantiomeric excesses (ee ) of the product. Palladium‐catalyzed reaction of N ‐(2‐iodophenyl)‐N ‐methyl methacrylamide derivatives with oxadiazole afforded, by a double enantioselective carbopalladation/intermolecular heteroarene C−H alkylation sequence, homodimers in good yields with excellent ee values. The dimer was subsequently elaborated to the monomer in which the linker (oxadiazole) was incorporated into the target product.     

Palladium‐Catalyzed Pyrazole‐Directed sp3 C−H Bond Arylation for the Synthesis of β‐Phenethylamines

We have developed a method for palladium‐catalyzed, pyrazole‐directed sp³ C−H bond arylation by aryl iodides. The reaction employs a Pd(OAc)₂ catalyst at 5–10 mol % loading and silver(I) oxide as a halide‐removal agent, and it proceeds in acetic acid or acetic acid/hexafluoroisopropanol solvent. Ozonolysis of the pyrazole moiety affords pharmaceutically important β‐phenethylamines.     

Synthesis of Active Hexafluoroisopropyl Benzoates through a Hydrogen‐Bond‐Enabled Palladium(II)‐Catalyzed C−H Alkoxycarbonylation Reaction

A Pd^II‐catalyzed ortho C−H alkoxycarbonylation reaction of aryl silanes toward active hexafluoroisopropyl (HFIP) benzoate esters has been developed. This efficient reaction features high selectivity and good functional‐group tolerance. Notably, given the general nature of the silyl‐tethered directing group, this method delivers products bearing two independently modifiable sites. NMR studies reveal the presence of hydrogen bonding between HFIP and a pyrimidine nitrogen atom of the directing group, and it is thought to be crucial for the success of this alkoxycarbonylation reaction.     

meta‐C−H Arylation and Alkylation of Benzylsulfonamide Enabled by a Palladium(II)/Isoquinoline Catalyst

Palladium(II)‐catalyzed meta ‐C−H arylation and alkylation of benzylsulfonamide using 2‐carbomethoxynorbornene (NBE‐CO₂Me) as a transient mediator are realized by using a newly developed electron‐deficient directing group and isoquinoline as a ligand. This protocol features broad substrate scope and excellent functional‐group tolerance. The meta ‐substituted benyzlsulfonamides can be readily transformed into sodium sulfonates, sulfonate esters, and sulfonamides, as well as styrenes by Julia‐type olefination. The unique impact of the isoquinoline ligand underscores the importance of subtle matching between ligands and the directing groups.     

Enantioselective Synthesis of C−N Axially Chiral N‐Aryloxindoles by Asymmetric Rhodium‐Catalyzed Dual C−H Activation

The first enantioselective Satoh–Miura‐type reaction is reported. A variety of C?N axially chiral N‐aryloxindoles have been enantioselectively synthesized by an asymmetric rhodium‐catalyzed dual C?H activation reaction of N‐aryloxindoles and alkynes. High yields and enantioselectivities were obtained (up to 99 % yield and up to 99 % ee). To date, it is also the first example of the asymmetric synthesis of C?N axially chiral compounds by such a C?H activation strategy.     

Carboxy Group as a Remote and Selective Chelating Group for C−H Activation of Arenes

The first example of carboxy group assisted, remote‐selective C(sp²)?H activation with a Pd^II catalyst has been developed and proceeds through a possible κ² coordination of the carboxy group, thus suppressing the ortho‐C?H activation through κ¹ coordination. Besides meta‐C?H olefination, direct meta‐arylation of hydrocinnamic acid derivatives with low‐cost aryl iodides has been achieved for the first time. These findings may motivate the exploration of novel reactivities of the carboxy assisted C?H activation reactions with intriguing selectivities.     

Chelation versus Non‐Chelation Control in the Stereoselective Alkenyl sp2 C−H Bond Functionalization Reaction

A hydroxy group chelation‐assisted stereospecific oxidative cross‐coupling reaction between alkenes was developed under mild reaction conditions. In the presence of palladium catalyst, the alkenes tethered with hydroxy functionality can couple efficiently with electron‐deficient alkenes to form the corresponding multi‐substituted olefin products. The hydroxy group on the substrate could play dual roles in reaction, acting as the directing group for alkenyl C−H bond activation and controlling the stereoselectivity of the products.     

Access to Chiral Hydropyrimidines through Palladium‐Catalyzed Asymmetric Allylic C−H Amination

A palladium‐catalyzed asymmetric intramolecular allylic C−H amination controlled by a chiral phosphoramidite ligand was established for the preparation of various substituted chiral hydropyrimidinones, the precursors of hydropyrimidines, in high yields with high enantioselectivities. In particular, dienyl sodium N ‐sulfonyl amides bearing an arylethene‐1‐sulfonyl group underwent a sequential allylic C−H amination and intramolecular Diels–Alder (IMDA) reaction to produce chiral fused tricyclic tetrahydropyrimidinone frameworks in high yields and with high levels of stereoselectivity. Significantly, this method was used as the key step in an asymmetric synthesis of letermovir.     

Asymmetric Cycloisomerization of o‐Alkenyl‐N‐Methylanilines to Indolines by Iridium‐Catalyzed C(sp3)−H Addition to Carbon–Carbon Double Bonds

Highly enantioselective cycloisomerization of N ‐methylanilines, bearing o ‐alkenyl groups, into indolines is established. An iridium catalyst bearing a bidentate chiral diphosphine effectively promotes the intramolecular addition of the C(sp³)−H bond across a carbon–carbon double bond in a highly enantioselective fashion. The reaction gives indolines bearing a quaternary stereogenic carbon center at the 3‐position. The reaction mechanism involves rate‐determining oxidative addition of the N ‐methyl C−H bond, followed by intramolecular carboiridation and subsequent reductive elimination.     

Enantioselective Palladium‐Catalyzed Carbene Insertion into the N−H Bonds of Aromatic Heterocycles

C3‐substituted indoles and carbazoles react with α‐aryl‐α‐diazoesters under palladium catalysis to form α‐(N‐indolyl)‐α‐arylesters and α‐(N‐carbazolyl)‐α‐arylesters. The products result from insertion of a palladium‐carbene ligand into the N−H bond of the aromatic N‐heterocycles. Enantioselection was achieved using a chiral bis(oxazoline) ligand, in many cases with high enantioselectivity (up to 99 % ee). The method was applied to synthesize the core of a bioactive carbazole derivative in a concise manner.     

Palladium‐Catalyzed Alkylation with Alkyl Halides by C(sp3)−H Activation

Utilizing halogens as traceless directing goups represents an attractive strategy for C−H functionalization. A two C−H alkylation system, initiated by the oxidative addition of organohalides to Pd⁰, has been developed. The first reaction involves an intermolecular alkylation of palladacycles to form C(sp³)−C(sp²) bonds followed by C(sp²)−H activation/cyclization to deliver alkylated benzocyclobutenes as the final products. In the second reaction, two C−C bonds are formed by the reaction of palladacycles with CH₂Br₂, and provides a facile and efficient method for the synthesis of indanes. The alkylated benzocyclobutene products can be transformed into tricyclic hyrocarbons, and the indane derivatives are essential structural motifs in bioactive and odorant molecules.