Copper‐Catalyzed Enantioselective Arylative Desymmetrization of Prochiral Cyclopentenes with Diaryliodonium Salts

A copper‐catalyzed enantioselective arylative desymmetrization of prochiral cyclopentenes with diaryliodonium salts was developed. In the presence of a catalytic amount of a chiral copper–bisoxazoline complex, which was generated in situ, the reaction of 4‐substituted or 4,4‐disubstituted cyclopent‐1‐enes with diaryliodonium hexafluoroarsenates afforded the chiral arylated products in good yields with excellent enantioselectivity. A cyclohexyl‐containing Box ligand was essential for the high enantioselectivity. Transformation of the enantiomerically enriched adducts into other chiral building blocks is also documented.     

Alkenylation of C(sp3)−H Bonds by Zincation/Copper‐Catalyzed Cross‐Coupling with Iodonium Salts

α‐Vinylation of phosphonates, phosphine oxides, sulfones, sulfonamides, and sulfoxides has been achieved by selective C?H zincation and copper‐catalyzed C(sp³)?C(sp²) cross‐coupling reaction using vinylphenyliodonium salts. The vinylation transformation proceeds in high efficiency and stereospecificity under mild reaction conditions. This zincative cross‐coupling reaction represents a general alkenylation strategy, which is also applicable for α‐alkenylation of esters, amides, and nitriles in the synthesis of β,γ‐unsaturated carbonyl compounds.     

Stereoretentive Copper‐Catalyzed Directed Thioglycosylation of C(sp2)−H Bonds of Benzamides

An efficient thioglycosylation of C(sp²)?H bonds with thiosugars has been established for the first time. Using only Cu(OAc)₂?H₂O as a catalyst and Ag₂CO₃ as an additive in DMSO, the protocol proved to have broad scope, and a variety of complex thioglycosides have been prepared in good yields with exclusive β‐selectivity.     

Copper‐Catalyzed Direct Oxyphosphorylation of Enamides with P(O)‐H Compounds and Dioxygen

A simple and convenient copper‐catalyzed direct oxyphosphorylation of enamides with P(O)‐H compounds and dioxygen has been developed under mild conditions. This methodology can allow the synthesis of a series of valuable β ‐ketophosphine oxides/β ‐ketophosphonates in moderate to good yields with a broad substrate scope simply by using readily‐available starting materials.     

Intermolecular Amination of Unactivated C(sp3)−H Bonds with Cyclic Alkylamines: Formation of C(sp3)−N Bonds through Copper/Oxygen‐Mediated C(sp3)−H/N−H Activation

The first example of intermolecular amination of unactivated C(sp³)?H bonds by cyclic alkylamines mediated by Cu(OAc)₂/O₂ is reported. This method avoids the use of benzoyloxyamines as the aminating reagent, which are normally prepared from alkylamines in extra steps. A variety of unnatural β^{2, 2}‐amino acid analogues are synthesized by this simple and efficient procedure. This approach offers a solution to the previous unmet challenge of C(sp³)?H/N?H activation for the formation of C(sp³)?N bonds.     

Copper‐Mediated Aromatic 1,1‐Difluoroethylation with (1,1‐Difluoroethyl)trimethylsilane (TMSCF2CH3)

A new method for the formation of 1,1‐difluoroethyl copper species (“CuCF₂CH₃”) with 1,1‐difluoroethylsilane (TMSCF₂CH₃) has been developed. The “CuCF₂CH₃” species can be applied to the efficient 1,1‐difluoroethylation of diaryliodonium salts under mild conditions, affording (1,1‐difluoroethyl)arenes in good to excellent yields. This convenient procedure tolerates a wide range of functional groups and thus serves as a practical synthetic tool for the introduction of CF₂CH₃ group(s) into complex molecules.     

Copper‐Catalyzed Arylation of Remote C(sp3)−H Bonds in Carboxamides and Sulfonamides

Reported herein is an unprecedented copper‐catalyzed arylation of remote C(sp³)?H bonds. Stirring a trifluorotoluene solution of either N‐fluorocarboxamides or N‐fluorosulfonamides and arylboronic acids in the presence of a catalytic amount of copper(II) trifluoroacetylacetonate, 2,2′‐bipyridine, and sodium tert‐butoxide afforded the γ‐ and δ‐C(sp³)?H arylated carboxamides and sulfonamides, respectively, in good to high yields. Mechanistic studies indicate that the reaction might proceed through an amidyl radical generation, 1,5‐hydrogen atom transfer (HAT), and copper‐catalyzed cross‐coupling of the resulting carbon radical with arylboronic acids.     

Catalytic Aerobic Oxidation of C(sp3)−H Bonds

Oxidation reactions are a key technology to transform hydrocarbons from petroleum feedstock into chemicals of a higher oxidation state, allowing further chemical transformations. These bulk‐scale oxidation processes usually employ molecular oxygen as the terminal oxidant as at this scale it is typically the only economically viable oxidant. The produced commodity chemicals possess limited functionality and usually show a high degree of symmetry thereby avoiding selectivity issues. In sharp contrast, in the production of fine chemicals preference is still given to classical oxidants. Considering the strive for greener production processes, the use of O₂, the most abundant and greenest oxidant, is a logical choice. Given the rich functionality and complexity of fine chemicals, achieving regio/chemoselectivity is a major challenge. This review presents an overview of the most important catalytic systems recently described for aerobic oxidation, and the current insight in their reaction mechanism.     

Copper‐Catalyzed Insertion into Heteroatom–Hydrogen Bonds with Trifluorodiazoalkanes

Copper‐catalyzed Si?H, B?H, P?H, S?H, and N?H insertion reactions of 2,2,2‐trifluoro‐1‐diazoethane and 1‐aryl 2,2,2‐trifluorodiazoethanes generated a large number of new fluorine‐containing chemical entities for medicinal chemists. With selected Si?H and B?H insertion reactions, we demonstrate successful extension to asymmetric catalysis.     

Copper‐catalyzed C‐N coupling reaction of tosylhydrazones

Tosylhydrazones are a kind of labile and highly reactive compounds, which are apt to be transformed into reactive diazo compounds and then into extremely reactive carbenes under the basic condition. In order to fulfil the valuable C‐N coupling reaction, diaryliodonium salts are evaluated and prove to be a class of efficient electrophiles. The reaction with ligand‐free copper salt as catalyst shows a wide range of substrate scope. A plausible mechanism is proposed.     

Access to 2‐Arylindoles via Decarboxylative C−C Coupling in Aqueous Medium and to Heteroaryl Carboxylates under Base‐Free Conditions using Diaryliodonium Salts

Easily accessible heteroaromatic carboxylic acids and diaryliodonium salts were successfully employed to construct valuable 2‐arylindoles and heteroaryl carboxylates in a regioselective fashion. C2‐arylated indoles were produced using a Pd‐catalyzed decarboxylative strategy in water without any base, oxidant, or ligand. Heteroaryl carboxylates were prepared under metal and base‐free conditions. This protocol was successfully utilized to synthesize Paullone, a cyclin‐dependent kinase (CDK) inhibitor.     

Iron‐Catalyzed Intramolecular Aminations of C(sp3)−H Bonds in Alkylaryl Azides

The nucleophilic iron complex Bu₄N[Fe(CO)₃(NO)] (TBA[Fe]) catalyzes the direct intramolecular amination of unactivated C(sp³)−H bonds in alkylaryl azides, which results in the formation of substituted indoline and tetrahydroquinoline derivatives.     

Copper‐Catalyzed 8‐Amido Chelation‐Induced Remote C−H Amination of Quinolines

A copper‐catalyzed 8‐amide chelation‐induced remote C?H amination of quinolines has been developed. This direct amination with readily available azodicarboxylates proceeded with perfect C5‐regioselectivity offering amino‐substituted 8‐aminoquinolines, important bioactive molecular scaffolds, in very high yields (up to 96 %). A single‐electron transfer (SET)‐mediated mechanism with k_H/k_D=1.1 was proposed after trapping of the radical intermediate.     

Copper‐Catalyzed Regioselective Cascade Alkylation and Cyclocondensation of Quinoline N‐Oxides with Diazo Esters: Direct Access to Conjugated π‐Systems

An inexpensive copper‐catalyzed cascade regioselective alkylation, followed by cyclocondensation of quinoline N‐oxides with α‐diazo esters has been achieved successfully to provide heteroarene‐containing conjugated π‐systems. The developed method is simple, straightforward, and economical with a broad range of substrate scope. The dual role of copper catalyst in the C?H bond functionalization and in Lewis acid‐promoted cyclization was explored.     

Copper‐Catalyzed Radical/Radical CH/PH Cross‐Coupling: α‐Phosphorylation of Aryl Ketone O‐Acetyloximes

The selective radical/radical cross‐coupling of two different organic radicals is a great challenge due to the inherent activity of radicals. In this paper, a copper‐catalyzed radical/radical C? H/P? H cross‐coupling has been developed. It provides a radical/radical cross‐coupling in a selective manner. This work offers a simple way toward β‐ketophosphonates by oxidative coupling of aryl ketone o‐acetyloximes with phosphine oxides using CuCl as catalyst and PCy₃ as ligand in dioxane under N₂ atmosphere at 130 °C for 5 h, and yields ranging from 47 % to 86 %. The preliminary mechanistic studies by electron paramagnetic resonance (EPR) showed that, 1) the reduction of ketone o‐acetyloximes generates iminium radicals, which could isomerize to α‐sp³‐carbon radical species; 2) phosphorus radicals were generated from the oxidation of phosphine oxides. Various aryl ketone o‐acetyloximes and phosphine oxides were suitable for this transformation.     

Copper‐Catalyzed Enantioselective Sonogashira Type Coupling of Alkynes with α‐Bromoamides

An asymmetric copper‐catalyzed Sonogashira type coupling between alkynes and α‐bromoamides has been developed. This method represents a facile approach to synthetically useful β, γ‐alkynyl amides from two readily available starting materials in a highly enantioselective manner. A Bisoxazoline diphenylanaline (BOPA) serves as the effective chiral ligand. Preliminary mechanistic studies support the formation of alkyl radical species .