Synthesis of Carbazoles and Related Heterocycles from Sulfilimines by Intramolecular C−H Aminations

While direct nitrene insertions into C?H bonds have become an important tool for building C?N bonds in modern organic chemistry, the generation of nitrene intermediates always requires transition metals, high temperatures, ultraviolet or laser light. We report a mild synthesis of carbazoles and related building blocks through a visible light‐induced intramolecular C?H amination reaction. A striking advantage of this new method is the use of more reactive aryl sulfilimines instead of the corresponding hazardous azides. Different catalysts and divergent light sources were tested. The reaction scope is broad and the product yield is generally high. An efficient gram‐scale synthesis of Clausine C demonstrates the applicability and scalability of this new method.     

Enantioselective Copper(I)/Chiral Phosphoric Acid Catalyzed Intramolecular Amination of Allylic and Benzylic C−H Bonds

Radical‐involved enantioselective oxidative C?H bond functionalization by a hydrogen‐atom transfer (HAT) process has emerged as a promising method for accessing functionally diverse enantioenriched products, while asymmetric C(sp³)?H bond amination remains a formidable challenge. To address this problem, described herein is a dual Cu^I/chiral phosphoric acid (CPA) catalytic system for radical‐involved enantioselective intramolecular C(sp³)?H amination of not only allylic positions but also benzylic positions with broad substrate scope. The use of 4‐methoxy‐NHPI (NHPI=N‐hydroxyphthalimide) as a stable and chemoselective HAT mediator precursor is crucial for the fulfillment of this transformation. Preliminary mechanistic studies indicate that a crucial allylic or benzylic radical intermediate resulting from a HAT process is involved.     

Recent Trends in Copper‐Catalyzed C−H Amination Routes to Biologically Important Nitrogen Scaffolds

Nitrogen‐containing heterocycles have found remarkable applications in natural product research, material sciences, and pharmaceuticals. Although the synthesis of this interesting class of compounds attracted the interest of generations of organic chemists, simple and straightforward assembly methods based on transition‐metal catalysis have regularly been elusive. The recent advancements in the development of C?H functionalization have helped in accomplishing the synthesis of a variety of complex heterocycles from simple precursors. This Focus Review summarizes the recent advances in one particular field: the copper‐catalyzed C?N bond formation reactions via C?H bond functionalization to furnish a comprehensive range of nitrogen heterocycles. Applicability and synthetic feasibility of a particular reaction represent major requirements for the inclusion in this review.     

Cu/Fe Catalyzed Intermolecular Oxidative Amination of Benzylic C−H Bonds

We report a Cu/Fe co‐catalyzed Ritter‐type C?H activation/amination reaction that allows efficient and selective intermolecular functionalization of benzylic C?H bonds. This new reaction is featured by simple reaction conditions, readily available reagents and general substrate scope, allowing facile synthesis of biologically interesting nitrogen containing heterocycles. The Cu and Fe salts were found to play distinct roles in this cooperative catalysis.     

Copper‐Catalyzed N−F Bond Activation for Uniform Intramolecular C−H Amination Yielding Pyrrolidines and Piperidines

The dual function of the N?F bond as an effective oxidant and subsequent nitrogen source in intramolecular aliphatic C?H functionalization reactions is explored. Copper catalysis is demonstrated to exercise full regio‐ and chemoselectivity control, which opens new synthetic avenues to nitrogenated heterocycles with predictable ring sizes. For the first time, a uniform catalysis manifold has been identified for the construction of both pyrrolidine and piperidine cores. The individual steps of this new copper oxidation catalysis were elucidated by control experiments and computational studies, clarifying the singularity of the N?F function and characterizing the catalytic cycle to be based on a copper(I/II) manifold.     

Multiple Catalytic C−H Bond Functionalization for Natural Product Synthesis

In the past decade, multiple catalytic C?H bond functionalization has been successfully applied in natural product synthesis as a strategy to reduce the number of steps, increase overall yield and employ more easily available starting materials. This minireview presents selected examples making use of multiple C?H bond functionalization in conceptually different ways. First, linear syntheses are discussed, wherein multiple C?H functionalization is employed either from simple (hetero)cyclic cores, at a late stage, or to build polycyclic systems. Second, the use of multiple C?H functionalization as a strategic tool in convergent synthesis to access and couple complex fragments is discussed. Information on the scalability of the employed methods is provided when available. The presented cases indicate that multiple C?H functionalization strategies should play a great role to shape the future synthesis of functional complex molecules with improved sustainability.     

Catalyst‐Dependent Chemoselective Formal Insertion of Diazo Compounds into C−C or C−H Bonds of 1,3‐Dicarbonyl Compounds

A catalyst‐dependent chemoselective one‐carbon insertion of diazo compounds into the C?C or C?H bonds of 1,3‐dicarbonyl species is reported. In the presence of silver(I) triflate, diazo insertion into the C(=O)?C bond of the 1,3‐dicarbonyl substrate leads to a 1,4‐dicarbonyl product containing an all‐carbon α‐quaternary center. This reaction constitutes the first example of an insertion of diazo‐derived carbenoids into acyclic C?C bonds. When instead scandium(III) triflate was applied as the catalyst, the reaction pathway switched to formal C?H insertion, affording 2‐alkylated 1,3‐dicarbonyl products. Different reaction pathways are proposed to account for this powerful catalyst‐dependent chemoselectivity.     

Copper‐Catalyzed Direct Sulfoximination of Heteroaromatic N‐Oxides by Dual C−H/N−H Dehydrogenative Cross‐Coupling

A dual C?H/N?H dehydrogenative coupling of quinoline‐type N‐oxides with sulfoximines that leads to N‐(hetero)arylsulfoximines in high yields has been realized by using a catalytic amount of CuBr in air. The method does not require any additional ligand, base, reactivity modifier or oxidant and provides a practical route towards a series of sulfoximidoyl‐functionalized quinolines and 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.     

Nickel‐Catalyzed Oxidative C−H/N−H Isocyanide Insertion: An Efficient Synthesis of Iminoisoindolinone Derivatives

Transition metal‐catalyzed isocyanide insertion has served as a fundamental and important chemical transformation. Classical isocyanide insertion usually occurs between organohalides and nucleophiles, which normally involves tedious and non‐atom‐economical prefunctionalization processes. However, oxidative C?H/N?H isocyanide insertion offers an efficient and green alternative. Herein, a nickel‐catayzed oxidative C?H/N?H isocyanide insertion of aminoquinoline benzamides has been developed. Different kinds of iminoisoindolinone derivatives could be synthesized in good yields by utilizing Ni(acac)₂ as the catalyst. In this transformation, isocyanide serves as an efficient C1 connector, which further inserted into two simple nucleophiles (C?H/N?H), representing an effective way to construct heterocycles.     

Copper Catalyzed C−H Activation

Activation of C?H bonds and their application in cross coupling chemistry has received a wider interest in recent years. The conventional strategy in cross coupling reaction involves the pre‐functionalization step of coupling reactants such as organic halides, pseudo‐halides and organometallic reagents. The C?H activation facilitates a simple and straight forward approach devoid of pre‐functionalization step. This approach also addresses the environmental and economical issues involved in several chemical reactions. In this account, we have reported C?H bond activation of small organic molecules, for example, formamide C?H bond can be activated and coupled with β‐dicarbonyl or 2‐carbonyl substituted phenols under oxidative conditions to yield carbamates using inexpensive copper catalysts. Phenyl carbamates were successfully synthesized in moderate to good yields by cross dehydrogenative coupling (CDC) of phenols with formamides using copper catalysts in presence of a ligand. We have also prepared unsymmetrical urea derivatives by oxidative cross coupling of formamides with amines using copper catalysts. Synthesis of N,N‐dimethyl substituted amides, 5‐substituted‐γ‐lactams and α‐acyloxy ethers was carried out from carboxylic acids using recyclable CuO nanoparticles. Copper nanoparticles afforded N‐aryl‐γ‐amino‐γ‐lactams by oxidative coupling of aromatic amines with 2‐pyrrolidinone. Reusable transition metal HT‐derived oxide catalyst was used for the synthesis of N,N‐dimethyl substituted amides by the oxidative cross‐coupling of carboxylic acids and substituted benzaldehydes. Overview of our work in this area is summarized.     

Mild C−H/C−C Activation by Z‐Selective Cobalt Catalysis

Cationic cobalt complexes enable unprecedented cobalt‐catalyzed C?H/C?C functionalizations with unique selectivity features. The versatile cobalt catalyst proved broadly applicable, enabled efficient C?H/C?C cleavage at room temperature, and delivered Z‐alkenes with excellent diastereocontrol.     

C−H Coupling Reactions Directed by Sulfoxides: Teaching an Old Functional Group New Tricks

Sulfoxides are classical functional groups for directing the stoichiometric metalation and functionalization of C?H bonds. In recent times, sulfoxides have been given a new lease on life owing to the development of modern synthetic methods that have arisen because of their unique reactivity. They have recently been used in catalytic C?H activation proceeding via coordination of an internal sulfoxide to a metal or through the action of an external sulfoxide ligand. Furthermore, sulfoxides are able to capture nucleophiles and electrophiles to give sulfonium salts, which subsequently enable the formation of C?C bonds at the expense of C?H bonds. This Review summarizes a renaissance period in the application of sulfoxides arising from their versatility in directing C?H functionalization.     

Mechanistic Insight into the Intramolecular Benzylic C−H Nitrene Insertion Catalyzed by Bimetallic Paddlewheel Complexes: Influence of the Metal Centers

The intramolecular benzylic C?H amination catalyzed by bimetallic paddlewheel complexes was investigated by using density functional theory calculations. The metal–metal bonding characters were investigated and the structures featuring either a small HOMO–LUMO gap or a compact SOMO energy scope were estimated to facilitate an easier one‐electron oxidation of the bimetallic center. The hydrogen‐abstraction step was found to occur through three manners, that is, hydride transfer, hydrogen migration, and proton transfer. The imido N species are more preferred in the Ru–Ru and Pd–Mn cases whereas coexisting N species, namely, singlet/triplet nitrene and imido, were observed in the Rh–Rh and Pd–Co cases. On the other hand, the triplet nitrene N species were found to be predominant in the Pd–Ni and Pd–Zn systems. A concerted asynchronous mechanism was found to be modestly favorable in the Rh–Rh‐catalyzed reactions whereas the Pd–Co‐catalyzed reactions demonstrated a slight preference for a stepwise pathway. Favored stepwise pathways were seen in each Ru–Ru‐ and Pd–Mn‐catalyzed reactions and in the triplet nitrene involved Pd–Ni and Pd–Zn reactions. The calculations suggest the feasibility of the Pd–Mn, Pd–Co, and Pd–Ni paddlewheel complexes as being economical alternatives for the expensive dirhodium/diruthenium complexes in C?H amination catalysis.     

Cobalt‐Catalyzed Oxidative C−H/C−H Cross‐Coupling between Two Heteroarenes

The first example of cobalt‐catalyzed oxidative C?H/C?H cross‐coupling between two heteroarenes is reported, which exhibits a broad substrate scope and a high tolerance level for sensitive functional groups. When the amount of Co(OAc)₂?4 H₂O is reduced from 6.0 to 0.5 mol %, an excellent yield is still obtained at an elevated temperature with a prolonged reaction time. The method can be extended to the reaction between an arene and a heteroarene. It is worth noting that the Ag₂CO₃ oxidant is renewable. Preliminary mechanistic studies by radical trapping experiments, hydrogen/deuterium exchange experiments, kinetic isotope effect, electron paramagnetic resonance (EPR), and high resolution mass spectrometry (HRMS) suggest that a single electron transfer (SET) pathway is operative, which is distinctly different from the dual C?H bond activation pathway that the well‐described oxidative C?H/C?H cross‐coupling reactions between two heteroarenes typically undergo.     

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.     

Electrophilic Aromatic Substitution with Silicon Electrophiles: Catalytic Friedel–Crafts C−H Silylation

Electrophilic aromatic substitution is a fundamental reaction in synthetic chemistry. It converts C−H bonds of sufficiently nucleophilic arenes into C−X and C−C bonds using either stoichiometrically added or catalytically generated electrophiles. These reactions proceed through Wheland complexes, cationic intermediates that rearomatize by proton release. Hence, these high‐energy intermediates are nothing but protonated arenes and as such strong Brønsted acids. The formation of protons is an issue in those rare cases where the electrophilic aromatic substitution is reversible. This situation arises in the electrophilic silylation of C−H bonds as the energy of the intermediate Wheland complex is lowered by the β‐silicon effect. As a consequence, protonation of the silylated arene is facile, and the reverse reaction usually occurs to afford the desilylated arene. Several new approaches to overcome this inherent challenge of C−H silylation by S_EAr were recently disclosed, and this Minireview summarizes this progress.     

Non‐Diazo C−H Insertion Approach to Cyclobutanones through Oxidative Gold Catalysis

Cyclobutanones are synthetically versatile compounds that often require extensive effort to access. Herein, we report a facile synthesis of cyclobutanones based on the C(sp³)?H insertion chemistry of oxidatively generated gold carbenes. Various cyclobutanones were obtained in synthetically useful yields from substrates with minimal structural prefunctionalization. This discovery reveals new synthetic utilities of gold‐catalyzed oxidative transformations of alkynones.     

Metal‐ and Oxidant‐Free Alkenyl C−H/Aromatic C−H Cross‐Coupling Using Electrochemically Generated Iodosulfonium Ions

A three‐step transformation consisting of 1) addition of electrochemically generated iodosulfonium ions to vinylarenes to give (1‐aryl‐2‐iodoethoxy)sulfonium ions, 2) nucleophilic substitution by subsequently added aromatic compounds to give 1,1‐diaryl‐2‐iodoethane, and 3) elimination of HI with a base to give 1,1‐diarylethenes was developed. The transformation serves as a powerful metal‐ and chemical‐oxidant‐free method for alkenyl C?H/aromatic C?H cross‐coupling.