Copper‐Catalyzed Site‐Selective Intramolecular Amidation of Unactivated C(sp3)H Bonds

The intramolecular dehydrogenative amidation of aliphatic amides, directed by a bidentate ligand, was developed using a copper‐catalyzed sp³ C? H bond functionalization process. The reaction favors predominantly the C? H bonds of β‐methyl groups over the unactivated methylene C? H bonds. Moreover, a preference for activating sp³ C? H bonds of β‐methyl groups, via a five‐membered ring intermediate, over the aromatic sp² C? H bonds was also observed in the cyclometalation step. Additionally, sp³ C? H bonds of unactivated secondary sp³ C? H bonds could be functionalized by favoring the ring carbon atoms over the linear carbon atoms.     

Microtubing‐Reactor‐Assisted Aliphatic C−H Functionalization with HCl as a Hydrogen‐Atom‐Transfer Catalyst Precursor in Conjunction with an Organic Photoredox Catalyst

Chlorine radical, which is classically generated by the homolysis of Cl₂ under UV irradiation, can abstract a hydrogen atom from an unactivated C(sp³)?H bond. We herein demonstrate the use of HCl as an effective hydrogen‐atom‐transfer catalyst precursor activated by an organic acridinium photoredox catalyst under visible‐light irradiation for C?H alkylation and allylation. The key to success relied on the utilization of microtubing reactors to maintain the volatile HCl catalyst. This photomediated chlorine‐based C?H activation protocol is effective for a variety of unactivated C(sp³)?H bond patterns, even with primary C(sp³)?H bonds, as in ethane. The merit of this strategy is illustrated by rapid access to several pharmaceutical drugs from abundant unfunctionalized alkane feedstocks.     

Cu‐Catalyzed Intramolecular Amidation of Unactivated C(sp3)−H Bonds To Synthesize N‐Substituted Indolines

A copper‐catalyzed intramolecular amidation of unactivated C(sp³)?H bonds to construct indoline derivatives has been developed. Such an amidation proceeded well at primary C?H bonds preferred to secondary C?H bonds. The transformation owned a broad substrate scope. The corresponding indolines were obtained in good to excellent yields. N‐Formal and other carbonyl groups were suitable and were easily deprotected and transformed into methyl or long‐chained alkyl groups. Preliminary mechanistic studies suggested a radical pathway.     

Transition Metal‐Catalyzed Dicarbofunctionalization of Unactivated Olefins

Transition metal (TM)‐catalyzed difunctionalization of unactivated olefins with two carbon‐based entities is a powerful method to construct complex molecular architectures rapidly from simple and readily available feedstock chemicals. While dicarbofunctionalization of unactivated olefins has a long history typically with the use of either carbon monoxide to intercept C(sp³)‐[M] (alkyl‐TM) species or substrates lacking in β‐hydrogen (β‐Hs), development of this class of reaction still remains seriously limited due to complications of β‐H elimination arising from the in situ‐generated C(sp³)‐[M] intermediates. Over the years, different approaches have been harnessed to suppress β‐H elimination, which have led to the development of various types of olefin dicarbofunctionalization reactions even in substrates that generate C(sp³)‐[M] intermediates bearing β‐Hs with a wide range of electrophiles and nucleophiles. In this review, these developments will be discussed both through the lens of historical perspectives as well as the strategies scrutinized over the years to address the issue of β‐H elimination. However, this review article by no means is designed to be exhaustive in the field, and is merely presented to provide the readers an overview of the key reaction developments.     

Palladium‐Catalyzed Arylation of Unactivated γ‐Methylene C(sp3)H and δ‐CH Bonds with an Oxazoline‐Carboxylate Auxiliary

A palladium‐catalyzed arylation of unactivated γ‐methylene C(sp³)?H and remote δ‐C?H bonds by using an oxazoline‐carboxylate directing group has been developed. Arylation occurs with a broad substrate scope and high tolerance of functional groups (i.e., halogen, nitro, cyano, ether, trifluoromethyl, amine, and ester). The oxazoline‐type auxiliary can be removed under acidic conditions.     

Copper‐Promoted Site‐Selective Acyloxylation of Unactivated C(sp3)H Bonds

The site‐selective acyloxylation of aliphatic amides was achieved via a copper‐promoted C(sp³)? H bond functionalization process directed by a bidentate ligand. The reaction showed a great preference for activating C? H bonds of β‐methyl groups over those of γ‐methyl and unactivated methylene groups.     

Nickel‐Catalyzed Site‐Selective Amidation of Unactivated C(sp3)H Bonds

Intramolecular dehydrogenative cyclization of aliphatic amides was achieved on unactivated sp³ carbon atoms by a nickel‐catalyzed C?H bond functionalization process with the assistance of a bidentate directing group. The reaction favors the C?H bonds of β‐methyl groups over the γ‐methyl or β‐methylene groups. Additionally, a predominant preference for the β‐methyl C?H bonds over the aromatic sp² C?H bonds was observed. Moreover, this process also allows for the effective functionalization of benzylic secondary sp³ C?H bonds.     

Site‐Selective δ‐C(sp3)−H Alkylation of Amino Acids and Peptides with Maleimides via a Six‐Membered Palladacycle

The site‐selective functionalization of unactivated C(sp³)?H bonds remains one of the greatest challenges in organic synthesis. Herein, we report on the site‐selective δ‐C(sp³)?H alkylation of amino acids and peptides with maleimides via a kinetically less favored six‐membered palladacycle in the presence of more accessible γ‐C(sp³)?H bonds. Experimental studies revealed that C?H bond cleavage occurs reversibly and preferentially at γ‐methyl over δ‐methyl C?H bonds while the subsequent alkylation proceeds exclusively at the six‐membered palladacycle that is generated by δ‐C?H activation. The selectivity can be explained by the Curtin–Hammett principle. The exceptional compatibility of this alkylation with various oligopeptides renders this procedure valuable for late‐stage peptide modifications. Notably, this process is also the first palladium(II)‐catalyzed Michael‐type alkylation reaction that proceeds through C(sp³)?H activation.     

2,4‐Dinitrophenol‐Catalyzed α‐C(sp3)−H and C(sp)−H Bond Functionalization of Cyclic Amines and Alkynes: Highly Regio‐/Diastereoselective Synthesis of α‐Alkynyl‐3‐Amino‐2‐Oxindoles

A transition‐metal‐ and oxidant‐free DNP (2,4‐dinitrophenol)‐catalyzed atom‐economical regio‐ and diastereoselective synthesis of monofunctionalized α‐alkynyl‐3‐amino‐2‐oxindole derivatives by C?H bond functionalization of cyclic amines and alkynes with indoline‐2,3‐diones has been developed. This cascade event sequentially involves the reductive amination of indoline‐2,3‐dione by imine formation and cross coupling between C(sp³)?H and C(sp)?H of the cyclic amines and alkynes. This reaction offers an efficient and attractive pathway to different types of α‐alkynyl‐3‐amino‐2‐oxindole derivatives in good yields with a wide tolerance of functional groups. The salient feature of this methodology is that it completely suppresses the homocoupling of alkynes. To the best of our knowledge, this is the first example of a DNP‐catalyzed metal‐free direct C(sp³)?H and C(sp)?H bond functionalization providing biologically active α‐alkynyl‐3‐amino‐2‐oxindole scaffolds.     

Directing‐Group‐mediated C−H‐Alkynylations

C?C triple bonds are amongst the most versatile functional groups in synthetic chemistry. Complementary to the Sonogashira coupling the direct metal‐catalyzed alkynylation of C?H bonds has emerged as a highly promising approach in recent years. To guarantee a high regioselectivity suitable directing groups (DGs) are necessary to guide the transition metal (TM) into the right place. In this Focus Review we present the current developments in DG‐mediated C(sp²)?H and C(sp³)?H modifications with terminal alkynes under oxidative conditions and with electrophilic alkynylation reagents. We will discuss further modifications of the alkyne, in particular subsequent cyclizations to carbo‐ and heterocycles and modifications of the DG in the presence of the alkyne.     

Complementary Strategies for Directed C(sp3)−H Functionalization: A Comparison of Transition‐Metal‐Catalyzed Activation,Hydrogen Atom Transfer,and Carbene/Nitrene Transfer

The functionalization of C(sp³)?H bonds streamlines chemical synthesis by allowing the use of simple molecules and providing novel synthetic disconnections. Intensive recent efforts in the development of new reactions based on C?H functionalization have led to its wider adoption across a range of research areas. This Review discusses the strengths and weaknesses of three main approaches: transition‐metal‐catalyzed C?H activation, 1,n‐hydrogen atom transfer, and transition‐metal‐catalyzed carbene/nitrene transfer, for the directed functionalization of unactivated C(sp³)?H bonds. For each strategy, the scope, the reactivity of different C?H bonds, the position of the reacting C?H bonds relative to the directing group, and stereochemical outcomes are illustrated with examples in the literature. The aim of this Review is to provide guidance for the use of C?H functionalization reactions and inspire future research in this area.     

Visible‐Light‐Mediated Remote Aliphatic C−H Functionalizations through a 1,5‐Hydrogen Transfer Cascade

A redox‐neutral, light‐mediated functionalization of unactivated C(sp³)−H bonds via iminyl radicals is presented here. A 1,5‐H transfer followed by the functionalization of a C(sp²)−H bond takes place in aqueous media producing a variety of elaborated fused ketones. Mechanistic investigations have revealed 1,5‐H transfer as the reversible, rate‐determining step in this transformation. Divergent scaffolds are also accessible via C(sp³)−N bond formation upon a careful choice of the reaction additives.     

Regioselective Vinylation of Remote Unactivated C(sp3)−H Bonds: Access to Complex Fluoroalkylated Alkenes

Regioselective incorporation of a particular functional group into aliphatic sites by direct activation of unreactive C?H bonds is of great synthetic value. Despite advances in radical‐mediated functionalization of C(sp³)?H bonds by a hydrogen‐atom transfer process, the site‐selective vinylation of remote C(sp³)?H bonds still remains underexplored. Reported herein is a new protocol for the regioselective vinylation of unactivated C(sp³)?H bonds. The remote C(sp³)?H activation is promoted by a C‐centered radical instead of the commonly used N and O radicals. The reaction possesses high product diversity and synthetic efficiency, furnishing a plethora of synthetically valuable E alkenes bearing tri‐/di‐/mono‐fluoromethyl and perfluoroalkyl groups.     

A Highly Efficient Gold‐Catalyzed Photoredox α‐C(sp3)H Alkynylation of Tertiary Aliphatic Amines with Sunlight

A new α‐C(sp³)? H alkynylation of unactivated tertiary aliphatic amines with 1‐iodoalkynes as radical alkynylating reagents in the presence of [Au₂(μ‐dppm)₂]²⁺ in sunlight provides propargylic amines. Based on mechanistic studies, a C? C coupling of an α‐aminoalkyl radical and an alkynyl radical is proposed for the C(sp³)? C(sp) bond formation. The mild, convenient, efficient, and highly selective C(sp³)? H alkynylation reaction shows excellent regioselectivity and good functional‐group compatibility. A scale‐up to gram quantities is possible with sunlight used as a clean and sustainable energy source.     

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.     

Manganese‐Catalyzed Redox‐Neutral C−H Olefination of Ketones with Unactivated Alkenes

Since 1987, stoichiometric cyclomanganation of ketones and subsequent reactions with olefins in the presence of either palladium salts or trimethylamine N‐oxide (Me₃N⁺O^?) have been reported, but the catalytic versions remain untouched so far. Herein, the first manganese‐catalyzed redox‐neutral C?H olefination of ketones with unactivated alkenes is described, and shows a distinct reactivity with its parent stoichimetric reactions. Remarkably, mechanistic experiments and DFT calculations uncovers a unique concerted bis‐metalation deprotonation (CBMD) mechanism of the Mn‐Zn‐enabled C?H bond activation.     

Copper‐Catalyzed Alkylarylation of Unactivated Alkenes: Synthesis of 3‐Alkyl Indolines from N‐Allyl Anilines and Alkanes

A rare example of C(sp³)?H functionalization of simple alkanes with unactivated alkenes is presented. In the presence of a copper salt and di‐tert‐butyl peroxide (DTBP), N‐allyl anilines underwent exo‐selective alkylation/cyclization cascade with unactivated alkenic bonds as radical acceptors and simple alkanes as radical precursors, providing a direct access to 3‐alkyl indolines. The present protocol features simple operation, broad substrate scope and great exo selectivity.     

Rhodium(III)‐Catalyzed [3+2] Annulation of 5‐Aryl‐2,3‐dihydro‐1H‐pyrroles with Internal Alkynes through C(sp2)H/Alkene Functionalization

This study describes a new rhodium(III)‐catalyzed [3+2] annulation of 5‐aryl‐2,3‐dihydro‐1H‐pyrroles with internal alkynes using a Cu(OAc)₂ oxidant for building a spirocyclic ring system, which includes the functionalization of an aryl C(sp²)? H bond and addition/protonolysis of an alkene C?C bond. This method is applicable to a wide range of 5‐aryl‐2,3‐dihydro‐1H‐pyrroles and internal alkynes, and results in the assembly of the spiro[indene‐1,2′‐pyrrolidine] architectures in good yields with excellent regioselectivities.     

Lewis Acid Mediated Vinyl‐Transfer Reaction of Alkynes to N‐Alkylimines by Using the N‐Alkyl Residue as a Sacrificial Hydrogen Donor

A variety of N‐alkyl‐α,α‐dichloroaldimines were vinylated by terminal acetylenes in the presence of Lewis acids such as In(OTf)₃ or BF₃ ? OEt₂ and hexafluoroisopropanol (HFIP) as an additive. The reaction proceeds at ambient temperature and leads to geometrically pure allylic β,β‐dichloroamines. This approach is complementary to previously reported transition‐metal‐catalyzed vinyl‐transfer methods, which are not applicable to aliphatic imines and are restricted to imines that contain an electron‐withdrawing nitrogen substituent. In the present approach, terminal alkynes were used as a source of the vinyl residue, and the N‐alkyl moiety of the imine acts as a sacrificial hydrogen donor. The additional advantage of this methodology is the fact that no external toxic or hazardous reducing agents or molecular hydrogen has to be used. This new methodology nicely combines a C(sp²)? C(sp) bond formation, hydride transfer, and an unusual cleavage of an unactivated C? N bond, thereby giving rise to functionalized primary allylic amines. A detailed experimental study supported by DFT calculations of the mechanism has been done.     

PdII‐Catalyzed Intermolecular Amination of Unactivated C(sp3)H Bonds

Pd^II‐catalyzed intermolecular amination of unactivated C(sp³)?H bonds has been successfully developed for the first time. This method provides a new way to achieve the challenging intermolecular amination of unactivated C(sp³)?H bonds, producing a variety of unnatural β²‐amino carboxylic acid analogues. This C(sp³)?H amination protocol is demonstrated with a broad substrate scope, good functional‐group tolerance, and chemoselectivity. It is operated without use of phosphine ligand or external oxidant.