MnI/AgI Relay Catalysis: Traceless Diazo‐Assisted C(sp2)–H/C(sp3)–H Coupling to β‐(Hetero)Aryl/Alkenyl Ketones

An unprecedented Mn^I/Ag^I‐relay‐catalyzed C(sp²)?H/C(sp³)?H coupling of (vinyl)arenes with α‐diazoketones is reported, wherein the diazo group was exploited as a traceless auxiliary for control of regioselectivity. Challenging β‐(hetero)aryl/alkenyl ketones were obtained through this operationally simple approach. The cascade process merges denitrogenation, carbene rearrangement, C?H activation, and hydroarylation/hydroalkenylation. The robustness of this method was demonstrated at preparative scale and applied to late‐stage diversification of natural products.     

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.     

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.     

α‐Aminoxy‐Acid‐Auxiliary‐Enabled Intermolecular Radical γ‐C(sp3)−H Functionalization of Ketones

A method for site‐specific intermolecular γ‐C(sp³)?H functionalization of ketones has been developed using an α‐aminoxy acid auxiliary applying photoredox catalysis. Regioselective activation of an inert C?H bond is achieved by 1,5‐hydrogen atom abstraction by an oxidatively generated iminyl radical. Tertiary and secondary C‐radicals thus formed at the γ‐position of the imine functionality undergo radical conjugate addition to various Michael acceptors to provide, after reduction and imine hydrolysis, the corresponding γ‐functionalized ketones.     

Synthesis of 3,4‐Fused Tricyclic Indoles Using 3‐Alkylidene Indolines as Versatile Precursors

In this personal account, our recent studies of novel synthetic methods of 3,4‐fused tricyclic indole derivatives using 3‐alkylidene indoline derivatives as versatile precursors are discussed. Two types of cascade reactions producing 3,4‐fused tricyclic 3‐alkylidene indolines were developed based on a palladium‐catalyzed intramolecular Heck insertion to an allene‐allylic amination cascade and a platinum‐catalyzed intramolecular Friedel‐Crafts type C?H coupling‐allylic amination cascade. Furthermore, three types of 3,4‐fused tricyclic indoles were accessible from a single 3‐alkylidene indoline precursor via acid‐promoted olefin isomerization or oxidative treatments. The application of the developed methods to the synthesis of natural products bearing a 3,4‐fused tricyclic indole skeleton, (?)‐aurantioclavine, fargesine, and synthetic studies of dragmacidin E are also highlighted.     

Direct Regio‐ and Diastereoselective Synthesis of δ‐Lactams from Acrylamides and Unactivated Alkenes Initiated by RhIII‐Catalyzed C−H Activation

We report a Rh^III‐catalyzed regio‐ and diastereoselective synthesis of δ‐lactams from readily available acrylamide derivatives and unactivated alkenes. The reaction provides a rapid route to a diverse set of δ‐lactams in good yield and stereoselectivity, which serve as useful building blocks for substituted piperidines. The regioselectivity of the reaction with unactivated terminal alkene is significantly improved by using Cp^t ligand on the Rh^III catalyst. The synthetic utility of the reaction is demonstrated by the preparation of a potential drug candidate containing a trisubstituted piperidine moiety. Mechanistic studies show that the reversibility of the C?H activation depends on the choice of Cp ligand on the Rh^III catalyst. The irreversible C?H activation is observed and becomes turnover‐limiting with [Cp^tRhCl₂]₂ as catalyst.     

Easily Accessible Auxiliary for Palladium‐Catalyzed Intramolecular Amination of C(sp2)H and C(sp3)H Bonds at δ‐ and ε‐Positions

An easily synthesized and accessible N,O‐bidentate auxiliary has been developed for selective C? H activation under palladium catalysis. The novel auxiliary showed its first powerful application in C? H functionalization of remote positions. Both C(sp²)? H and C(sp³)? H bonds at δ‐ and ε‐positions were effectively activated, thus giving tetrahydroquinolines, benzomorpholines, pyrrolidines, and indolines in moderate to excellent yields by palladium‐catalyzed intramolecular C? H amination.     

Activation of CH Bonds through Oxidant‐Free Photoredox Catalysis: Cross‐Coupling Hydrogen‐Evolution Transformation of Isochromans and β‐Keto Esters

The direct and controlled activation of a C(sp³)?H bond adjacent to an O atom is of particular synthetic value for the conventional derivatization of ethers or alcohols. In general, stoichiometric amounts of an oxidant are required to remove an electron and a hydrogen atom of the ether for subsequent transformations. Herein, we demonstrate that the activation of a C?H bond next to an O atom could be achieved under oxidant‐free conditions through photoredox‐neutral catalysis. By using a commercial dyad photosensitizer (Acr⁺‐Mes ClO₄^?, 9‐mesityl‐10‐methylacridinium perchlorate) and an easily available cobaloxime complex (Co(dmgBF₂)₂?2 MeCN, dmg=dimethylglyoxime), the nucleophilic addition of β‐keto esters to oxonium species, which is rarely observed in photocatalysis, leads to the corresponding coupling products and H₂ in moderate to good yields under visible‐light irradiation. Mechanistic studies suggest that both isochroman and the cobaloxime complex quench the electron‐transfer state of this dyad photosensitizer and that benzylic C?H bond cleavage is probably the rate‐determining step of this cross‐coupling hydrogen‐evolution transformation.     

Divergent and Stereoselective Synthesis of β‐Silyl‐α‐Amino Acids through Palladium‐Catalyzed Intermolecular Silylation of Unactivated Primary and Secondary C−H Bonds

A general and practical Pd^II‐catalyzed intermolecular silylation of primary and secondary C?H bonds of α‐amino acids and simple aliphatic acids is reported. This method provides divergent and stereoselective access to a variety of optical pure β‐silyl‐α‐amino acids, which are useful for genetic technologies and proteomics. It can also be readily performed on a gram scale and the auxiliary can be easily removed with retention of configuration. The synthetic importance of this method is further demonstrated by the late‐stage functionalization of biological small molecules, such as (?)‐santonin and β‐cholic acid. Moreover, several key palladacycles were successfully isolated and characterized to elucidate the mechanism of this β?C(sp³)‐H silylation process.     

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.     

Ligand‐Enabled Triple CH Activation Reactions: One‐Pot Synthesis of Diverse 4‐Aryl‐2‐quinolinones from Propionamides

Diverse 4‐aryl‐2‐quinolinones are prepared from propionamides in one pot by ligand‐promoted triple sequential C? H activation reactions and a stereospecific Heck reaction. In these cascade reactions, three new C? C bonds and one C? N bond are formed to rapidly build molecular complexity from propionic acid.     

RhIII‐Catalyzed Hydroacylation Reactions between N‐Sulfonyl 2‐Aminobenzaldehydes and Olefins

Metal‐catalyzed hydroacylation of olefins represents an important atom‐economic synthetic process in C?H activation. For the first time highly efficient Rh^IIICp*‐catalyzed hydroacylation was realized in the coupling of N‐sulfonyl 2‐aminobenzaldehydes with both conjugated and aliphatic olefins, leading to the synthesis of various aryl ketones. Occasionally, oxidative coupling occurred when a silver(I) oxidant was used.     

Manganese(I)‐Catalyzed C−H Activation: The Key Role of a 7‐Membered Manganacycle in H‐Transfer and Reductive Elimination

Manganese‐catalyzed C?H bond activation chemistry is emerging as a powerful and complementary method for molecular functionalization. A highly reactive seven‐membered Mn^I intermediate is detected and characterized that is effective for H‐transfer or reductive elimination to deliver alkenylated or pyridinium products, respectively. The two pathways are determined at Mn^I by judicious choice of an electron‐deficient 2‐pyrone substrate containing a 2‐pyridyl directing group, which undergoes regioselective C?H bond activation, serving as a valuable system for probing the mechanistic features of Mn C?H bond activation chemistry.     

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.     

Synthesis of Extended π‐Systems through C–H Activation

Activation of aromatic C? H bonds by a transition metal catalyst has received significant attention in the synthetic chemistry community. In recent years, rapid and site‐selective extension of π‐electron systems by C–H activation has emerged as an ideal methodology for preparing organic materials with extended π‐systems. This Review focuses on recently reported π‐extending C–H activation reactions directed toward new optoelectronic conjugated materials.     

Triiodide‐Mediated δ‐Amination of Secondary C−H Bonds

The C_δ?H amination of unactivated, secondary C?H bonds to form a broad range of functionalized pyrrolidines has been developed by a triiodide (I₃^?)‐mediated strategy. By in situ 1) oxidation of sodium iodide and 2) sequestration of the transiently generated iodine (I₂) as I₃^?, this approach precludes undesired I₂‐mediated decomposition which can otherwise limit synthetic utility to only weak C(sp³)?H bonds. The mechanism of this triiodide‐mediated cyclization of unbiased, secondary C(sp³)?H bonds, by either thermal or photolytic initiation, is supported by NMR and UV/Vis data, as well as intercepted intermediates.     

Palladium‐Catalyzed γ‐C(sp3)−H Arylation of Thiols by a Detachable Protecting/Directing Group

Reported herein is a palladium‐catalyzed, directed γ‐C(sp³)?H arylation of protected thiols. The key is to utilize Michael acceptors as a dual reagent to install a protecting/directing group on thiols by a thiol‐Michael click reaction, and remove it later under basic conditions. The C?H arylation proceeds with high functional‐group tolerance and the deprotected thiols can be further transformed into other sulfur‐containing compounds. This unique mode of activation could open the door for site‐selective functionalization of thiols or other sulfur‐containing compounds at unactivated positions.     

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.     

η3‐Allyl Coordination at Tin(II)—Reactivity towards Alkynes and Benzonitrile

We herein report the synthesis and characterization of a terphenyl‐substituted Sn^II allyl compound featuring an η³ coordination mode in solution and in the solid state. Two examples for the interesting reactivity of the allyl Sn^II molecule are presented: Reactions with terminal alkynes result in the formation of tricyclic compounds by C? C bond formation and the dimerization of two Sn moieties whereas the reaction with benzonitrile leads to a sixteen‐membered ring system through C? H activation.     

Practical Synthesis of anti‐β‐Hydroxy‐α‐Amino Acids by PdII‐Catalyzed Sequential C(sp3)H Functionalization

An improved and practical procedure for the stereoselective synthesis of anti‐β‐hydroxy‐α‐amino acids (anti‐βhAAs), by palladium‐catalyzed sequential C(sp³)?H functionalization directed by 8‐aminoquinoline auxiliary, is described. followed by a previously established monoarylation and/or alkylation of the β‐methyl C(sp³)?H of alanine derivative, β‐acetoxylation of both alkylic and benzylic methylene C(sp³)?H bonds affords various anti‐β‐hydroxy‐α‐amino acid derivatives. As an example, the synthesis of β‐mercapto‐α‐amino acids, which are highly important to the extension of native chemical ligation chemistry beyond cysteine, is described. The synthetic potential of this protocol is further demonstrated by the synthesis of diverse β‐branched α‐amino acids. The observed diastereoselectivities are strongly influenced by electronic effects of aromatic AAs and steric effects of the linear side‐chain AAs, which could be explained by the competition of intramolecular C?OAc bond reductive elimination from Pd^IV intermediates vs. intermolecular attack by an external nucleophile (AcO^?) in an S_N2‐type process.