Ligand‐Promoted Borylation of C(sp3)H Bonds with Palladium(II) Catalysts

A quinoline‐based ligand effectively promotes the palladium‐catalyzed borylation of C(sp³)? H bonds. Primary β‐C(sp³)? H bonds in carboxylic acid derivatives as well as secondary C(sp³)? H bonds in a variety of carbocyclic rings, including cyclopropanes, cyclobutanes, cyclopentanes, cyclohexanes, and cycloheptanes, can thus be borylated. This directed borylation method complements existing iridium(I)‐ and rhodium(I)‐catalyzed C? H borylation reactions in terms of scope and operational conditions.     

Iron‐Catalyzed C(sp2)H and C(sp3)H Methylations of Amides and Anilides

The so‐called magic methyl effect significantly boosts the bioactivities and physical properties of pharmacologically active drugs. Direct introduction of the methyl group by C?H activation was accomplished with a versatile iron catalyst, which enabled the C?H methylation of (hetero)benzamides, anilides, alkenes, and even alkanes by triazole assistance in a chemo‐, site‐ and diastereo‐selective fashion.     

Sulfonamide‐Promoted Palladium(II)‐Catalyzed Alkylation of Unactivated Methylene C(sp3)H Bonds with Alkyl Iodides

The alkylation of unactivated β‐methylene C(sp³)? H bonds of α‐amino acid substrates with a broad range of alkyl iodides using Pd(OAc)₂ as the catalyst is described. The addition of NaOCN and 4‐Cl‐C₆H₄SO₂NH₂ was found to be crucial for the success of this transformation. The reaction is compatible with a diverse array of functional groups and proceeds with high diastereoselectivity. Furthermore, various β,β‐hetero‐dialkyl‐ and β‐alkyl‐β‐aryl‐α‐amino acids were prepared by sequential C(sp³)? H functionalization of an alanine‐derived substrate, thus providing a versatile strategy for the stereoselective synthesis of unnatural β‐disubstituted α‐amino acids.     

C(sp3)H Activation without a Directing Group: Regioselective Synthesis of N‐Ylide or N‐Heterocyclic Carbene Complexes Controlled by the Choice of Metal and Ligand

N‐Ylide complexes of Ir have been generated by C(sp³)?H activation of α‐pyridinium or α‐imidazolium esters in reactions with [Cp*IrCl₂]₂ and NaOAc. These reactions are rare examples of C(sp³)?H activation without a covalent directing group, which—even more unusually—occur α to a carbonyl group. For the reaction of the α‐imidazolium ester [ 3 H]Cl, the site selectivity of C?H activation could be controlled by the choice of metal and ligand: with [Cp*IrCl₂]₂ and NaOAc, C(sp³)?H activation gave the N‐ylide complex 4 ; in contrast, with Ag₂O followed by [Cp*IrCl₂]₂, C(sp²)?H activation gave the N‐heterocyclic carbene complex 5 . DFT calculations revealed that the N‐ylide complex 4 was the kinetic product of an ambiphilic C?H activation. Examination of the computed transition state for the reaction to give 4 indicated that unlike in related reactions, the acetate ligand appears to play the dominant role in C?H bond cleavage.     

Palladium‐Catalyzed C(sp3)H Activation: A Facile Method for the Synthesis of 3,4‐Dihydroquinolinone Derivatives

3,4‐Dihydroquinolinones were synthesized by the palladium‐catalyzed, oxidative‐addition‐initiated activation and arylation of inert C(sp³)? H bonds. Pd(OAc)₂ and P(o‐tol)₃ were used as the catalyst and ligand, respectively, to improve the efficiency of the reaction. A further advantage of this reaction is that it could be performed in air. A relatively rare seven‐membered palladacycle was proposed as a key intermediate of the catalytic cycle.     

Rhodium(III)‐Catalyzed Alkenylation Reactions of 8‐Methylquinolines with Alkynes by C(sp3)H Activation

The alkenylation reactions of 8‐methylquinolines with alkynes, catalyzed by [{Cp*RhCl₂}₂], proceeds efficiently to give 8‐allylquinolines in good yields by C(sp³)? H bond activation. These reactions are highly regio‐ and stereoselective. A catalytically competent five‐membered rhodacycle has been structurally characterized, thus revealing a key intermediate in the catalytic cycle.     

Chemo‐ and Regioselective C(sp3)H Arylation of Unactivated Allylarenes by Deprotonative Cross‐Coupling

The combination of aryl bromides, allylbenzene, base and a palladium catalyst usually results in a Heck reaction. Herein we combine these same reagents, but override the Heck pathway by employing a strong base. In the presence of LiN(SiMe₃)₂, allylbenzene derivatives undergo reversible deprotonation. Transmetalation of the resulting allyllithium intermediate to LPdAr(Br) and reductive elimination provide the 1,1‐diarylprop‐2‐enes, which are not accessible by the Heck reaction. The regioselectivity in this deprotonative cross‐coupling process is catalyst‐controlled and very high.     

Iron‐Catalyzed C(sp2)H and C(sp3)H Arylation by Triazole Assistance

Modular 1,2,3‐triazoles enabled iron‐catalyzed C? H arylations with broad scope. The novel triazole‐based bidentate auxiliary is easily accessible in a highly modular fashion and allowed for user‐friendly iron‐catalyzed C(sp²)? H functionalizations of arenes and alkenes with excellent chemo‐ and diastereoselectivities. The versatile iron catalyst also proved applicable for challenging C(sp³)? H functionalizations, and proceeds by an organometallic mode of action. The triazole‐assisted C? H activation strategy occurred under remarkably mild reaction conditions, and the auxiliary was easily removed in a traceless fashion. Intriguingly, the triazole group proved superior to previously used auxiliaries.     

Palladium(0)/PAr3‐Catalyzed Intermolecular Amination of C(sp3)H Bonds: Synthesis of β‐Amino Acids

An intermolecular C(sp³)? H amination using a Pd⁰/PAr₃ catalyst was developed. The reaction begins with oxidative addition of R₂N? OBz to a Pd⁰/PAr₃ catalyst and subsequent cleavage of a C(sp³)? H bond by the generated Pd? NR₂ intermediate. The catalytic cycle proceeds without the need for external oxidants in a similar manner to the extensively studied palladium(0)‐catalyzed C? H arylation reactions. The electron‐deficient triarylphosphine ligand is crucial for this C(sp³)? H amination reaction to occur.     

Copper‐Catalyzed Intramolecular C(sp3)H and C(sp2)H Amidation by Oxidative Cyclization

The first copper‐catalyzed intramolecular C(sp³)? H and C(sp²)? H oxidative amidation has been developed. Using a Cu(OAc)₂ catalyst and an Ag₂CO₃ oxidant in dichloroethane solvent, C(sp³)? H amidation proceeded at a terminal methyl group, as well as at the internal benzylic position of an alkyl chain. This reaction has a broad substrate scope, and various β‐lactams were obtained in excellent yield, even on gram scale. Use of CuCl₂ and Ag₂CO₃ under an O₂ atmosphere in dimethyl sulfoxide, however, leads to 2‐indolinone selectively by C(sp²)? H amidation. Kinetic isotope effect (KIE) studies indicated that C? H bond activation is the rate‐determining step. The 5‐methoxyquinolyl directing group could be removed by oxidation.     

A General and Scalable Synthesis of Aeruginosin Marine Natural Products Based on Two Strategic C(sp3)H Activation Reactions

An efficient and scalable access to the aeruginosin family of marine natural products, which exhibit potent inhibitory activity against serine proteases, is reported. This synthesis was enabled by the strategic use of two different, recently implemented C(sp³)? H activation reactions. The first method led to the common 2‐carboxy‐6‐hydroxyoctahydroindole (Choi) core of the target molecules on a large scale, whereas the second one provided rapid and divergent access to the various hydroxyphenyllactic (Hpla) subunits. This strategy allowed the synthesis of the aeruginosins 98B and 298A, with the latter being obtained in unprecedentedly large quantities.     

Transition Metal‐Catalyzed Carbonylative CH Bond Functionalization of Arenes and C(sp3)H Bond of Alkanes

In this article, we present the progress made in the area of carbonylative C? H functionalization, with special emphasis on arenes and alkanes. The importance of directing group assistance and C? H functionalization using CO surrogates is also included. The budding development in the area of transition metal‐catalyzed C(sp³)? H activation makes us feel it necessary to file a summary on the past, as well as current, contributions and a prospective outlook on the transition metal‐catalyzed carbonylative transformation of C? H bonds, which is the focus of this review.     

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.     

Access to β‐Lactams by Enantioselective Palladium(0)‐Catalyzed C(sp3)H Alkylation

β‐Lactams are very important structural motifs because of their broad biological activities as well as their propensity to engage in ring‐opening reactions. Transition‐metal‐catalyzed C? H functionalizations have emerged as strategy enabling yet uncommon highly efficient disconnections. In contrast to the significant progress of Pd⁰‐catalyzed C? H functionalization for aryl–aryl couplings, related reactions involving the formation of saturated C(sp³)? C(sp³) bonds are elusive. Reported here is an asymmetric C? H functionalization approach to β‐lactams using readily accessible chloroacetamide substrates. Important aspects of this transformation are challenging C(sp³)? C(sp³) and strain‐building reductive eliminations to for the four‐membered ring. In general, the β‐lactams are formed in excellent yields and enantioselectivities using a bulky taddol phosphoramidite ligand in combination with adamantyl carboxylic acid as cocatalyst.     

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.     

Room‐Temperature ortho‐Alkoxylation and ‐Halogenation of N‐Tosylbenzamides by Using Palladium(II)‐Catalyzed CH Activation

The N‐tosylcarboxamide group can direct the room‐temperature palladium‐catalyzed C?H alkoxylation and halogenation of substituted arenes in a simple and mild procedure. The room‐temperature stoichiometric cyclopalladation of N‐tosylbenzamide was first studied, and the ability of the palladacycle to react with oxidants to form C?X and C?O bonds under mild conditions was demonstrated. The reaction conditions were then adapted to promote room‐temperature ortho‐alkoxylations and ortho‐halogenations of N‐tosylbenzamides using palladium as catalyst. The scope and limitation of both alkoxylations and halogenations was studied and the subsequent functional transformation of the N‐tosylcarboxamide group through nucleophilic additions was evaluated. This methodology offers a simple and mild route to diversely functionalized arenes.     

Silver‐Catalyzed Oxidative Activation of Benzylic CH Bonds for the Synthesis of Difluoromethylated Arenes

A mild and catalytic method to form difluoromethylated arenes through the activation of benzylic C? H bonds has been developed. Utilizing AgNO₃ as the catalyst, various arenes with diverse functional groups undergo activation/fluorination of benzylic C? H bonds with commercially available Selectfluor reagent as a source of fluorine in aqueous solution. The reaction is operationally simple and amenable to gram‐scale synthesis.