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.     

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.     

Triazole‐Assisted Ruthenium‐Catalyzed CH Arylation of Aromatic Amides

Site‐selective ruthenium(II)‐catalyzed direct arylation of amides was achieved through C?H cleavages with modular auxiliaries, derived from easily accessible 1,2,3‐triazoles. The triazolyldimethylmethyl (TAM) bidentate directing group was prepared in a highly modular fashion through copper(I)‐catalyzed 1,3‐dipolar cycloaddition and allowed for ruthenium‐catalyzed C?H arylations on arenes and heteroarenes, as well as alkenes, by using easy‐to‐handle aryl bromides as the arylating reagents. The triazole‐assisted C?H activation strategy was found to be widely applicable, to occur under mild reaction conditions, and the catalytic system was tolerant of important electrophilic functionalities. Notably, the flexible triazole‐based auxiliary proved to be a more potent directing group for the optimized ruthenium(II)‐catalyzed direct arylations, compared with pyridyl‐substituted amides or substrates derived from 8‐aminoquinoline.     

Cobalt‐Catalyzed,Aminoquinoline‐Directed C(sp2)H Bond Alkenylation by Alkynes

A method for cobalt‐catalyzed, aminoquinoline‐ and picolinamide‐directed C(sp²)? H bond alkenylation by alkynes was developed. The method shows excellent functional‐group tolerance and both internal and terminal alkynes are competent substrates for the coupling. The reaction employs a Co(OAc)₂?4 H₂O catalyst, Mn(OAc)₂ co‐catalyst, and oxygen (from air) as a terminal oxidant.     

Synthesis of Pyrrolophenanthridine Alkaloids Based on C(sp3)H and C(sp2)H Functionalization Reactions

Assoanine, pratosine, hippadine, and dehydroanhydrolycorine belong to the pyrrolophenanthridine family of alkaloids, which are isolated from plants of the Amaryllidaceae species. Structurally, these alkaloids are characterized by a tetracyclic skeleton that contains a biaryl moiety and an indole core, and compounds belonging to this class have received considerable interest from researchers in a number of fields because of their biological properties and the challenges associated with their synthesis. Herein, a strategy for the total synthesis of these alkaloids by using C? H activation chemistry is described. The tetracyclic skeleton was constructed in a stepwise manner by C(sp³)? H functionalization followed by a Catellani reaction, including C(sp²)? H functionalization. A one‐pot reaction involving both C(sp³)? H and C(sp²)? H functionalization was also attempted. This newly developed strategy is suitable for the facile preparation of various analogues because it uses simple starting materials and does not require protecting groups.     

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.     

Redox‐Neutral Rhodium‐Catalyzed CH Functionalization of Arylamine N‐Oxides with Diazo Compounds: Primary C(sp3)H/C(sp2)H Activation and Oxygen‐Atom Transfer

An unprecedented rhodium(III)‐catalyzed regioselective redox‐neutral annulation reaction of 1‐naphthylamine N‐oxides with diazo compounds was developed to afford various biologically important 1H‐benzo[g]indolines. This coupling reaction proceeds under mild reaction conditions and does not require external oxidants. The only by‐products are dinitrogen and water. More significantly, this reaction represents the first example of dual functiaonalization of unactivated a primary C(sp³)? H bond and C(sp²)? H bond with diazocarbonyl compounds. DFT calculations revealed that an intermediate iminium is most likely involved in the catalytic cycle. Moreover, a rhodium(III)‐catalyzed coupling of readily available tertiary aniline N‐oxides with α‐diazomalonates was also developed under external oxidant‐free conditions to access various aminomandelic acid derivatives by an O‐atom‐transfer reaction.     

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.     

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.     

Palladium‐Catalyzed Cross‐Dehydrogenative Functionalization of C(sp2)H Bonds

The catalytic cross‐dehydrogenative coupling (CDC) reaction has received intense attention in recent years. The attractive feature of this coupling process is the formation of a C? C bond from two C? H moieties under oxidative conditions. In this Focus Review, recent advances in the palladium‐catalyzed CDC reactions of C(sp²)? H bond are summarized, with a focus on the period from 2011 to early 2013.     

Manganese‐Catalyzed Direct Nucleophilic C(sp2)H Addition to Aldehydes and Nitriles

Herein, a manganese‐catalyzed nucleophilic addition of inert C(sp²)? H bonds to aldehydes and nitriles is disclosed by virtue of a dual activation strategy. The reactions feature mild reaction conditions, excellent regio‐ and stereoselectivity, and a wide substrate scope, which includes both aromatic and olefinic C? H bonds, as well as a large variety of aldehydes and nitriles. Moreover, mechanistic studies shed light on possible catalytic cycles.     

Cobalt‐Catalyzed C(sp2)H Alkoxylation of Aromatic and Olefinic Carboxamides

The cobalt‐catalyzed alkoxylation of C(sp²)? H bonds in aromatic and olefinic carboxamides has been developed. The reaction proceeded under mild conditions in the presence of Co(OAc)₂?4H₂O as the catalyst and tolerates a wide range of both alcohols and benzamide substrates, including even olefinic carboxamides. In addition, this reaction is the first example of the direct alkoxylation of alkenes through C? H bond activation.     

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.     

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.     

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.     

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.     

Asymmetric Organocatalytic Direct C(sp2)H/C(sp3)H Oxidative Cross‐Coupling by Chiral Iodine Reagents

An asymmetric organocatalytic direct C? H/C? H oxidative coupling reaction of N¹,N³‐diphenylmalonamides has been well established by using chiral organoiodine compounds as catalysts, wherein four C? H bonds were stereoselectively functionalized to give structurally diverse spirooxindoles with high levels of enantioselectivity. More importantly, the findings indicated that chiral hypervalent organoiodine reagents can serve as alternative catalysts for the creation of enantioselective functionalization of inactive C? H bonds.