Distal γ‐C(sp3)−H Olefination of Ketone Derivatives and Free Carboxylic Acids

Reported herein is the distal γ‐C(sp³)?H olefination of ketone derivatives and free carboxylic acids. Fine tuning of a previously reported imino‐acid directing group and using the ligand combination of a mono‐N‐protected amino acid (MPAA) and an electron‐deficient 2‐pyridone were critical for the γ‐C(sp³)?H olefination of ketone substrates. In addition, MPAAs enabled the γ‐C(sp³)?H olefination of free carboxylic acids to form diverse six‐membered lactones. Besides alkyl carboxylic acids, benzylic C(sp³)?H bonds also could be functionalized to form 3,4‐dihydroisocoumarin structures in a single step from 2‐methyl benzoic acid derivatives. The utility of these protocols was demonstrated in large scale reactions and diversification of the γ‐C(sp³)?H olefinated products.     

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.     

Nickel Catalysis Enables Oxidative C(sp2)–H/C(sp2)–H Cross‐Coupling Reactions between Two Heteroarenes

Nickel can be used to promote oxidative C(sp²)?H/C(sp²)?H cross‐coupling between two heteroarenes. The reaction scope can be extended to aromatic carboxamides as the coupling partner. The reaction exhibits high functional‐group compatibility and broad substrate scope. The silver oxidant can be recycled to reduce costs and waste, which is very useful for practical applications.     

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.     

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.     

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.     

PdII‐Catalyzed Enantioselective C(sp3)–H Arylation of Cyclobutyl Ketones Using a Chiral Transient Directing Group

The use of chiral transient directing groups (TDGs) is a promising approach for developing Pd^II‐catalyzed enantioselective C(sp³)?H activation reactions. However, this strategy is challenging because the stereogenic center on the TDG is often far from the C?H bond, and both TDG covalently attached to the substrate and free TDG are capable of coordinating to Pd^II centers, which can result in a mixture of reactive complexes. We report a Pd^II‐catalyzed enantioselective β‐C(sp³)?H arylation reaction of aliphatic ketones using a chiral TDG. A chiral trisubstituted cyclobutane was efficiently synthesized from a mono‐substituted cyclobutane through sequential C?H arylation reactions, thus demonstrating the utility of this method for accessing structurally complex products from simple starting materials. The use of an electron‐deficient pyridone ligand is crucial for the observed enantioselectivity. Interestingly, employing different silver salts can reverse the enantioselectivity.     

Merging Photochemistry with Electrochemistry: Functional‐Group Tolerant Electrochemical Amination of C(sp3)−H Bonds

Direct amination of C(sp³)?H bonds is of broad interest in the realm of C?H functionalization because of the prevalence of nitrogen heterocycles and amines in pharmaceuticals and natural products. Reported here is a combined electrochemical/photochemical method for dehydrogenative C(sp³)?H/N?H coupling that exhibits good reactivity with both sp² and sp³ N?H bonds. The results show how use of iodide as an electrochemical mediator, in combination with light‐induced cleavage of intermediate N?I bonds, enables the electrochemical process to proceed at low electrode potentials. This approach significantly improves the functional‐group compatibility of electrochemical C?H amination, for example, tolerating electron‐rich aromatic groups that undergo deleterious side reactions in the presence of high electrode potentials.     

Synthesis and Reactivity of Paramagnetic Nickel Polypyridyl Complexes Relevant to C(sp2)–C(sp3)Coupling Reactions

A number of new transition metal catalyzed methods for the formation of C(sp²)–C(sp³) bonds have recently been described. These reactions often utilize bidentate polypyridyl‐ligated Ni catalysts, and paramagnetic Ni^I halide or aryl species are proposed in the catalytic cycles. However, there is little knowledge about complexes of this type. Here, we report the synthesis of paramagnetic bidentate polypyridyl‐ligated Ni halide and aryl complexes through elementary reactions proposed in catalytic cycles for C(sp²)–C(sp³) bond formation. We investigate the ability of these complexes to undergo organometallic reactions that are relevant to C(sp²)–C(sp³) coupling through stoichiometric studies and also explore their catalytic activity.     

Enantioselective C(sp3)–H Amidation of Thioamides Catalyzed by a CobaltIII/Chiral Carboxylic Acid Hybrid System

Recent advances in Cp^xM^III catalysis (M=Co, Rh, Ir) have enabled a variety of enantioselective C(sp²)?H functionalization reactions, but enantioselective C(sp³)?H functionalization is still largely unexplored. We describe an asymmetric C(sp³)?H amidation of thioamides using an achiral Co^III/chiral carboxylic acid hybrid catalytic system, which provides easy and straightforward access to chiral β‐amino thiocarbonyl and β‐amino carbonyl building blocks with a quaternary carbon stereocenter.     

Temperature-modulated selective C(sp3)–H or C(sp2)–H arylation through palladium catalysis

Transition metal-catalysed C–H bond functionalisations have been extensively developed in organic and medicinal chemistry. Among these catalytic approaches, the selective activation of C(sp³)–H and C(sp²)–H bonds is particularly appealing for its remarkable synthetic versatility, yet it remains highly challenging. Herein, we demonstrate the first example of temperature-dependent selective C–H functionalisation of unactivated C(sp³)–H or C(sp²)–H bonds at remote positions through palladium catalysis using 7-pyridyl-pyrazolo[1,5-a]pyrimidine as a new directing group. At 120 °C, C(sp³)–H arylation was triggered by the chelation of a rare [6,5]-fused palladacycle, whereas at 140 °C, C(sp²)–H arylation proceeded instead through the formation of a 16-membered tetramer containing four 7-pyridyl-pyrazolo[1,5-a]pyrimidine–palladium chelation units. The subsequent mechanistic study revealed that both C–H activations shared a common 6-membered palladacycle intermediate, which was then directly transformed to either the [6,5]-fused palladacycle for C(sp³)–H activation at 120 °C or the tetramer for C(sp²)–H arylation at 140 °C with catalytic amounts of Pd(OAc)₂ and AcOH. Raising the temperature from 120 °C to 140 °C can also convert the [6,5]-fused palladacycle to the tetramer with the above-mentioned catalysts, hence completing the C(sp²)–H arylation ultimately.

Unprecedented 16-membered tetramer or [6,5]-fused palladacycle, mutually shadowboxing-like transformed from the shared common intermediate, accomplishes the Pd-catalysed temperature-dependent selective arylation of C(sp²)–H or C(sp³)–H.     

Catalytic Enantioselective Methylene C(sp3)−H Amidation of 8‐Alkylquinolines Using a Cp*RhIII/Chiral Carboxylic Acid System

Catalytic enantioselective directed methylene C(sp³)?H amidation reactions of 8‐alkylquinolines using a Cp*Rh^III/chiral carboxylic acid (CCA) hybrid catalytic system are described. A binaphthyl‐based chiral carboxylic acid efficiently differentiates between the enantiotopic methylene C?H bonds, which leads to the formation of C?N bonds with good enantioselectivity.     

Mechanism of Nickel(II)‐Catalyzed Oxidative C(sp2)−H/C(sp3)−H Coupling of Benzamides and Toluene Derivatives

The Ni‐catalyzed C(sp²)?H/C(sp³)?H coupling of benzamides with toluene derivatives was recently successfully achieved with mild oxidant iC₃F₇I. Herein, we employ density functional theory (DFT) methods to resolve the mechanistic controversies. Two previously proposed mechanisms are excluded, and our proposed mechanism involving iodine‐atom transfer (IAT) between iC₃F₇I and the Ni^II intermediate was found to be more feasible. With this mechanism, the presence of a carbon radical is consistent with the experimental observation that (2,2,6,6‐tetramethylpiperidin‐1‐yl)oxyl (TEMPO) completely quenches the reaction. Meanwhile, the hydrogen‐atom abstraction of toluene is irreversible and the activation of the C(sp²)?H bond of benzamides is reversible. Both of these conclusions are in good agreement with Chatani's deuterium‐labeling experiments.     

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.     

Ligand‐Promoted C(sp3)−H Olefination en Route to Multi‐functionalized Pyrazoles

A Pd‐catalyzed/N‐heterocycle‐directed C(sp³)?H olefination has been developed. The monoprotected amino acid ligand (MPAA) is found to significantly promote Pd‐catalyzed C(sp³)?H olefination for the first time. Cu(OAc)₂ instead of Ag⁺ salts are used as the terminal oxidant. This reaction provides a useful method for the synthesis of alkylated pyrazoles.     

Anthranil: An Aminating Reagent Leading to Bifunctionality for Both C(sp3)−H and C(sp2)−H under Rhodium(III) Catalysis

Previous direct C?H nitrogenation suffered from simple amidation/amination with limited atom‐economy and is mostly limited to C(sp²)?H substrates. In this work, anthranil was designed as a novel bifunctional aminating reagent for both C(sp²)?H and C(sp³)?H bonds under rhodium(III) catalysis, thus affording a nucleophilic aniline tethered to an electrophilic carbonyl. A tridendate rhodium(III) complex has been isolated as the resting state of the catalyst, and DFT studies established the intermediacy of a nitrene species.     

Palladium‐Catalyzed Intramolecular Carbene Insertion into C(sp3)−H Bonds

A palladium‐catalyzed carbene insertion into C(sp³)?H bonds leading to pyrrolidines was developed. The coupling reaction can be catalyzed by both Pd⁰ and Pd^II, is regioselective, and shows a broad functional group tolerance. This reaction is the first example of palladium‐catalyzed C(sp³)?C(sp³) bond assembly starting from diazocarbonyl compounds. DFT calculations revealed that this direct C(sp³)?H bond functionalization reaction involves an unprecedented concerted metalation–deprotonation step.     

Direct Acylation of C(sp3)−H Bonds Enabled by Nickel and Photoredox Catalysis

Using nickel and photoredox catalysis, the direct functionalization of C(sp³)?H bonds of N‐aryl amines by acyl electrophiles is described. The method affords a diverse range of α‐amino ketones at room temperature and is amenable to late‐stage coupling of complex and biologically relevant groups. C(sp³)?H activation occurs by photoredox‐mediated oxidation to generate α‐amino radicals which are intercepted by nickel in catalytic C(sp³)?C coupling. The merger of these two modes of catalysis leverages nickel's unique properties in alkyl cross‐coupling while avoiding limitations commonly associated with transition‐metal‐mediated C(sp³)?H activation, including requirements for chelating directing groups and high reaction temperatures.     

Selective Functionalization of Aromatic C(sp2)−H Bonds in the Presence of Benzylic C(sp3)−H Bonds by Electron‐Deficient Carbenoids Generated from 4‐Acyl‐1‐Sulfonyl‐1,2,3‐Triazoles

A rhodium(II)‐catalyzed reaction of newly prepared 4‐acyl‐1‐sulfonyl‐1,2,3‐triazoles with benzene, and its derivatives, is investigated. Acceptor/acceptor carbenoids generated from 4‐acyltriazoles undergo selective insertion at aromatic C(sp²)−H bonds in the presence of benzylic C(sp³)−H bonds to produce N ‐sulfonylenaminones.     

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.