Redox‐Neutral Manganese(I)‐Catalyzed C−H Activation: Traceless Directing Group Enabled Regioselective Annulation

A strategy is reported in which traceless directing groups (TDGs) are used to promote the redox‐neutral Mn^I‐catalyzed regioselective synthesis of N‐heterocycles. Alkyne coupling partners bearing a traceless directing group, which serves as both the chelator and internal oxidant, were used to control the regioselectivity of the annulation reactions. This operationally simple approach is highly effective with previously challenging unsymmetrical alkyne systems, including unbiased dialkyl alkynes, with perfect regioselectivity. The simple conditions and the ability to carry out synthesis on a gram scale underscore the usefulness of this method. The application of this strategy in the concise synthesis of the bioactive compound PK11209 and the pharmaceutical moxaverine is also described.     

Cobalt‐Catalyzed Cyclization of N‐Methoxy Benzamides with Alkynes using an Internal Oxidant through C−H/N−O Bond Activation

The cyclization of substituted N‐methoxy benzamides with alkynes in the presence of an easily affordable cobalt complex and NaOAc provides isoquinolone derivatives in good to excellent yields. The cyclization reaction is compatible with a range of functional group‐substituted benzamides, as well as ester‐ and alcohol‐substituted alkynes. The cobalt complex [Co^IIICp*(OR)₂] (R=Me or Ac) serves as an efficient catalyst for the cyclization reaction. Later, isoquinolone derivatives were converted into 1‐chloro and 1‐bromo substituted isoquinoline derivatives in excellent yields in the presence of POCl₃ or PBr₃.     

Manganese‐Catalyzed Dehydrogenative [4+2] Annulation of NH Imines and Alkynes by CH/NH Activation

Described herein is a manganese‐catalyzed dehydrogenative [4+2] annulation of N? H imines and alkynes, a reaction providing highly atom‐economical access to diverse isoquinolines. This transformation represents the first example of manganese‐catalyzed C? H activation of imines; the stoichiometric variant of the cyclomanganation was reported in 1971. The redox neutral reaction produces H₂ as the major byproduct and eliminates the need for any oxidants, external ligands, or additives, thus standing out from known isoquinoline synthesis by transition‐metal‐catalyzed C? H activation. Mechanistic studies revealed the five‐membered manganacycle and manganese hydride species as key reaction intermediates in the catalytic cycle.     

Cobalt‐Catalyzed Oxidative Annulation of Nitrogen‐Containing Arenes with Alkynes: An Atom‐Economical Route to Heterocyclic Quaternary Ammonium Salts

Four cobalt‐catalyzed oxidative annulation reactions of nitrogen‐containing arenes with alkynes proceeds by C?H activation, thus leading to biologically useful quaternary ammonium salts, including pyridoisoquinolinium, cinnolinium, isoquinolinium, and quinolizinium salts, in high yields. The results are comparable to those reactions catalyzed by rhodium and ruthenium complexes. The transformation of the salts into various N‐heterocycles has also been demonstrated.     

Ruthenium‐Catalyzed C−C Bond Cleavage of 2H‐Azirines: A Formal [3+2+2] Cycloaddition to Fused Azepine Skeletons

2H‐azirines can serve as three‐atom synthons by C?C bond cleavage, however, it involves a high energy barrier under thermal conditions (>50.0 kcal mol^?1). Reported is a ruthenium‐catalyzed [3+2+2] cycloaddition reaction of 2H‐azirines with diynes, thus leading to the formation of fused azepine skeletons. This approach features an unprecedented metal‐catalyzed C?C bond cleavage of 2H‐azirines at room temperature, and the challenging construction of aza‐seven‐membered rings from diynes. The results of this study provide a new reaction pattern for constructing nitrogen‐containing seven‐membered rings and may find applications in the synthesis of other complex heterocycles.     

Construction of Hexahydrophenanthrenes By Rhodium(I)‐Catalyzed Cycloisomerization of Benzylallene‐Substituted Internal Alkynes through C−H Activation

The treatment of benzylallene‐substituted internal alkynes with [RhCl(CO)₂]₂ effects a novel cycloisomerization by C(sp²)?H bond activation to produce hexahydrophenanthrene derivatives. The reaction likely proceeds through consecutive formation of a rhodabicyclo[4.3.0] intermediate, σ‐bond metathesis between the C(sp²)?H bond on the benzene ring and the C(sp²)?Rh^III bond, and isomerization between three σ‐, π‐, and σ‐allylrhodium(III) species, which was proposed based on experiments with deuterated substrates.     

1,4‐Iron Migration for Expedient Allene Annulations through Iron‐Catalyzed C−H/N−H/C−O/C−H Functionalizations

C?H activation bears great potential for enabling sustainable molecular syntheses in a step‐ and atom‐economical manner, with major advances having been realized with precious 4d and 5d transition metals. In contrast, we employed earth abundant, nontoxic iron catalysts for versatile allene annulations through a unique C?H/N?H/C?O/C?H functionalization sequence. The powerful iron catalysis occurred under external‐oxidant‐free conditions even at room temperature, while detailed mechanistic studies revealed an unprecedented 1,4‐iron migration regime for facile C?H activations.     

Chelation‐Assisted Nickel‐Catalyzed Oxidative Annulation via Double C−H Activation/Alkyne Insertion Reaction

A nickel/NHC system for regioselective oxidative annulation by double C?H bond activation and concomitant alkyne insertion is described. The catalytic reaction requires a bidentate directing group, such as an 8‐aminoquinoline, embedded in the substrate. Various 5,6,7,8‐tetrasubstituted‐N‐(quinolin‐8‐yl)‐1‐naphthamides can be prepared as well as phenanthrene and benzo[h]quinoline amide derivatives. Diarylalkynes, dialkylalkynes, and arylalkylalkynes can be used in the system. A Ni⁰/Ni^II catalytic cycle is proposed as the main catalytic cycle. The alkyne plays a double role as a two‐component coupling partner and as a hydrogen acceptor.     

trans‐Carbocarbonation of Internal Alkynes through a Formal anti‐Carbopalladation/C−H Activation Cascade

An intramolecular Pd‐catalyzed cascade reaction is presented that consists of a formal anti‐carbopalladation of a C?C triple bond followed by C?H activation. As a result, oligocyclic ring systems with an embedded tetrasubstituted double bond are formed. The key to success in affording the trans geometry of the emerging double bond are alkyne units with residues that must not undergo β‐hydride elimination (e.g., t‐butyl or silyl groups). Silyl groups proved to be a perfect handle to further convert the tetrasubstituted alkenes. The evaluation of kinetic data with a deuterium‐labeled compound and X‐ray analyses of trapped intermediates provided additional insight into the catalytic cycle.     

Copper‐Catalyzed N−F Bond Activation for Uniform Intramolecular C−H Amination Yielding Pyrrolidines and Piperidines

The dual function of the N?F bond as an effective oxidant and subsequent nitrogen source in intramolecular aliphatic C?H functionalization reactions is explored. Copper catalysis is demonstrated to exercise full regio‐ and chemoselectivity control, which opens new synthetic avenues to nitrogenated heterocycles with predictable ring sizes. For the first time, a uniform catalysis manifold has been identified for the construction of both pyrrolidine and piperidine cores. The individual steps of this new copper oxidation catalysis were elucidated by control experiments and computational studies, clarifying the singularity of the N?F function and characterizing the catalytic cycle to be based on a copper(I/II) manifold.     

Electrochemical C−H/N−H Activation by Water‐Tolerant Cobalt Catalysis at Room Temperature

Electrochemistry enabled C?H/N?H functionalizations at room temperature by external oxidant‐free cobalt catalysis. Thus, the sustainable cobalt electrocatalysis manifold proceeds with excellent levels of chemoselectivity and positional selectivity, and with ample scope, thus allowing electrochemical C?H activation under exceedingly mild reaction conditions at room temperature in water.     

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.     

Diastereoselective [3+2] Annulation of Aromatic/Vinylic Amides with Bicyclic Alkenes through Cobalt‐Catalyzed C−H Activation and Intramolecular Nucleophilic Addition

A highly diastereoselective method for the synthesis of dihydroepoxybenzofluorenone derivatives from aromatic/vinylic amides and bicyclic alkenes is described. This new transformation proceeds through cobalt‐catalyzed C?H activation and intramolecular nucleophilic addition to the amide functional group. Transition‐metal‐catalyzed C?H activation reactions of secondary amides with alkenes usually lead to [4+2] or [4+1] annulation; to the best of our knowledge, this is the first time that a [3+2] cycloaddition is described in this context. The reaction proceeds under mild conditions and tolerates a wide range of functional groups. Mechanistic studies imply that the C?H bond cleavage may be the rate‐limiting step.     

Expedient Iron‐Catalyzed C−H Allylation/Alkylation by Triazole Assistance with Ample Scope

Triazole assistance set the stage for a unified strategy for the iron‐catalyzed C?H allylation of arenes, heteroarenes, and alkenes with ample scope. The versatile catalyst also proved competent for site‐selective methylation, benzylation, and alkylation with challenging primary and secondary halides. Triazole‐assisted C?H activation proceeded chemo‐, site‐, and diastereo‐selectively, and the modular TAM directing group was readily removed in a traceless fashion under exceedingly mild reaction conditions.     

Rhodium(III)‐Catalyzed Atroposelective Synthesis of Biaryls by C−H Activation and Intermolecular Coupling with Sterically Hindered Alkynes

Reported herein is the atroposelective synthesis of biaryl NH isoquinolones by Rh^III‐catalyzed C?H activation of benzamides and intermolecular [4+2] annulation for a broad scope of 2‐substituted 1‐alkynylnaphthalenes, as well as sterically hindered, symmetric diarylacetylenes. The axial chirality is constructed based on dynamic kinetic transformation of the alkyne in redox‐neutral annulation with benzamides, with alkyne insertion being stereodetermining. The reaction accommodates both benzamides and heteroaryl carboxamides and proceeds in excellent regioselectivity (if applicable) and enantioselectivities (average 91.8 % ee). An enantiomerically and diastereomerically pure rhodacyclic complex was prepared and offers insight into enantiomeric control of the coupling system, wherein the steric interactions between the amide directing group and the alkyne substrate dictate both the regio‐ and enantioselectivity.     

Palladium‐Catalyzed C−H Alkynylation of Unactivated Alkenes

Palladium‐catalyzed regio‐ and diastereoselective C?H functionalization with bromoalkynes and electronically unbiased olefins is reported. The picolinamide directing group enables the formation of putative 5 and 6‐exo‐metallacycles as intermediates to afford monoalkynylated products in up to 91 % yield in a stereospecific fashion. The systematic study reveals that substrates with a wide range of substituents on the olefin and bromoalkyne coupling partners are tolerated. Chemoselective transformations were demonstrated for the obtained amides, olefins, and alkynes.     

Copper Catalyzed C−H Activation

Activation of C?H bonds and their application in cross coupling chemistry has received a wider interest in recent years. The conventional strategy in cross coupling reaction involves the pre‐functionalization step of coupling reactants such as organic halides, pseudo‐halides and organometallic reagents. The C?H activation facilitates a simple and straight forward approach devoid of pre‐functionalization step. This approach also addresses the environmental and economical issues involved in several chemical reactions. In this account, we have reported C?H bond activation of small organic molecules, for example, formamide C?H bond can be activated and coupled with β‐dicarbonyl or 2‐carbonyl substituted phenols under oxidative conditions to yield carbamates using inexpensive copper catalysts. Phenyl carbamates were successfully synthesized in moderate to good yields by cross dehydrogenative coupling (CDC) of phenols with formamides using copper catalysts in presence of a ligand. We have also prepared unsymmetrical urea derivatives by oxidative cross coupling of formamides with amines using copper catalysts. Synthesis of N,N‐dimethyl substituted amides, 5‐substituted‐γ‐lactams and α‐acyloxy ethers was carried out from carboxylic acids using recyclable CuO nanoparticles. Copper nanoparticles afforded N‐aryl‐γ‐amino‐γ‐lactams by oxidative coupling of aromatic amines with 2‐pyrrolidinone. Reusable transition metal HT‐derived oxide catalyst was used for the synthesis of N,N‐dimethyl substituted amides by the oxidative cross‐coupling of carboxylic acids and substituted benzaldehydes. Overview of our work in this area is summarized.     

Annulation of Alkynyl Aryl Ethers with Allyl Pivalates To Give 2,3‐Bismethylenechromanes through Double C−H Bond Cleavage

The treatment of silylethynyloxyarenes with allylic pivalates in the presence of a palladium catalyst led to efficient C?H bond cleavage in both substrates and a novel annulation reaction to give 2,3‐bismethylenechromanes. When ortho‐allylated silylethynyloxybenzenes were used as the substrates, the same products were obtained. This result shows that site‐selective intramolecular hydrovinylation is involved in the annulation reaction. The synthetic utility of the products was demonstrated by the construction of condensed polycycles.     

Access to Silylated Pyrazole Derivatives by Palladium‐Catalyzed C−H Activation of a TMS group

A simple and efficient approach to new silylated heterocycles of potential interest in medicinal chemistry is presented. A set of bromophenyl trimethylsilyl pyrazole intermediates can be transformed by direct organometallic routes into two families of regioisomeric iodoaryl substrates; using either arylzinc or aryllithium chemistry, the TMS group remains on the pyrazole ring or translocates to the aryl moiety. These two families can then be efficiently transformed into benzo silino pyrazoles thanks to a single‐step cyclization relying on the Pd‐catalyzed activation of a non‐activated C(sp³)?H bond alpha to a silicon atom. The experimental conditions used, which are fully compatible with the pyrazole ring, suggest that this reaction evolves through a concerted metalation–deprotonation (CMD) mechanism.     

Advancements in the Synthesis and Applications of Cationic N‐Heterocycles through Transition Metal‐Catalyzed C−H Activation

Cationic N‐heterocycles are an important class of organic compounds largely present in natural and bioactive molecules. They are widely used as fluorescent dyes for biological studies, as well as in spectroscopic and microscopic methods. These compounds are key intermediates in many natural and pharmaceutical syntheses. They are also a potential candidate for organic light‐emitting diodes (OLEDs). Because of these useful applications, the development of new methods for the synthesis of cationic N‐heterocycles has received a lot of attention. In particular, many C?H activation methodologies that realize high step‐ and atom‐economies toward these compounds have been developed. In this review, recent advancements in the synthesis and applications of cationic N‐heterocycles through C?H activation reactions are summarized. The new C?H activation reactions described in this review are preferred over their classical analogs.