Palladium‐Catalyzed C−H Silylation through Palladacycles Generated from Aryl Halides

A highly efficient palladium‐catalyzed disilylation reaction of aryl halides through C?H activation has been developed for the first time. The reaction has broad substrate scope. A variety of aryl halides can be disilylated by three types of C?H activation, including C(sp²)?H, C(sp³)?H, and remote C?H activation. In particular, the reactions are also unusually efficient. The yields are essentially quantitative in many cases, even in the presence of less than 1 mol % catalyst and 1 equivalent of the silylating reagent under relatively mild conditions. The disilylated biphenyls can be converted into disiloxane‐bridged biphenyls.     

Pd‐Catalyzed C—S Cyclization via C—H Functionalization Strategy: Access to Sulfur‐containing Benzoheterocyclics

A C—H sulfurated cyclization protocol starting from thioacetates is developed for straightforward construction of sulfur‐containing benzoheterocyclics. The diversiform functional dihydrobenzothiophenes and thiochromans were comprehensively achieved through the Pd‐catalyzed carbon‐ sulfur cyclization. Mechanistic studies indicated that C—H bond cleavage was involved in the rate‐determining step. [1]Benzothieno‐[3,2‐b]‐ [1]benzothiophene (BTBT) and benzo[b]thieno[2,3‐d]thiophene (BTT) were efficiently established as the well‐known organic field‐effect transistor (OFET) material molecules through this methodology.     

Cobalt‐Catalyzed Tandem C−H Activation/C−C Cleavage/C−H Cyclization of Aromatic Amides with Alkylidenecyclopropanes

A cobalt‐catalyzed chelation‐assisted tandem C?H activation/C?C cleavage/C?H cyclization of aromatic amides with alkylidenecyclopropanes is reported. This process allows the sequential formation of two C?C bonds, which is in sharp contrast to previous reports on using rhodium catalysts for the formation of C?N bonds. Here the inexpensive catalyst system exhibits good functional‐group compatibility and relatively broad substrate scope. The desired products can be easily transformed into polycyclic lactones with m‐CPBA. Mechanistic studies revealed that the tandem reaction proceeds through a C?H cobaltation, β‐carbon elimination, and intramolecular C?H cobaltation sequence.     

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.     

Late‐Stage Diversification through Manganese‐Catalyzed C−H Activation: Access to Acyclic,Hybrid, and Stapled Peptides

Bioorthogonal C?H allylation with ample scope was accomplished through a versatile manganese(I)‐catalyzed C?H activation for the late‐stage diversification of structurally complex peptides. The unique robustness of the manganese(I) catalysis manifold was reflected by full tolerance of sensitive functional groups, such as iodides, esters, amides, and OH‐free hydroxy groups, thereby setting the stage for the racemization‐free synthesis of C?H fused peptide hybrids featuring steroids, drug molecules, natural products, nucleobases, and saccharides.     

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.     

Enantioselective Pallada‐Electrocatalyzed C−H Activation by Transient Directing Groups: Expedient Access to Helicenes

Asymmetric pallada‐electrocatalyzed C?H olefinations were achieved through the synergistic cooperation with transient directing groups. The electrochemical, atroposelective C?H activations were realized with high position‐, diastereo‐, and enantio‐control under mild reaction conditions to obtain highly enantiomerically‐enriched biaryls and fluorinated N?C axially chiral scaffolds. Our strategy provided expedient access to, among others, novel chiral BINOLs, dicarboxylic acids and helicenes of value to asymmetric catalysis. Mechanistic studies by experiments and computation provided key insights into the catalyst's mode of action.     

Transition Metal Catalyzed Coupling Reactions under C−H Activation

C−C coupling by transition metal catalyzed C−H activation has developed into a diverse area of research. The applicable catalysts are manifold, and the variety of products obtained range from basic chemicals to pharmaceuticals and building blocks for carbon networks. One reaction, in which several C−C bonds are formed under C−H activation of a methyl group, is the conversion of ortho-iodoanisole according to Equation (1).     

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.     

Mild and Efficient Palladium‐Catalyzed Direct Trifluoroethylation of Aromatic Systems by C−H Activation

The introduction of trifluoroalkyl groups into aromatic molecules is an important transformation in the field of organic and medicinal chemistry. However, the direct installation of fluoroalkyl groups onto aromatic molecules still represents a challenging and highly demanding synthetic task. Herein, a simple trifluoroethylation process that relies on the palladium‐catalyzed C?H activation of aromatic compounds is described. With the utilization of a highly active trifluoroethyl(mesityl)iodonium salt, the developed catalytic method enables the first highly efficient and selective trifluoroethylation of aromatic compounds. The robust catalytic procedure provides the desired products in up to 95 % yield at 25 °C in 1.5 to 3 hours and tolerates a broad range of functional groups. The utilization of hypervalent reagents opens new synthetic possibilities for direct alkylations and fluoroalkylations in the field of transition‐metal‐catalyzed C?H activation.     

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.     

Late‐Stage Peptide Macrocyclization by Palladium‐Catalyzed Site‐Selective C−H Olefination of Tryptophan

Transition‐metal‐catalyzed C?H activation has shown potential in the functionalization of peptides with expanded structural diversity. Herein, the development of late‐stage peptide macrocyclization methods by palladium‐catalyzed site‐selective C(sp²)?H olefination of tryptophan residues at the C2 and C4 positions is reported. This strategy utilizes the peptide backbone as endogenous directing groups and provides access to peptide macrocycles with unique Trp–alkene crosslinks.     

Bioorthogonal Diversification of Peptides through Selective Ruthenium(II)‐Catalyzed C–H Activation

Methods for the chemoselective modification of amino acids and peptides are powerful techniques in biomolecular chemistry. Among other applications, they enable the total synthesis of artificial peptides. In recent years, significant momentum has been gained by exploiting palladium‐catalyzed cross‐coupling for peptide modification. Despite major advances, the prefunctionalization elements on the coupling partners translate into undesired byproduct formation and lengthy synthetic operations. In sharp contrast, we herein illustrate the unprecedented use of versatile ruthenium(II)carboxylate catalysis for the step‐economical late‐stage diversification of α‐ and β‐amino acids, as well as peptides, through chemo‐selective C−H arylation under racemization‐free reaction conditions. The ligand‐accelerated C−H activation strategy proved water‐tolerant and set the stage for direct fluorescence labelling as well as various modes of peptide ligation with excellent levels of positional selectivity in a bioorthogonal fashion. The synthetic utility of our approach is further demonstrated by twofold C−H arylations for the complexity‐increasing assembly of artificial peptides within a multicatalytic C−H activation manifold.     

Mild C−H/C−C Activation by Z‐Selective Cobalt Catalysis

Cationic cobalt complexes enable unprecedented cobalt‐catalyzed C?H/C?C functionalizations with unique selectivity features. The versatile cobalt catalyst proved broadly applicable, enabled efficient C?H/C?C cleavage at room temperature, and delivered Z‐alkenes with excellent diastereocontrol.     

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.