Arene‐Free Ruthenium(II/IV)‐Catalyzed Bifurcated Arylation for Oxidative C−H/C−H Functionalizations

Experimental and computational studies provide detailed insight into the selectivity‐ and reactivity‐controlling factors in bifurcated ruthenium‐catalyzed direct C?H arylations and dehydrogenative C?H/C?H functionalizations. Thorough investigations revealed the importance of arene‐ligand‐free complexes for the formation of biscyclometalated intermediates within a ruthenium(II/IV/II) mechanistic manifold.     

Palladium‐catalyzed regioselective C2‐arylation of 5‐aminoindole

Pd(II)‐catalyzed C‐H arylations of 5‐aminoindole using iodobenzenes as aryl source was studied. Despite pivalamide directing group at 5‐position of the indole, the direct C2‐arylation of the indole observed in high yields and with high regioselectivity.     

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.     

Photo‐Induced Ruthenium‐Catalyzed C−H Arylations at Ambient Temperature

Ambient temperature ruthenium‐catalyzed C?H arylations were accomplished by visible light without additional photocatalysts. The robustness of the ruthenium‐catalyzed C?H functionalization protocol was reflected by a broad range of sensitive functional groups and synthetically useful pyrazoles, triazoles and sensitive nucleosides and nucleotides, as well as multifold C?H functionalizations. Biscyclometalated ruthenium complexes were identified as the key intermediates in the photoredox ruthenium catalysis by detailed computational and experimental mechanistic analysis. Calculations suggested that the in situ formed photoactive ruthenium species preferably underwent an inner‐sphere electron transfer.     

An Enantioselective Bidentate Auxiliary Directed Palladium‐Catalyzed Benzylic C−H Arylation of Amines Using a BINOL Phosphate Ligand

A new enantioselective palladium(II)‐catalyzed benzylic C?H arylation reaction of amines is enabled by the bidentate picolinamide (PA) directing group. This reaction provides the first example of enantioselective benzylic γ‐C?H arylations of alkyl amines, and proceeds with up to 97 % ee. The 2,2′‐dihydroxy‐1,1′‐binaphthyl (BINOL) phosphoric acid ligand, Cs₂CO₃, and solvent‐free conditions are essential for high enantioselectivity. Mechanistic studies suggest that multiple BINOL ligands are involved in the stereodetermining C?H palladation step.     

Cobalt‐Catalyzed CH Arylations with Weakly‐Coordinating Amides and Tetrazoles: Expedient Route to Angiotensin‐II‐Receptor Blockers

Cobalt‐catalyzed C?H arylations enabled the synthesis of biaryl tetrazoles, which are key structural motifs in antihypertensive angiotensin‐II‐receptor blockers. Thus, weakly‐coordinating benzamides were employed for step‐economical C?H arylations with ample scope. Further, a low‐valent NHC complex enabled first cobalt‐catalyzed C?H functionalization by tetrazole assistance.     

Product Control using Substrate Design: Ruthenium‐Catalysed Oxidative C−H Olefinations of Cyclic Weinreb Amides

A new class of Weinreb amides has been developed as directing groups for the ruthenium‐catalysed regioselective oxidative C?H olefination. The new Weinreb amides successfully inhibit the N?O bond reductive cleavage usually associated with the cationic ruthenium system, thereby keeping intact the synthetic utility of Weinreb amides. Mechanistic studies reveal interesting aspects of the directing group capabilities of Weinreb amides when compared to simple amides of similar structures.     

Thioketone‐Directed Palladium(II)‐Catalyzed C−H Arylation of Ferrocenes with Aryl Boronic Acids

A palladium(II)‐catalyzed thioketone‐chelation‐assisted direct C?H arylation of ferrocenes is described. With thioketone as an efficient directing group, various monoaryl‐ and diaryl‐substituted thiocarbonylferrocenes were obtained by palladium‐catalyzed direct C?H functionalization in high yields under mild and base‐free reaction conditions. Furthermore, the arylated thiocarbonylferrocene could undergo diverse transformations.     

Ruthenium(II)‐Catalyzed C−C Arylations and Alkylations: Decarbamoylative C−C Functionalizations

Ruthenium(II)biscarboxylate catalysis enabled selective C−C functionalizations by means of decarbamoylative C−C arylations. The versatility of the ruthenium(II) catalysis was reflected by widely applicable C−C arylations and C−C alkylations of aryl amides, as well as acids with modifiable pyrazoles, through facile organometallic C−C activation.     

Micellar Catalysis for Ruthenium(II)‐Catalyzed C−H Arylation: Weak‐Coordination‐Enabled C−H Activation in H2O

Chemoselective C?H arylations were accomplished through micellar catalysis by a versatile single‐component ruthenium catalyst. The strategy provided expedient access to C?H‐arylated ferrocenes with wide functional‐group tolerance and ample scope through weak chelation assistance. The sustainability of the C?H arylation was demonstrated by outstanding atom‐economy and recycling studies. Detailed computational studies provided support for a facile C?H activation through thioketone assistance.     

C7‐Indole Amidations and Alkenylations by Ruthenium(II) Catalysis

C7?H‐functionalized indoles are ubiquitous structural units of biological and pharmaceutical compounds for numerous antiviral agents against SARS‐CoV or HIV‐1. Thus, achieving site‐selective functionalizations of the C7?H position of indoles, while discriminating among other bonds, is in high demand. Herein, we disclose site‐selective C7?H activations of indoles by ruthenium(II) biscarboxylate catalysis under mild conditions. Base‐assisted internal electrophilic‐type substitution C?H ruthenation by weak O‐coordination enabled the C7?H functionalization of indoles and offered a broad scope, including C?N and C?C bond formation. The versatile ruthenium‐catalyzed C7?H activations were characterized by gram‐scale syntheses and the traceless removal of the directing group, thus providing easy access to pharmaceutically relevant scaffolds. Detailed mechanistic studies through spectroscopic and spectrometric analyses shed light on the unique nature of the robust ruthenium catalysis for the functionalization of the C7?H position of indoles.     

Transition‐Metal‐Catalyzed Direct Arylation of (Hetero)Arenes by C?H Bond Cleavage

The area of transition‐metal‐catalyzed direct arylation through cleavage of C? H bonds has undergone rapid development in recent years, and is becoming an increasingly viable alternative to traditional cross‐coupling reactions with organometallic reagents. In particular, palladium and ruthenium catalysts have been described that enable the direct arylation of (hetero)arenes with challenging coupling partners—including electrophilic aryl chlorides and tosylates as well as simple arenes in cross‐dehydrogenative arylations. Furthermore, less expensive copper, iron, and nickel complexes were recently shown to be effective for economically attractive direct arylations.     

Ruthenium Oxidase Catalysis for Site‐Selective C–H Alkenylations with Ambient O2 as the Sole Oxidant

Ruthenium(II) oxidase catalysis by direct dioxygen‐coupled turnover enabled step‐economical oxidative C? H alkenylation reactions at ambient pressure. Versatile ruthenium(II) biscarboxylate catalysts displayed ample substrate scope and proved applicable to weakly coordinating and removable directing groups. The twofold C? H functionalization strategy was characterized by exceedingly mild reaction conditions as well as excellent positional selectivity.     

Aniline Carbamates: A Versatile and Removable Motif for Palladium‐Catalyzed Directed CH Activation

The aniline carbamate is introduced as a new removable directing group for C?H activation. Its versatility and ability as a directing group are demonstrated by its use in the ortho‐arylation of a wide variety of aniline derivatives under palladium(II) catalysis, with symmetric diaryliodonium salts as aryl donors. The reaction differs from previously reported arylations in its selectivity and its mechanism, as elucidated by kinetic and isotopic experiments. The directing group can also be easily removed under a variety of conditions.     

C−H Oxygenation Reactions Enabled by Dual Catalysis with Electrogenerated Hypervalent Iodine Species and Ruthenium Complexes

The catalytic generation of hypervalent iodine(III) reagents by anodic electrooxidation was orchestrated towards an unprecedented electrocatalytic C?H oxygenation of weakly coordinating aromatic amides and ketones. Thus, catalytic quantities of iodoarenes in concert with catalytic amounts of ruthenium(II) complexes set the stage for versatile C?H activations with ample scope and high functional group tolerance. Detailed mechanistic studies by experiment and computation substantiate the role of the iodoarene as the electrochemically relevant species towards C?H oxygenations with electricity as a sustainable oxidant and molecular hydrogen as the sole by‐product. para‐Selective C?H oxygenations likewise proved viable in the absence of directing groups.     

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.     

Amidines for Versatile Ruthenium(II)‐Catalyzed Oxidative CH Activations with Internal Alkynes and Acrylates

Cationic ruthenium complexes derived from KPF₆ or AgOAc enabled efficient oxidative C?H functionalizations on aryl and heteroaryl amidines. Thus, oxidative annulations of diversely decorated internal alkynes provided expedient access to 1‐aminoisoquinolines, while catalyzed C?H activations with substituted acrylates gave rise to structurally novel 1‐iminoisoindolines. The powerful ruthenium(II) catalysts displayed a remarkably high site‐, regio‐ and, chemoselectivity. Therefore, the catalytic system proved tolerant of a variety of important electrophilic functional groups. Detailed mechanistic studies provided strong support for the cationic ruthenium(II) catalysts to operate by a facile, reversible C?H activation.     

Cobalt‐Catalyzed C(sp2)−H Methylation by using Dicumyl Peroxide as both the Methylating Reagent and Hydrogen Acceptor

The first cobalt‐catalyzed direct methylation of a C(sp²)?H bond using dicumyl peroxide (DCP) as both the methylating reagent and hydrogen acceptor has been established. The reaction proceeded without the use of any additives, and was proven to be applicable to various amides bearing a 2‐pyridinylisopropyl (PIP) directing group, providing an efficient access to o‐methyl aryl amides with high functional‐group tolerance. Preliminary mechanistic studies suggest a radical process would be involved in the catalytic process.     

Electrooxidative Ruthenium‐Catalyzed C−H/O−H Annulation by Weak O‐Coordination

Electrocatalysis has been identified as a powerful strategy for organometallic catalysis, and yet electrocatalytic C?H activation is restricted to strongly N‐coordinating directing groups. The first example of electrocatalytic C?H activation by weak O‐coordination is presented, in which a versatile ruthenium(II) carboxylate catalyst enables electrooxidative C?H/O?H functionalization for alkyne annulations in the absence of metal oxidants; thereby exploiting sustainable electricity as the sole oxidant. Mechanistic insights provide strong support for a facile organometallic C?H ruthenation and an effective electrochemical reoxidation of the key ruthenium(0) intermediate.     

Ruthenium(II)‐Catalyzed CH Activation with Isocyanates: A Versatile Route to Phthalimides

A cationic ruthenium(II)‐complex was utilized in the efficient synthesis of phthalimide derivatives by C?H activation with synthetically useful amides. The reaction proceeded through a mechanistically unique insertion of a cycloruthenated species into a C?Het multiple bond of isocyanate. The novel method also proved applicable for the synthesis of heteroaromatic unsymmetric diamides as well as a potent COX‐2 enzyme inhibitor.