Tandem Catalysis: Alcohol Oxidation and C?C Bond Formation via C?H Bond Activation

A tandem process involving oxidation of a benzylic alcohol functionality followed by hydroarylation is described. These two atom‐economic sequences are very convenient to access functionalized aromatic ketones, using simple ruthenium trichloride as catalyst precursor. Moreover they appear to be highly compatible, tolerant, and selective toward various functional groups, and the ease of the protocol should make it very convenient for synthetic purposes.     

Shuttling Catalyst: Facilitating C−C Bond Formation via Cross-Couplings with a Thermoresponsive Polymeric Ligand

A poly(ethylene glycol) (PEG) linked ortho-MeO-phenyldicyclohexylphosphine (MeO-WePhos) ligand has been synthesized to promote Pd-catalyzed carbon-carbon bond formation by cross-couplings including Sonogashira, Heck, Hiyama and Stille reactions, providing corresponding (hetero)aryl substituted alkynes, alkenes and bi(hetero)aryls in good to excellent isolated yields with low Pd loadings. Facilitated by the lower critical solution temperature behaviour of the polymeric monophosphine ligand, the metal-complex could rapidly shuttle between organic and water phases as regulated by temperature, enabling highly efficient catalyst recycling via a simple phase separation. The chemical structure of ligand was determined by matrix-assisted laser desorption/ionization-time of flight mass spectrometry, nuclear magnetic resonance spectrometry and size-exclusion chromatography measurements. Notably, as demonstrated by the inductively coupled plasma-atomic emission spectrometry measurement, 98% Pd was kept in the water phase after 6 cycles of catalyst recycling experiments. Given the profound impact of transition-metal-catalyzed covalent bond formation and the increasing demand of sustainable chemistry, this work provides an alternative method to conduct cross-couplings with a polymeric shuttling catalyst.     

Recent Advances in Electrochemical,Ni-Catalyzed C−C Bond Formation

Nickel-catalyzed cross-electrophile coupling (XEC) is an efficient method to form carbon-carbon bonds and has become an important tool for building complex molecules. While XEC has most often used stoichiometric metal reductants, these transformations can also be driven electrochemically. Electrochemical XEC (eXEC) is attractive because it can increase the greenness of XEC and this potential has resulted in numerous advances in recent years. The focus of this review is on electrochemical, Ni-catalyzed carbon-carbon bond forming reactions reported since 2010 and is categorized by the type of anodic half reaction: sacrificial anode, sacrificial reductant, and convergent paired electrolysis. The key developments are highlighted and the need for more scalable options is discussed.     

Recent Advances in Late-Stage Construction of Stapled Peptides via C−H Activation

Stapled peptides have been widely applied in many fields, including pharmaceutical chemistry, diagnostic reagents, and materials science. However, most traditional stapled peptide preparation methods rely on prefunctionalizations, which limit the diversity of stapled peptides. Recently, the emergence of late-stage transition metal-catalyzed C−H activation in amino acids and peptides has attracted wide interest due to its robustness and applicability for peptide stapling. In this review, we summarize the methods for late-stage construction of stapled peptides via transition metal-catalyzed C−H activation.     

Photochemical C−H Activation: An Early Story

An early investigation in the author‘s laboratory into photochemical C−H bond activation and functionalization is recounted. Specifically, d⁸ Ir(I) and Rh(I) carbonyl phosphine complexes were found to promote benzene C−H bond activtion and functionalization to give benzaldehyde upon near-UV irradiation. The carbonylation of benzene is thermodynamically unfavorable resulting in only low yields of benzaldehyde. The photochemical process was suggested as ligand dissociation to yield a 14 e⁻ Ir(I) or Rh(I) intermediate capable of benzene C−H oxidative additions. The research set the stage for subsequent photochemical C−H activation and functionalization studies by others in the late 1980’s.     

C?C Bond Formation via C?H Activation and C?N Bond Formation via Oxidative Amination Catalyzed by Palladium‐ Polyoxometalate Nanomaterials Using Dioxygen as the Terminal Oxidant

An efficient heterogeneous palladium‐polyoxometalate catalyst with the formula Pd‐H₆PV₃Mo₉O₄₀/C has been successfully developed for carbon‐carbon (C C) bond formation via carbon‐hydrogen (C H) activation and carbon‐nitrogen (C N) bond formation via oxidative amination using oxygen as the terminal oxidant. The coupling processes are simple, and use relatively mild conditions to form the desired products. In addition, less waste is generated as no additional reagents such as organic/inorganic oxidants are required, and water is the only by‐product generated.     

Hydrogen-Mediated C−C Bond Formation: Stereo- and Site-Selective Chemical Synthesis Beyond Stoichiometric Organometallic Reagents

Stereo- and site-selective methods for the byproduct-free modification of unprotected organic compounds that occur through the addition or redistribution of hydrogen are natural endpoints in the advancement of methods for efficient chemical synthesis. Progress toward this goal requires a departure from reactants that embody non-native structural elements, including stoichiometric organometallic reagents, directing/protecting groups and chiral auxiliaries. In this perspective, we highlight how hydrogen-mediated C−C bond formations developed in our laboratory have enabled progress toward ideal chemical syntheses of this type.     

Selective C−H Bond Functionalization of Unprotected Indoles by Donor-Acceptor Carbene Insertion

Copper catalysts containing alkoxydiaminophosphine (ADAP) ligand catalyze the selective C3−H functionalization of unprotected indoles upon carbene transfer from donor-acceptor diazo compounds, the N−H bond remaining unaltered during the transformation. Mechanistic studies, including DFT calculations, allows proposing the existence of two competitive pathways, none of them occurring through the formation of cyclopropane intermediates, at variance with previously reported systems.     

Flow Metal‐Free Ar?C Bond Formation via Photogenerated Phenyl Cations

A convenient photochemical flow protocol for the formation of aryl‐carbon bonds via photogenerated phenyl cations has been developed. A wide range of phenylated products, including biaryls, allylarenes, 2‐arylacetals and benzyl γ‐lactones, was smoothly synthesized in satisfactory yields under metal‐free conditions. The adoption of a flow reactor often allowed us to adopt higher concentrations of substrates and shorter irradiation times compared to those usually employed in batch systems.

     

Efficient Palladium‐Catalyzed Oxidative Indolation of Allylic Compounds with DDQ via sp3 C?H Bond Activation and Carbon‐Carbon Bond Formation Under Mild Conditions

An efficient oxidative cross‐coupling reaction between 1,3‐diarylpropenes and indoles in the presence of palladium chloride was achieved with 2,3‐dichloro‐5,6‐dicyanoquinone (DDQ) as oxidant. The reaction afforded 1,3‐diphenylallylindoles in moderate to high yields under mild conditions, thus providing a novel methodology to synthesize the respective products.     

Convergent Synthesis of α-Branched Amines by Transition-Metal-Catalyzed C−H Bond Additions to Imines

α-Branched amines are ubiquitous in drugs and natural products, and consequently, synthetic methods that provide convergent and efficient entry to these structures are of considerable value. Transition-metal-catalyzed C−H bond additions to imines have the potential to be highly practical and atom-economic approaches for the synthesis of a diverse and complex array of α-branched amine products. These strategies typically employ readily available starting inputs, display high functional group compatibility, and often avoid the production of stoichiometric waste byproducts. A number of C−H functionalization methods have also been developed that incorporate cascade cyclization pathways to give amine-substituted carbocycles, and in many cases, proceed with the formation of multiple stereogenic centers. Advances in the area of asymmetric C−H bond additions to imines have also been achieved through the use of chiral imine N-substituents as well as by enantioselective catalysis.     

Site-Selective Pyridination of Benzylic and Allylic C−H bonds via Radical-Radical Cross-Coupling

Herein, we report a modular photocatalytic platform for the site-selective pyridination of saturated hydrocarbon compounds employing organic photoredox catalysis to forge new carbon-carbon bonds. The site-selective C−H pyridination could couple benzylic/allylic C−H bonds with pyridylphosphonium salts, which installed directly and regioselectively from C−H heteroarenes through a radical-radical cross coupling mechanism. This synthetic methodology could tolerate a variety of functional groups, complex heteroarenes, even late-stage functionalization of pharmaceuticals selectively.     

C−H Amination via Nitrene Transfer Catalyzed by Mononuclear Non-Heme Iron-Dependent Enzymes

Expanding the reaction scope of natural metalloenzymes can provide new opportunities for biocatalysis. Mononuclear non-heme iron-dependent enzymes represent a large class of biological catalysts involved in the biosynthesis of natural products and catabolism of xenobiotics, among other processes. Here, we report that several members of this enzyme family, including Rieske dioxygenases as well as α-ketoglutarate-dependent dioxygenases and halogenases, are able to catalyze the intramolecular C−H amination of a sulfonyl azide substrate, thereby exhibiting a promiscuous nitrene transfer reactivity. One of these enzymes, naphthalene dioxygenase (NDO), was further engineered resulting in several active site variants that function as C−H aminases. Furthermore, this enzyme could be applied to execute this non-native transformation on a gram scale in a bioreactor, thus demonstrating its potential for synthetic applications. These studies highlight the functional versatility of non-heme iron-dependent enzymes and pave the way to their further investigation and development as promising biocatalysts for non-native metal-catalyzed transformations.     

Palladium-Catalyzed Direct Ortho C–O bond construction of Azobenzenes with Iodobenzene diacetate via C–H Activation

Abstract

A method of direct synthesis of ortho-acyloxylated azoarenes via palladium-catalyzed C–H bond activation was developed. The reaction proceeded was smoothly at room temprature and have better yield in shorter times. The obtained ortho-acyloxylated azoarenes could be efficiently converted into 2-hydroxyazobenzenes in good yields through a hydrolysis process.

Graphical Abstract

Many various ortho-acyloxylated azoarenes were obtained in moderate to high yields by palladium-catalyzed direct C(sp²)-H acyloxylation of aromatic azo compounds with PhI(OAc)₂

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Tackling Remote sp3 C−H Functionalization via Ni-Catalyzed “chain-walking” Reactions

Nickel catalysts have recently played an important role for rapidly and reliably converting feedstock chemicals into valuable compounds of interest for both pharmaceutical and academic laboratories. Herein, we summarize the recent advances on the ability of nickel catalysts to trigger olefin isomerization via “chain-walking”, causing a displacement of the nickel catalyst throughout the alkyl chain while opening up new grounds for forging C−C and C-heteroatom linkages at remote, yet unfunctionalized, sp³ C−H bonds.     

Computational Mechanistic Investigations of Biocatalytic Nitrenoid C−H Functionalizations via Engineered Heme Proteins

Engineered heme proteins were developed to possess numerous excellent biocatalytic nitrenoid C−H functionalizations. Computational approaches such as density functional theory (DFT), hybrid quantum mechanics/molecular mechanics (QM/MM), and molecular dynamics (MD) calculations were employed to help understand some important mechanistic aspects of these heme nitrene transfer reactions. This review summarizes advances of computational reaction pathway results of these biocatalytic intramolecular and intermolecular C−H aminations/amidations, focusing on mechanistic origins of reactivity, regioselectivity, enantioselectivity, diastereoselectivity as well as effects of substrate substituent, axial ligand, metal center, and protein environment. Some important common and distinctive mechanistic features of these reactions were also described with brief outlook of future development.     

New Trends and Future Opportunities in the Enzymatic Formation of C−C,C−N,and C−O bonds

Organic chemistry provides society with fundamental products we use daily. Concerns about the impact that the chemical industry has over the environment is propelling major changes in the way we manufacture chemicals. Biocatalysis offers an alternative to other synthetic approaches as it employs enzymes, Nature's catalysts, to carry out chemical transformations. Enzymes are biodegradable, come from renewable sources, operate under mild reaction conditions, and display high selectivities in the processes they catalyse. As a highly multidisciplinary field, biocatalysis benefits from advances in different areas, and developments in the fields of molecular biology, bioinformatics, and chemical engineering have accelerated the extension of the range of available transformations (E. L. Bell et al., Nat. Rev. Meth. Prim. 2021 , 1, 1–21). Recently, we surveyed advances in the expansion of the scope of biocatalysis via enzyme discovery and protein engineering (J. R. Marshall et al., Tetrahedron 2021 , 82, 131926). Herein, we focus on novel enzymes currently available to the broad synthetic community for the construction of new C−C, C−N and C−O bonds, with the purpose of providing the non-specialist with new and alternative tools for chiral and sustainable chemical synthesis.     

Bifunctional Transition Metal-Based Molecular Catalysts for Asymmetric C–C and C–N Bond Formation

This paper describes recent advances in the development of the asymmetric catalytic reactions promoted by conceptually new bifunctional molecular catalysts. These reactions include the enantioselective Michael addition of 1,3-dicarbonyl compounds to cyclic enones and nitroalkenes, and the enantioselective direct amination of α-cyanoacetates to diazoesters. The nature of the catalyst in each particular case was delicately tuned by adjusting the combination of the central metal together with the structures of the cooperating ligands, applied solvents, and the reaction conditions to achieve the utmost catalytic performance in terms of reactivity and selectivity. In the presence of the optimized catalyst the addition reactions proceeded smoothly with a 1:1 M ratio of the reagents to give the corresponding chiral adducts with excellent yields and ee’s. Preliminary mechanistic studies based on NMR spectroscopy and DFT analysis showed that the key step of the catalytic cycle is the interaction of the bifunctional catalyst with a pronucleophilic reagent that leads to stereoselective formation of C-, O-, or N-bound amino complexes. The resulting amino catalyst bearing metal-bound nucleophiles readily reacts with an electrophile that acquires the reactive conformation through the cooperative effect of the acidic NH protons. This results in the formation of a C–C or a C–N bond yielding the corresponding products in a highly stereoselective manner.     

Recent Progress in Functionalization of the Pyridine Ring through C−S Bond Formation under Transition Metal Catalyst Free Conditions

Pyridines and quinolines substituted with sulfur-containing functional groups are widely used as drugs, drug candidates, organic materials, N,S-ligands and others. Traditional synthetic routes to produce these compounds are based on nucleophilic aromatic substitution reactions and transition metal-catalyzed cross-coupling reactions of (pseudo)halopyridines. While effective in many cases, both approaches are limited due to using forcing conditions and expensive, specifically designed catalytic systems. In the last decade, a number of innovative methods for the functionalization of the pyridine ring via the formation of a C−S bond have been developed. Most of these methods proceed through the direct or indirect C−H functionalization of unfunctionalized pyridines, thus avoiding the use of oftentimes not readily available halopyridines as the starting materials. Deoxygenative C−H functionalization of pyridine-N-oxides and deaminative transformation of aminopyridines have been also employed for the introduction of diverse organosulfur functionality into the pyridine ring. All these processes can be easily performed under mild conditions, typically affording value pyridines and quinolines in good to high yields. Usually being highly chemo- and regioselective, these methods allow the late-stage functionalization of complex molecules including drugs and natural products. In this Review, we summarize the most recent synthetic methods for functionalization of pyridines and fused pyridines with sulfur-containing functional groups reported mostly since 2018. For a better understanding of the processes, the mechanisms of the described reactions are briefly discussed.     

Base-Assisted C−H Bond Cleavage in Cross-Coupling: Recent Insights into Mechanism,Speciation, and Cooperativity

This review analyzes recent mechanistic studies that have provided new insights into how the structure of a metal complex influences the rate and selectivity of base-assisted C−H cleavage. Partitioning a broader mechanistic continuum into classes delimited by the polarization between catalyst and substrate during C−H cleavage is postulated as a method to identify catalysts favoring electrophilic or nucleophilic reactivity patterns, which may be predictive based on structural features of the metal complex (i. e., oxidation state, d-electron count, charge). Multi-metallic cooperativity and polynuclear speciation also provide new avenues to affect energy barriers for C−H cleavage and site selectivity beyond the limitations of single metal catalysts. An improved understanding of mechanistic nuances and structure-activity relationships on this important bond activation step carries important implications for efficiency and controllable site selectivity in non-directed C−H functionalization.