Nickel-Catalyzed Csp2−OMe Functionalization for Chemoselective Aromatic Homologation En Route to Nanographenes

A Ni-catalyzed C_sp2−OMe ortho-functionalization methodology to form chemoselectively alkyne monoannulation or aromatic homologation products is reported as a novel protocol towards the valorisation of substrates containing C_sp2−OMe units. Double activation of C_sp2−OMe and C_sp2−F bonds is also demonstrated. Further use of aromatic homologation products towards the synthesis of nanographene-like compounds is described.     

Efficient and Direct Functionalization of Allylic sp3 C−H Bonds with Concomitant CO2 Reduction

Solar-driven CO₂ reduction integrated with C−C/C−X bond-forming organic synthesis represents a substantially untapped opportunity to simultaneously tackle carbon neutrality and create an atom-/redox-economical chemical synthesis. Herein, we demonstrate the first cooperative photoredox catalysis of efficient and tunable CO₂ reduction to syngas, paired with direct alkylation/arylation of unactivated allylic sp³ C−H bonds for accessing allylic C−C products, over SiO₂-supported single Ni atoms-decorated CdS quantum dots (QDs). Our protocol not only bypasses additional oxidant/reductant and pre-functionalization of organic substrates, affording a broad of allylic C−C products with moderate to excellent yields, but also produces syngas with tunable CO/H₂ ratios (1 : 2–5 : 1). Such win-win coupling catalysis highlights the high atom-, step- and redox-economy, and good durability, illuminating the tantalizing possibility of a renewable sunlight-driven chemical feedstocks manufacturing industry.     

Stereoselective Unsymmetrical 1,1-Diborylation of Alkynes with a Neutral sp2−sp3 Diboron Reagent

The incorporation of two distinct boryl groups at the same carbon center in organic molecules has attracted growing research interest due to its potential for facilitating controlled, precise synthesis through stepwise dual carbon-boron bond transformations. Here we report a method to access u nsymmetrical 1,1- d i b oryl a lkene (UDBA) stereoselectively via the reaction of readily available alkynes with a neutral sp²−sp³ diboron reagent (NHC) B H₂- B pin (NHC=N-heterocyclic carbene). Attributing to the chemically easily distinguishable nature of the sp² and sp³ boryl moieties, controllable stepwise derivatization of the resultant UDBAs is realized. This process leads to various multifunctionalized olefins and organoborons, such as acylboranes, which are difficult to prepare by other methods.     

Amidyl Radical Directed γ-C(sp3)−H Functionalization with Silyl Enol Ethers via Photoredox Catalysis

Herein we reported an efficient photoredox-catalyzed reaction for site-selective C(sp³)−H functionalization of carboxamides with silyl enol ethers as radical acceptors. The reaction proceeded through amidyl radical-directed 1,5-hydrogen atom transfer (1,5-HAT) and C(sp³)−C(sp³) bond formation via radical addition of silyl enol ethers. The process features mild conditions and high functional-group tolerance, allowing the preparation of a series of carboxamides with pendant carbonyl moieties.     

C−H Functionalization of Aldehydes and Ketones with Transient Directing Groups: Recent Developments

In order to directly functionalize C−H bonds of complex molecules and, in particular, to control the regioselectivity of the reaction, a wide range of directing groups has been used. However, these directing groups need to be installed and removed for further applications, which may limit the use of C−H activation in synthesis. Concerning aldehydes and ketones, a transient directing group strategy has recently emerged to overcome this drawback. The addition of an additive, in general an amine, allowed the in situ formation of the real directing group to achieve C−H activation. This review presents the latest developments in the field over the period 2020–2023.     

Late-stage C−H Functionalization of Tryptophan-Containing Peptides with Thianthrenium Salts: Conjugation and Ligation

Bioorthogonal late-stage diversification of structurally complex peptides bears enormous potential for drug discovery and molecular imaging, among other applications. Herein, we report on a palladium-catalyzed C−H arylation of tryptophan-containing peptides with readily accessible and modular arylthianthrenium salts. Under exceedingly mild reaction conditions, the late-stage diversification of structurally complex peptides was accomplished. The tunability and ease of preparation of arylthianthrenium salts allowed the expedient stitching of tryptophan-containing peptides with drug, natural product, and peptidic scaffolds by forging sterically congested biaryl linkages. The robustness of the palladium catalysis regime was reflected by the full tolerance of a plethora of sensitive and coordinating functional groups. Hence, our manifold enabled efficient access to highly decorated, labelled, conjugated, and ligated linear and cyclic peptides.     

Palladium-Catalyzed Cascade sp2 C−H Functionalization/Intramolecular Asymmetric Allylation: From Aryl Ureas and 1,3-Dienes to Chiral Indolines

A chiral Pd^II-catalyzed cascade sp² C−H functionalization/intramolecular asymmetric allylation reaction is reported. A new chiral sulfoxide–oxazoline (SOX) ligand bearing single chiral center on the sulfur was identified as the optimal ligand for the reaction, being efficient both in the C−H cleavage step and the stereocontrol of the allylation step. The broad scope of this method with respect to aryl ureas and 1,3-dienes enables the rapid construction of valuable chiral indoline derivatives with high yields and enantioselectivities (up to 99 % yield, up to 95:5 e.r.).     

Rhodium(III)-Catalyzed C−H/N−H Functionalization with Hydrogen Evolution

A rhodium(III)-catalyzed C−H/N−H bond functionalization of benzimidates with α-chloroaldehydes to afford isoquinolin-3-ol derivatives is reported. No external oxidants are needed in this process, and interestingly, evolution of hydrogen gas is observed.     

Diastereoselective Double C−H Functionalization of Chiral Ferrocenes with Heteroaromatics

Diastereoselective double C−H heteroarylation of chiral ferrocenes provides valuable compounds with multiple functionalities using mild reaction conditions and simple reagents. Pd-Complexes with chiral mono-protected amino acids afforded corresponding heteroarylated ferrocenyl amines in good yields and high diastereomeric purities. In this way, a variety of indole, thiophene, pyrrole, or furan substituents were introduced to the ferrocene moiety. Furthermore, a range of relevant functional groups, for example ketone, ester, chloro, nitro, or silyl, are tolerated by this method. An alternative combination of amino acid and ferrocenyl amine configurations was leveraged to provide the complementary diastereomeric products. The products of C−H heteroarylation can be transformed into corresponding phosphines. Absolute configurations of CH-activation products were confirmed by the combination of X-ray crystallographic analysis and CD spectroscopy. ¹⁹F NMR kinetic study and DFT calculations provided insights into the reaction mechanism and reasons governing stereoinduction.     

Rhodium(III)-Catalyzed C−H Bond Functionalization of 2-Pyridones with Alkynes: Switchable Alkenylation,Alkenylation/Directing Group Migration and Rollover Annulation

Cp*Rh(III)-catalyzed chelation-assisted direct C−H bond functionalization of 1-(2-pyridyl)-2-pyridones with internal alkynes that can be controlled to give three different products in good yields has been realized. Depending on the reaction conditions, solvents and additives, the reaction pathway can be switched between alkenylation, alkenylation/directing group migration and rollover annulation. These reaction manifolds allow divergent access to a variety of valuable C6-alkenylated 1-(2-pyridyl)-2-pyridones, (Z)-6-(1,2-diaryl-2-(pyridin-2-yl)vinyl)pyridin-2(1H)-ones and 10H-pyrido[1,2-a][1,8]naphthyridin-10-ones from the same starting materials. These protocols exhibit excellent regio- and stereoselectivity, broad substrate scope, and good tolerance of functional groups. A combination of experimental and computational approaches have been employed to uncover the key mechanistic features of these reactions.     

Ligand-Enabled Double γ-C(sp3)−H Functionalization of Aliphatic Acids: One-Step Synthesis of γ-Arylated γ-Lactones

γ-methylene C(sp³)−H functionalization of linear free carboxylic acids remains a significant challenge. Here in we report a Pd(II)-catalyzed tandem γ-arylation and γ-lactonization of aliphatic acids enabled by a L,X-type CarboxPyridone ligand. A wide range of γ-arylated γ-lactones are synthesized in a single step from aliphatic acids in moderate to good yield. Arylated lactones can readily be converted into disubstituted tetrahydrofurans, a prominent scaffold amongst bioactive molecules.     

Cobalt-Catalyzed, 2-Aminopyridine-N-Oxide-Directed C(sp2)−H Bond Functionalization with Maleimides: Facile Access to Isoindolone Spirosuccinimides

A cobalt-catalyzed, N,O-bidentate directing group-assisted C−H bond functionalization of benzamides with maleimides was developed for the facile access to isoindolone spirosuccinimides in good to excellent yields. This C−H bond activation and spirocyclization employing pyridine N-oxide as directing group provided very good substrate scope and tolerated various functional groups. Furthermore, the mechanistic investigation revealed that the C−H bond activation is the rate-determining step of this reaction.     

Organocatalytic Asymmetric Direct C sp 3H Functionalization of Ethers: A Highly Efficient Approach to Chiral Spiroethers

Spiro compounds: An organocatalytic asymmetric method for the C?sp?3?H functionalization of the α?position of racemic cyclic ethers has been developed. The transformation, mediated by catalytic amounts of an imidazolidinone and strong acid, involves a tandem 1,5-hydride transfer/cyclization and provides access to a structurally diverse series of chiral spiroethers with high levels of enantioselectivity.     

C−H Functionalization and Allylic Amination for Post-Polymerization Modification of Polynorbornenes

Post-polymerization modification (PPM) via direct C−H functionalization is a powerful synthetic strategy to convert polymer feed-stocks into value-added products. We found that a metal-free, Se-catalyzed allylic C−H amination provided an efficient method for PPM of polynorbornenes (PNBs) produced via ring-opening metathesis polymerization. Inherent to the mechanism of the allylic amination, PPM on PNBs preserved the alkene functional groups along the polymer backbone, while also avoiding transposition of the double bonds. Amination using a series of aryl sulfonamides led to good control over the degree of functionalization, access to a range of functionalities, and tunable thermal properties from the resulting polymers.     

Site-Selective C−H Allylation of Alkanes: Facile Access to Allylic Quaternary sp3-Carbon Centers

The construction of allylic quaternary sp³-carbon centers has long been a formidable challenge in transition-metal-catalyzed alkyl-allyl coupling reactions due to the severe steric hindrance. Herein, we report an effective carbene strategy that employs well-defined vinyl-N-triftosylhydrazones as a versatile allylating reagent to enable direct assembly of these medicinally desirable structural elements from low-cost alkane feedstocks. The reaction exhibited excellent site selectivity for tertiary C−H bonds, broad scope (>60 examples and >20 : 1:0 r. r.) and good efficiency, even on a gram-scale, making it a convenient alternative to the well-known Trost–Tsuji allylation reaction for the formation of alkyl–allyl bonds. Combined experimental and computational studies were employed to unravel the mechanism and origin of site- and chemoselectivity of the reaction.     

Rational Development of Remote C−H Functionalization of Biphenyl: Experimental and Computational Studies

A simple and efficient nitrile-directed meta-C−H olefination, acetoxylation, and iodination of biaryl compounds is reported. Compared to the previous approach of installing a complex U-shaped template to achieve a molecular U-turn and assemble the large-sized cyclophane transition state for the remote C−H activation, a synthetically useful phenyl nitrile functional group could also direct remote meta-C−H activation. This reaction provides a useful method for the modification of biaryl compounds because the nitrile group can be readily converted to amines, acids, amides, or other heterocycles. Notably, the remote meta-selectivity of biphenylnitriles could not be expected from previous results with a macrocyclophane nitrile template. DFT computational studies show that a ligand-containing Pd–Ag heterodimeric transition state (TS) favors the desired remote meta-selectivity. Control experiments demonstrate the directing effect of the nitrile group and exclude the possibility of non-directed meta-C−H activation. Substituted 2-pyridone ligands were found to be key in assisting the cleavage of the meta-C−H bond in the concerted metalation–deprotonation (CMD) process.     

Ultrasound-Facilitated Direct meta-C−H Functionalization of Arenes: A Time-Economical Strategy under Ambient Temperature with Improved Yield and Selectivity

The horizon of ultrasound-assistance has been expanded to palladium-catalyzed distal C−H functionalization of arenes. Compared to thermal conditions, operationally simple ultrasound mediated distal C−H functionalization occurred with a shorter reaction time and enhanced reactivity of reactants to give superior yields with improved selectivity both in terms of meta:others and mono:di. A wide variety of meta-functionalizations such as olefination, alkylation, acetoxylation, allylation and cyanation were successfully carried out under ambient temperature.     

Catalytic Gold Chemistry: From Simple Salts to Complexes for Regioselective C−H Bond Functionalization

Gold coordinated to neutral phosphines (R₃P), N-heterocyclic carbenes (NHCs) or anionic ligands is catalytically active in functionalizing various C−H bonds with high selectivity. The sterics/electronic nature of the studied C−H bond, oxidation state of gold and stereoelectronic capacity of the coordinated auxiliary ligand are some of the associated selectivity factors in gold-catalyzed C−H bond functionalization reactions. Hence, in this review a comprehensive update about the action of different types of gold catalysts, from simple to sophisticated ones, on C−H bond reactions and their regiochemical outcome is disclosed. This review also highlights the catalytic applications of Au(I)- and Au(III)-species in creating new opportunities for the regio- and site-selective activation of challenging C−H bonds. Finally, it also intends to stress the potential applications in selective C−H bond activation associated with a variety of heterocycles recently described in the literature.     

Photochemical Functionalization of Heterocycles with EBX Reagents: C−H Alkynylation versus Deconstructive Ring Cleavage**

The development of novel methodologies for the functionalization of saturated heterocycles is highly desirable. Herein, we report a cheap and efficient photochemical method for the C−H functionalization of saturated O-heterocycles, as well as the deconstructive ring-cleavage of S-heterocycles, employing hypervalent iodine alkynylation reagents (ethynylbenziodoxolones, EBX). This photochemical alkynylation is performed utilizing phenylglyoxylic acid as the photoinitiator, leading to the corresponding products in good to high yields, under household fluorescent light bulb irradiation. When O-heterocycles were employed, the expected α-C−H alkynylation took place. In contrast, oxidative ring-opening to form a thioalkyne and an aldehyde was observed with S-heterocycles. Preliminary mechanistic experiments are presented to give first insights into this puzzling divergent reactivity.     

Imine Directed Cp*RhIII-Catalyzed N−H Functionalization and Annulation with Amino Amides,Aldehydes, and Diazo Compounds

A multicomponent annulation that proceeds by imine directed Cp*Rh^III-catalyzed N−H functionalization is disclosed. The transformation affords piperazinones displaying a range of functionality and is the first example of transition metal-catalyzed multicomponent N−H functionalization. A broad range of readily available α-amino amides, including those derived from glycine, α-substituted, and α,α-disubstituted amino acids, were effective inputs and enabled the incorporation of a variety of amino acid side chains with minimal racemization. Branched and unbranched alkyl aldehydes and various stabilized diazo compounds were also efficient reactants. The piperazinone products were further modified through efficient transformations. Mechanistic studies, including X-ray crystallographic characterization of a catalytically competent five-membered rhodacycle with imine and amide nitrogen chelation, provide support for the proposed mechanism.