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Highly chemo- and regio-selective C-H bond functionalization of unactivated arenes with propargyl α-aryl-α-diazoacetates has been developed using scandium catalysis. A variety of unactivated, mildly deactivated, and electronically activated arenes have been functionalized using this protocol. The synergistic combination of scandium triflate as a catalyst and propargyl α-aryl-α-diazoacetate as a reagent played a pivotal role in the effective C-H bond functionalization of arenes without the assistance of any directing group or ligand. The practicality of the protocol has been demonstrated by the gram-scale synthesis of very useful α,α-diarylacetates including antispasmodic drug-adiphenine. Based on the experimental observations, labeling experiment, and density functional theory calculations, a plausible reaction mechanism has been outlined.

Metathesis reactions represent powerful synthetic tools that have been used in a number of fields from the synthesis of natural product to functional material preparation. However, the C–H metathes...

The metal-insulator transition driven by electronic correlations is one of the most fundamental concepts in condensed matter. In mixed-valence compounds, this transition is often accompanied by charge ordering (CO), resulting in the emergence of complex phases and unusual behaviors. The famous example is the archetypal mixed-valence mineral magnetite, Fe3O4, exhibiting a complex charge-ordering below the Verwey transition, whose nature has been a subject of long-time debates. In our study, using high-resolution X-ray diffraction supplemented by resistance measurements and DFT+DMFT calculations, the electronic, magnetic, and structural properties of recently synthesized mixed-valence Fe4O5are investigated under pressure to ∼100 GPa. Our calculations, consistent with experiment, reveal that at ambient conditions Fe4O5is a narrow-gap insulator characterized by the original Verwey-type CO. Under pressure Fe4O5undergoes a series of electronic and magnetic-state transitions with an unusual compressional behavior above ∼50 GPa. A site-dependent collapse of local magnetic moments is followed by the site-selective insulator-to-metal transition at ∼84 GPa, occurring at the octahedral Fe sites. This phase transition is accompanied by a 2+ to 3+ valence change of the prismatic Fe ions and collapse of CO. We provide a microscopic explanation of the complex charge ordering in Fe4O5which "unifies" it with the behavior of two archetypal examples of charge- or bond-ordered materials, magnetite and rare-earth nickelates (RNiO3). We find that at low temperatures the Verwey-type CO competes with the "trimeron"/"dimeron" charge ordered states, allowing for pressure/temperature tuning of charge ordering. Summing up the available data, we present the pressure-temperature phase diagram of Fe4O5 © 2022 American Chemical Society. All rights reserved. EAR-1634415; National Science Foundation, NSF: EAR-1606856; U.S. Department of Energy, USDOE: DE-FG02-94ER14466; Office of Science, SC; Argonne National Laboratory, ANL: DE-AC02-06CH11357; Deutsche Forschungsgemeinschaft, DFG: OV-110/3-2; Russian Foundation for Basic Research, РФФИ: 20-42-660027; Israel Science Foundation, ISF: 1552/18, 1748/20; Russian Science Foundation, RSF: 19-72-30043; 122021000039-4 We thank L. S. Dubrovinsky, I. A. Abrikosov, and V. Prakapenka for their interest in this research and B. Lavina for fruitful discussions about in situ DAC synthesis. We are grateful to M. Hanfland for the assistance in using beamline ID-15B of ESRF, Grenoble, France. Portions of this work were performed at GeoSoilEnviroCARS (The University of Chicago, Sector 13), Advanced Photon Source (APS), Argonne National Laboratory. GeoSoilEnviroCARS is supported by the National Science Foundation-Earth Sciences (Grant EAR-1634415) and Department of Energy-GeoSciences (Grant DE-FG02-94ER14466). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. Use of the COMPRES-GSECARS gas loading system was supported by COMPRES under NSF Cooperative Agreement EAR-1606856 and by GSECARS through NSF Grant EAR-1634415 and DOE Grant DE-FG02-94ER14466. The work was partly supported by the Israel Science Foundation (Grants No. 1552/18 and 1748/20) and the Deutsche Forschungsgemeinschaft Grant No. OV-110/3-2. The theoretical analysis was supported by Russian Foundation for the Basic Research (Project No. 20-42-660027). The DFT calculations were supported by the state assignment of Minobrnauki of Russia (Theme “Electron” No. 122021000039-4). The DFT+DMFT calculations were supported by the Russian Science Foundation (Project No. 19-72-30043).

Many of the commonly used pharmaceuticals and biologically active natural products are nitrogen-containing compounds. Recently, the transition-metal-catalyzed or the radical-mediated 1,2-carboamina...

Acridinium dyes have been broadly used as photocatalysts, but it remains synthetically challenging to fine-tune their catalytic performance by functionalization of their structural cores. Acridiniu...

Amine-functionalized covalent organic frameworks (COFs) hold great potential in diversified applications. However, the synthesis is dominated by postsynthetic modification, while the de novo synthesis allowing for direct installation of amine groups remains a formidable challenge. Herein, we develop a site-selective synthetic strategy for the facile preparation of amine-functionalized hydrazone-linked COF for the first time. A new monomer 2-aminoterephthalohydrazide (NH

We present a base-mediated hydroamination protocol, using substoichiometric amounts of a hydrosilane and potassium tert-butoxide­, that operates under mild conditions at 30 °C. Many aryl- and heteroatom-substituted olefins as well as arylamines are tolerated, affording the desired products with complete regioselectivity. Preliminary mechanistic investigations reveal a non-radical pathway for hydroamination. A sequential remote hydroamination strategy involving an initial Fe-catalysed olefin isomerisation followed by our base-mediated hydroamination was also developed to directly access β-arylamines from terminal aliphatic alkenes.

A unified method for direct C4-H halogenation of indoles has been accomplished with the assistance of anthranilic acids as suitable transient directing groups. Exclusive site selectivity (one out of five potential reactive sites) as well as good functional group tolerance was obtained to install three kinds of halogen atoms (Cl, Br and I, respectively) by using inexpensive N-halosuccinimides (NXS) as halogen sources under mild conditions. Taking advantage of the rich functional groups in the product, a diversity of nitrogen-containing heterocycles were facily constructed via one-step late-stage derivations.

A new, simple, yet easily accessible, (1-selenocyanatoethyl)benzene has been designed and applied as a SeCN group transfer reagent for selenocyanation of aliphatic C(sp3)-H bonds for the first time. This protocol is featured with mild reaction conditions and wide substrate scope. Control experiments reveal that a radical-group transfer mechanism might be involved.

Straightforward access to [1,2]-annulated indoles, key substructures in natural products, is highly desirable yet challenging. Herein, a radical triggered fragmentary cyclization cascade reaction of ene-ynamides is presented, providing a rapid access into [1,2]-annulated indoles by an intermolecular radical addition, intramolecular cyclization, desulfonylative aryl migration, and site-selective C(sp2)-N cyclization sequence. DFT calculations support oxidation of N-centered radical species to cations prior to the C-N bond formation, followed by an unusual aza-Nazarov cyclization.

Methods to functionalize arenes and heteroarenes in a site-selective manner are highly sought after for rapidly constructing value-added molecules of medicinal, agrochemical, and materials interest. One effective approach is the site-selective cross-coupling of polyhalogenated arenes bearing multiple, but identical, halogen groups. Such cross-coupling reactions have proven to be incredibly effective for site-selective functionalization. However, they also present formidable challenges due to the inherent similarities in the reactivities of the halogen substituents. In this Review, we discuss strategies for site-selective cross-couplings of polyhalogenated arenes and heteroarenes bearing identical halogens, beginning first with an overview of the reaction types that are more traditional in nature, such as electronically, sterically, and directing-group-controlled processes. Following these examples is a description of emerging strategies, which includes ligand- and additive/solvent-controlled reactions as well as photochemically initiated processes.

Herein, we disclose a recyclable, hybrid manganese catalyst for site‐selective azine C−H activation by weak amide assistance. The novel, reusable catalyst enabled C3–H arylation and C3–H alkylation with ample scope, and was characterized by detailed transmission electron microscopy analysis., A recyclable hybrid‐manganese catalyst was developed for site‐selective azine C−H activation by weak amide‐assistance with ample substrate scope. The heterogeneous catalyst proved to be reusable, and was analyzed in detail by spectroscopy, spectrometry and transmission electron microscopy.

Carbamate-bearing carbohydrates contribute to the pharmacological properties of various natural glycosides. The catalytic site-selective carbamoylation of minimally protected pyranosides was achieved for the first time to bypass protection/deprotection sequences. 1-Carbamoylimidazoles were used as the carbamoylation reagents to circumvent the harmful and unstable phosgene and isocyanates. This borinic acid catalyzed transformation granted an expedient access to the tumor cell-binding carbamoylmannoside moiety of bleomycins and analogs in yields of 56% to 89%.

In the field of medicinal chemistry, the precise installation of a trideuteromethyl group is gaining ever‐increasing attention. Site‐selective incorporation of the deuterated “magic methyl” group can provide profound pharmacological benefits and can be considered an important tool for drug optimization and development. This review provides a structured overview, according to trideuteromethylation reagent, of currently established methods for site‐selective trideuteromethylation of carbon atoms. In addition to CD3, the selective introduction of CD2H and CDH2 groups is also considered. For all methods, the corresponding mechanism and scope are discussed whenever reported. As such, this review can be a starting point for synthetic chemists to further advance trideuteromethylation methodologies. At the same time, this review aims to be a guide for medicinal chemists, offering them the available C−CD3 formation strategies for the preparation of new or modified drugs., “3 D” drug development: The deuterated “magic methyl” group is attracting increased interest in pharmaceutical industry. In this review, we discuss the currently available methods for C−CD3 bond forming reactions and classify them according to the trideuteromethylation reagent. The mechanisms, scope and limitations of each method are considered in order to provide a guide for targeted trideutermethylation.

A straightforward and novel controllable site-selective construction of 2- and 4-substituted pyrimido[1,2-b]indazole from 3-aminoindazoles and ynals has been developed. The high regioselectivity of this reaction could be easily switched by converting different catalytic systems. In this way, a series of 2- and 4-substituted pyrimido[1,2-b]indazole derivatives were obtained in moderate to good yields. In addition, the photophysical properties of compound 3a prepared by the present method were discussed.

An unprecedented hydroalumination of C ═ O bonds catalyzed by zirconocene dichloride is reported herein and applied to the site-selective deprotection of peracetylated functional substrates. A mixed metal hydride, with 1:1 zirconium/aluminum stoichiometry, is also shown to be the reductive species. A catalytic cycle is finally proposed for this transformation with no precedent in the field of zirconium catalysis.

The iron-catalyzed δ-C(sp3)-H bond difluoromethylthiolation and difluoromethylselenation of aliphatic amides with high site selectivity are reported. Essential to the success is the employment of an amide radical formed in situ to activate the inert C(sp3)-H bond and the utilization of the easily handled PhSO2SCF2H and PhSO2SeCF2H as coupling reagents under mild conditions. This scalable protocol exhibits a broad substrate scope bearing versatile functional groups. Mechanistic studies indicate that the reaction proceeds through -SCF2H and -SeCF2H radical transfer.

Herein, we present an undirected para-selective two-step C–H alkylation of complex arenes useful for late-stage functionalization. The combination of a site-selective C–H thianthrenation with palladium-catalyzed reductive electrophile cross-coupling grants access to a diverse range of synthetically useful alkylated arenes which cannot be accessed otherwise with comparable selectivity, diversity, and practicality. The robustness of this transformation is further demonstrated by thianthrenium-based reductive coupling of two complex fragments.

The conservation of chemoselectivity becomes invalid for multiple electrophilic warheads during protein bioconjugation. Consequently, it leads to unpredictable heterogeneous labeling of proteins. Here, we report that a linchpin can create a unique chemical space to enable site-selectivity for histidine and aspartic acid modifications overcoming the pre-requisite of chemoselectivity., Linchpin-enabled promiscuous electrophile uncovers an unchartered reactivity landscape for the precision engineering of proteins.

Conventional C–H alkenylation with alkynes via low-valent transition-metal catalysis occurs at the C6 or C4 position of 2-pyridone with electron-deficient C–H bonds. A bifunctional ligand-bonded Ni...

A novel protocol for the synthesis of pyrido[2,3-b]indoles (α-carbolines, 3) from (E)-3-(2-oxo-2-phenylethylidene) indolin-2-one derivatives 1 and 1,1-enediamine (EDAM) 2a via an unexpected cascade reaction in ethanol was developed. Pyrido[2,3-b]indole derivatives 4 were obtained by the same reaction, albeit by stirring the mixture for a longer period of time (about 48 h). As a result, two kinds of functionalized α-carbolines 3 and 4 were synthesized by the facile reaction of the (E)-3-(2-oxo-2-phenylethylidene)indolin-2-one derivatives and 2-(nitromethylene)imidazolidine under basic conditions (Cs2CO3) in ethanol. In addition, a diverse array of EDAM substrates (2b-2k) were tested in this reaction to afford the expected target compounds 5. This protocol is suitable for the combinatorial and parallel syntheses of natural-like products, including highly functionalized α-carbolines and pyrroles, especially 2-oxoindolin-3-yl pyrroles. This approach features several advantages, such as being a simple and practical operation (requiring only filtration and washing without column chromatography), furnishing excellent yields (72-98%), and producing diverse libraries of target compounds with potential biological activities.

Acridinium dyes are among the most frequently studied classes of organic photocatalysts because of their favorable excited-state properties such as high reduction potential and good lifetime. Howev...

Site-selective modification of oligonucleotides serves as an indispensable tool in many fields of research including research of fundamental biological processes, biotechnology, and nanotechnology. Here we report chemo- and regioselective modification of oligonucleotides based on rhodium(I)-carbene catalysis in a programmable fashion. Extensive screening identifies a rhodium(I)-catalyst that displays robust chemoselectivity toward base-unpaired guanosines in single and double-strand oligonucleotides with structurally complex secondary structures. Moreover, high regioselectivity among multiple guanosines in a substrate is achieved by introducing guanosine-bulge loops in a duplex. This approach allows the introduction of multiple unique functional handles in an iterative fashion, the utility of which is exemplified in DNA-protein cross-linking in cell lysates., The methods for investigation of DNA-binding proteins require site-selective chemical modifications to be introduced into oligonucleotides. Here, the authors report a chemo- and regioselective method for the modification of unpaired guanosines in single- and double-stranded oligonucleotides, based on Rh(I)-carbene catalysis.

The first concise total syntheses of O-3'-senecioyl α-bisabolol β-D-fucopyranoside (4a) and O-3'-isovaleroyl α-bisabolol β-D-fucopyranoside (4b) were achieved through final-stage site-selective acylation via the activation of cis-vicinal diols by imidazole-containing boronic acid catalysts as a key step. This synthetic method was also effective for the syntheses of unnatural analogues with modified acyl side chains or carbohydrate moiety.

In this study, we developed an efficient fluorous tagging strategy for site-selective enzymatic fucosylation/sialylation in which appending a readily removable auxiliary tag (SF17) to the reducing ...

Separating the redox sites of photocatalysts is one of most promising strategies to promote an efficient photoinduced charge transfer of semiconductor photocatalysis. Herein, we present a site-sele...

In this issue of Chem Catalysis, the Larrosa research group develops a synthetic methodology that enables the formation of aryl–alkyl bonds, via C–H activation, by the use of a p-cymene-free mono-cyclometalated Ru(II) catalyst and primary alkyl bromides as coupling partners.

Catalytic methods for the direct introduction of hydrogen isotopes into organic molecules are essential to the development of improved pharmaceuticals and to the alteration of their absorption, distribution, metabolism, and excretion (ADME) properties. However, the development of homogeneous catalysts for selective incorporation of isotopes in the absence of directing groups under practical conditions remains a long-standing challenge. Here, we show that a phosphine-ligated, silver-carbonate complex catalyzes the site-selective deuteration of C–H bonds in five-membered aromatic heterocycles and active pharmaceutical ingredients that have been resistant to catalytic H/D exchange. The reactions occur with CH(3)OD as a low-cost source of the isotope. The silver catalysts react with five-membered heteroarenes lacking directing groups, tolerate a wide range of functional groups, and react in both polar and nonpolar solvents. Mechanistic experiments, including deuterium kinetic isotope effects, determination of kinetic orders, and identification of the catalyst resting state, support C–H bond cleavage from a phosphine-ligated, silver-carbonate intermediate as the rate-determining step of the catalytic cycle.

The site-selective modification of peptide backbones allows an outstanding fine-tuning of peptide conformation, folding ability, and physico-chemical and biological properties. However, to achieve selectivity in the core of these biopolymers is challenging. In the last few years, many advances towards this goal have been developed. This review addresses the selective modification of Cα- and N-positions, from the use of “customizable units” to the residue-directed introduction of substituents. The site-selective modification of the peptide bond, i.e. the formation of thioamides or heterocycles, which alters backbone rigidity and ability to form hydrogen bonds or recognition by enzymes, is also described. Moreover, not only the modifications in internal backbone positions, but also in the N- and C-termini are discussed. In addition to chemical methodologies, the review addresses some reactions, catalyzed by natural or engineered enzymes, that afford unprecedent regio- and stereoselectivity in backbone modifications., This work was mainly financed by project ProID2020010134 (Subvenciones a la Realización I + D Mª Carmen Betancourt y Molina, ACIISI-Gobierno de Canarias, with European Funds for Regional Development-FEDER) with contributions from project APOGEO (MAC/1.1.b./226, Cooperation Program INTERREG-MAC 2014–20 with FEDER funds, as well as Consejo Nacional de Ciencia y Tecnología (CONACYT, Mexico) through project 2015-01-807. D. H. also acknowledges her current contract (TRANSALUDAGRO) financed by Cabildo de Tenerife, Program TF INNOVA 2016-21 (with MEDI & FDCAN Funds). C. J. S. is currently recipient of a “Agustín de Betancourt”-Tenerife 2030 postdoctoral grant (Universidad de La Laguna-Cabildo de Tenerife, cofinanced by MEDI & FDCAN Funds). I. R-E. thanks CONACYT for Catedra contract 942.

Site-selective oxidations of carbohydrates, employing acridinium photocatalysis and quinuclidine hydrogen atom transfer catalysis, are presented. Protocols have been developed for oxidations of all-equatorial carbohydrates as well as those containing cis-1,2-diols. Site-selectivity reflects the relative rates of hydrogen atom transfer from the carbohydrate C-H bonds, and can be enhanced using a phosphate hydrogen-bonding or boronic acid catalyst.

A ligand-accelerated site-selective C–H alkynylation of weakly coordinated yet synthetically promising alcohols, via putative 6, 7 and 8-membered palladacycle intermediates, was developed. The endo-type C–H activation of olefins has been previously well developed, and in the current work we developed an exo C–H alkynylation of alkenols. Importantly, by making judicious choices of amide attached oximes, challenging secondary and tertiary Csp3–H alkynylations of alcohols were also realized.

Antibody-drug conjugates (ADCs) harness the highly specific targeting capabilities of an antibody to deliver a cytotoxic payload to specific cell types. They have garnered widespread interest in drug discovery, particularly in oncology, as discrimination between healthy and malignant tissues or cells can be achieved. Nine ADCs have received approval from the US Food and Drug Administration and more than 80 others are currently undergoing clinical investigations for a range of solid tumours and haematological malignancies. Extensive research over the past decade has highlighted the critical nature of the linkage strategy adopted to attach the payload to the antibody. Whilst early generation ADCs were primarily synthesised as heterogeneous mixtures, these were found to have sub-optimal pharmacokinetics, stability, tolerability and/or efficacy. Efforts have now shifted towards generating homogeneous constructs with precise drug loading and predetermined, controlled sites of attachment. Homogeneous ADCs have repeatedly demonstrated superior overall pharmacological profiles compared to their heterogeneous counterparts. A wide range of methods have been developed in the pursuit of homogeneity, comprising chemical or enzymatic methods or a combination thereof to afford precise modification of specific amino acid or sugar residues. In this review, we discuss advances in chemical and enzymatic methods for site-specific antibody modification that result in the generation of homogeneous ADCs.

A site-selective direct arylation reaction of carbazole and other N-heterocycles with diazo-naphthalen-2(1H)-ones has been developed. While Au(I)-NHC catalysts lead to selective C3-arylation, palladium acetate allows for selective N–H arylation, displaying complete site-selectivity each. To show the applicability of these arylation reactions, one-pot, two-fold diarylation reactions of carbazole were demonstrated.

Site-selective protein modification is of significant interest in chemical biology research, with lysine residues representing a particularly challenging target. Whilst lysines are popular for bioconjugation, due to their nucleophilicity, solvent accessibility and the stability of the resultant conjugates, their high abundance means site-selectivity is very difficult to achieve. Antibody–drug conjugates (ADCs) present a powerful therapeutic application of protein modification, and have often relied extensively upon lysine bioconjugation for their synthesis. Here we discuss advances in methodologies for achieving site-selective lysine modification, particularly within the context of antibody conjugate construction, including the cysteine-to-lysine transfer (CLT) protocol which we have recently reported., In this feature article we discuss developments in site-selective lysine modification methodologies and their application towards the synthesis of antibody–drug conjugates; including our recent work on a cysteine-to-lysine transfer (CLT) protocol.

An efficient and highly regioselective Pd-catalyzed direct arene C(sp2)–H acyloxylation of pyrrolo[2,3-d]pyrimidine derivatives is reported. The key strategy involves the utilization of the unique reactivity of pyrrolo[2,3-d]pyrimidine and the employment of pyrrolo[2,3-d]pyrimidine as the directing group. A variety of monoacyloxylated pyrrolo[2,3-d]pyrimidine derivatives can be achieved by switching the solvents under mild conditions, and they can be further modified and exhibit various biological activities.

Dodecahydrotriphenylene, a higher homologue of trindane chemoselectively undergoes unidirectional benzylic sp3 C–H oxidation and the central benzene ring remains intact unlike that in trindane under similar reaction conditions. RuO4 which generally attacks sp2 C–H to form oxidative products is found to give benzylic ketones via sp3 C–H oxidation. Density functional theory (DFT) calculations have also been performed to analyse the potential energy, energy barrier and HOMO–LUMO energy gap of the products.

Owing to the high synthetic value of deuteration in the pharmaceutical industry, we describe herein the conversion of a range of aromatic ketones to deuterium-labeled products in good to excellent yields. Efficient and site-selective deuteration of benzyl alcohols by D2O with visible light irradiation of quantum dots (QDs), together with gram-scale synthesis and photocatalyst recycling experiments indicated the potential of the developed method in practical organic synthesis.

The site-selective C-H bond functionalization of heteroarenes can eventually provide chemists with great techniques for editing and building complex molecular scaffolds. During the past decade, benzo-fused N-heterocycles such as indoles and quinolines have been among the most widely investigated organic templates. Early developments have led to site-selective C-H bond functionalization on the pyrrole and pyridine cores of indoles and quinolines; however, C-H functionalization on the benzenoid ring has remained a great challenge in catalysis. In this review, we elaborate on recent developments in the highly challenging functionalization of C-H bonds on the less-reactive benzenoid core of indoles and quinolines. These findings are mainly described as selective directing group assisted strategies, remote C-H functionalization techniques and their reaction mechanisms. The underlying principle in each strategy is elucidated, which aims to facilitate the design of a more advanced structure of heterocycles based on bioactive molecules, synthetic drugs, and material aspects. Moreover, the challenges and perspectives for catalytic C-H functionalization to access the arene backbone of indoles and quinolines are also proposed in the conclusion section.

Single-atom photocatalysis as an important organic transformation strategy has received increasing attention, with the performances largely depending on the design of catalysts. This protocol involves initially the fabrication of a single-atom photocatalyst Ni/TiO2 for the visible-light-induced site-selective sulfonation of enamides to give amidosulfones with 36 examples up to 99% yield. The experimental results show that this single-atom photocatalyst Ni/TiO2 can achieve site-selective sulfonation of enamide to construct α-amidosulfones and β-propionamidosulfones under visible light. Importantly, such a single-atom photocatalysis-based synthesis system exhibits favorable recyclability, high turnover number (up to 18 963), excellent tolerance of functional groups, and can be easily scaled up with good efficiency.