Search

The hypervalent iodine-mediated formation of steroidal 5/5-spiroiminals and 5/5-spiroaminals from steroidal amines is presented. Under the influence of excess PhI(OAc)2 and iodine in acetonitrile at 0 °C, steroidal amines smoothly underwent cyclization to give a mixture of 5/5-spiroiminals and 5/5-spiroaminals. This reaction represents the first example of a C-H-activation-mediated formation of a spiroiminal. Presumably, the formation of 5/5-spiroiminals occurs through aminyl radical-mediated cyclization followed by amine-to-imine oxidation. [ABSTRACT FROM AUTHOR]

The development of efficient synthetic procedures to access fused N, O-heterocyclic skeletons has been a pivotal research topic in organic synthesis for several years. Owing to the applications of N, O-fused heterocycles in organic synthesis, material sciences, and medicinal chemistry, significant efforts have been dedicated to design novel methods for their construction. To this end, 1,3-benzoxazin-4-ones are privileged candidates for N, O-heterocyclic molecules often found in natural products, agrochemicals, and materials science applications. In this review, we aim to summarize the existing literature on the synthesis of 1,3-benzoxazin-4-ones from 2010 onwards. Moreover, 1,3-benzoxazin-4-ones have also been identified as an excellent native directing group for the ortho-functionalization via C-H activation, which is often a strenuous task requiring pre-functionalized substrates. In the latter part of this report, we compiled several interesting examples of N-directed functionalizations of 1,3-benzoxazin-4-ones. Additionally, to emphasize biological importance, recent developments on the anticancer evaluations of benzoxazine-4-one core are included. We believe that by harnessing the methodologies discussed herein, new possibilities could be unlocked for the synthesis of fused N, O-heterocycles, leading to the development of novel biologically active compounds and functional materials. [ABSTRACT FROM AUTHOR]

Oxidative C–H bond activated palladium-catalyzed aromatic cross-coupling reactions offer advantages of fewer required synthetic steps but disadvantages of loss of inherent regioselectivity and selectivity. In one proposed catalytic cycle, each arene adds to a palladium carboxylate catalyst according to a concerted metalation deprotonation mechanism, followed by reductive elimination to couple the arenes and the replenishment of the catalyst by an oxidant. Using this proposed mechanism, molecular structures and free energy profiles were calculated for coupling of benzene with a range of heteroarenes containing various substituents and with several Pd-carboxylate catalysts. Reaction kinetics were analysed using the energetic span model, predicting turnover frequencies (TOFs) of heterocoupling (HB and BH) and homocoupling (HH and BB) pathways and assessing degrees of turnover frequency control (XTOFs). More electron-withdrawing carboxylate ligands and more electron-donating heteroarene substituents decrease activation and reaction free energies of addition steps, with C-2 more favourable than C-3. When heteroarene and catalyst choice are particularly favourable, the first association can become exergonic, causing a significant change in catalytic kinetics. When not exergonic, free energy for addition of benzene is almost always higher, leading to large energetic spans and slower TOFs (BB < HB < BH < HH). Non-exergonic pathways are also faster with more electron-withdrawing ligands and more electron-donating heteroarene substituents because of lower energy addition steps and a smaller energetic span. For exergonic associations, the low-energy arene–catalyst intermediate creates a larger energetic span, slowing down the HH and HB pathways. More electron-withdrawing ligands and more electron-donating substituents increase the relative TOF for BH, and the reaction requires only small excesses of benzene to induce heterocoupling. [ABSTRACT FROM AUTHOR]

The activation of inert C–H bonds remains a challenge in current chemistry. Here, we report the excellent reactivity of the anionic gallylene species [LGa:][Na(THF)3] (L = [(2,6-iPr2C6H3)NC(CH3)]22−, 1) that allows the selective activation one ortho sp2 C–H bond of several azobenzene and azide derivatives at ambient temperature, with the transfer of the hydrogen atom to one of the nitrogen atoms. The process leads to the formation of the aryl amido products [LGa-κ2N,C-PhNN(H)(p-R-C6H3)][Na(solvent)3] (2, R = H solvent = DME (1,2-Dimethoxyethane); 3, R = –OMe, solvent = DME; 4, R = –NMe2 solvent = THF), [LGa-κ2N,C-(m-CH3-C6H4)NN(H)(m-CH3-C6H3)][Na(15-C-5)2] (5) with new Ga–C and Ga–N bonds. Moreover, 1 is also effective for the C–H activation of two azides RN3 (R = 2,4,6-Me3C6H2 or 2,6-iPr2C6H3), resulting in the formation of gallium amides [LGa(NH-2-(CH2)-4,6-Me2C6H2)][Na(15-C-5)2] (6) and [LGa(NH-2,6-iPr2C6H3)2][Na(THF)5] (7) through intra- or intermolecular sp3 C–H amination. Significantly, these reactions occur for the highly challenging activation of inert C(sp2)–H and C(sp3)–H bonds, thus demonstrating the excellent reactivity of the Ga(I) species 1. The products 2–7 were characterized by X-ray crystallography, 1H and 13C NMR, UV–vis spectroscopy, and density functional theory (DFT) calculations. [ABSTRACT FROM AUTHOR]

The peroxygenases are ideal biocatalysts for the selective oxyfunctionalisation of stable C–H bonds. However, the catalytic efficiency of this approach is limited due to enzyme lability toward oxidant H2O2. Although the reported in-situ H2O2 generation system enables the stable biocatalytic process without deactivating the enzyme, the greatest catalytic potential of peroxygenases still cannot be fulfilled effectively. To address the above issue, a H2O2 generation-detection-regulation platform that integrated an effective organocatalyst-driven H2O2 generation system, a precise electrochemical H2O2 real-time detection device, and a convenient H2O2 regulation strategy was first developed. The suitable range of H2O2 generation rate for maximizing the catalytic efficiency of peroxygenases while minimizing inactivation of the enzyme was firstly obtained by simply adjusting the amount of organocatalyst. According to the determined suitable range, the C–H oxyfunctionalisation efficiency of peroxygenases for each substrate was significantly boosted, achieving ∼3-fold of the reported highest turnover frequency.

A biomass-based catalyst, CuxOy@CS-400, was employed as an excellent recyclable heterogeneous catalyst to realize the sulfonylation reaction of aniline derivatives with sodium sulfinates. Various substrates were compatible, giving the desired products moderate to good yields at room temperature. In addition, this heterogeneous copper catalyst was also easy to recover and was recyclable up to five times without considerably deteriorating in catalytic efficiency. Importantly, these sulfonylation products were readily converted to the corresponding 4-sulfonyl anilines via a hydrolysis step. The method offers a unique strategy for synthesizing arylsulfones and has the potential to create new possibilities for developing heterogeneous copper-catalyzed C-H functionalizations. [ABSTRACT FROM AUTHOR]

The indole moiety, a prevalent and versatile heterocyclic scaffold, plays a pivotal role in the realm of organic synthesis, underpinning the structural basis of myriad natural products, pharmaceuticals and advanced materials. This review comprehensively surveys the landscape of methodologies for indole synthesis, highlighting the evolution of techniques from classical to contemporary strategies. We investigate the Fischer Indole Synthesis, emphasizing its historical significance and mechanistic nuances and transition to discussing the Reissert Indole Synthesis, detailing its unique contributions to the synthesis of indole derivatives. Furthermore, the review explores advanced methodologies including metal-catalyzed reactions, C-H activation processes and green synthesis approaches, offering insights into their mechanisms, scope and limitations. Through this review, we aim to provide a holistic overview of indole synthesis, furnishing researchers with a detailed understanding of its complex mechanisms and the broad utility of the indole moiety in synthesizing biologically active compounds. The synthesis methods reviewed not only underscore the chemical diversity and adaptability of indole chemistry but also highlight ongoing challenges and future directions in the synthesis and transformation of derivatives of indole. This comprehensive examination serves as a valuable resource for chemists seeking to harness the indole scaffold's potential in novel synthetic applications. [ABSTRACT FROM AUTHOR]

A novel methodology for the synthesis of 2-pyridones bearing a 2-pyridyl group on nitrogen and carbon atoms, starting from 2-bromopyridines, was developed employing a simple Ru(II)–KOPiv–Na2CO3 catalytic system. Unsubstituted 2-bromopyridine was successfully converted to the penta-heteroarylated 2-pyridone product using this method. Preliminary mechanistic studies revealed a possible synthetic pathway leading to the multi-heteroarylated 2-pyridone products, involving consecutive oxygen incorporation, a Buchwald–Hartwig-type reaction, and C–H bond activation. [ABSTRACT FROM AUTHOR]

A novel route for C(sp3)-N bond formation via C(sp2)−H activation/reduction by metal-free which uses (E)- N ′-benzylideneacetohydrazide and (vinylsulfonyl)benzene to synthesize derivatives of (E)- N ′-benzylidene- N -(2-(phenylsulfonyl)ethyl)acetohydrazide has been reported. This methodology features good functional group tolerance and convenient operation. In addition, it uses inexpensive and insensitive chemical reagents as raw materials and provides an atom- and efficient method for the preparation of (E)- N ′-benzylidene- N -(2-(phenylsulfonyl)ethyl)acetohydrazides. [ABSTRACT FROM AUTHOR]

C–H bond activation is a crucial synthetic strategy widely utilized in both academic and industrial settings. Due to the strong and kinetically inert nature of the C–H bond, its functionalization typically requires metal-based catalysts. This review highlights the most significant advancements in homogeneously catalyzed reactions using pincer complexes with metals from groups 8–10, capable of promoting challenging C–H activation, published since 2010. In particular, it focuses on C–H bond activation for borylation, isomerization, and dehydrogenation, among other processes, discussing their scope and mechanistic insights. [ABSTRACT FROM AUTHOR]

Transition-metal-catalyzed directed C–H functionalization with various carbene precursors has been widely employed for constructing a wide range of complex and diverse active molecules through metal carbene migratory insertion processes. Among various carbene precursors, iodonium ylides serve as a novel and emerging carbene precursor with features including easy accessibility, thermal stability and high activity, which have attracted great attention from organic chemists and have achieved tremendous success in organic transformation. In this review, recent progress on the application of iodonium ylides with multifunctional coupling characteristics in C–H bond activation reactions is summarized, and the potential of iodonium ylides is discussed. [ABSTRACT FROM AUTHOR]

The peroxygenases are ideal biocatalysts for the selective oxyfunctionalisation of stable C-H bonds. However, the catalytic efficiency of this approach is limited due to enzyme lability toward oxidant H2O2. Although the reported in-situ H2O2 generation system enables the stable biocatalytic process without deactivating the enzyme, the greatest catalytic potential of peroxygenases still cannot be fulfilled effectively. To address the above issue, a H2O2 generation-detection-regulation platform that integrated an effective organocatalyst-driven H2O2 generation system, a precise electrochemical H2O2 real-time detection device, and a convenient H2O2 regulation strategy was first developed. The suitable range of H2O2 generation rate for maximizing the catalytic efficiency of perox-ygenases while minimizing inactivation of the enzyme was firstly obtained by simply adjusting the amount of organocatalyst. According to the determined suitable range, the C-H oxyfunctionalisation efficiency of peroxygenases for each substrate was significantly boosted, achieving ~3-fold of the reported highest turnover frequency. [ABSTRACT FROM AUTHOR]

Organic azides are convenient and versatile intermediates for the synthesis of various nitrogen-containing scaffolds, including biologically active compounds, approved drugs, functional materials, etc. Designing general approaches to deliberately chemo-, regio-, and steroselective synthesis of aliphatic azides is an urgent task of synthetic chemistry. Particularly challenging is direct azidation of non-activated C(sp3)−H groups, capable of providing ready access to remote and late-stage functionalization of complex targets without need for re-designing existing multistep synthetic procedures. This contribution surveys the C(sp3)−H azidation approaches known to date, both non-catalytic and catalytic, including enzyme-mediated ones, with the major focus on the synthetic perspective of these transformations. Essential mechanistic details are briefly discussed.

A novel palladium(II) catalyzed C–H annulation strategy has been developed for the synthesis of a diverse range of furo[3′,4':5,6]pyrido[3,4-b]indole-1,5(3H)-dione scaffolds. This is the first report on the construction of polycyclic carboline frameworks from indole-2-carboxamides and 4-hydroxy-2-alkynoates. This method provides a direct access to fused carbolines that are closely resemble to biologically active β-carboline frameworks.

Poly(ionic liquids) (PILs) combined with the macromolecular structure and unique properties of ionic liquids show unlimited potential in catalysis. In this work, a series of metal-based PIL with different ionic ratios were prepared for the selective oxidation of cyclohexane. Characterization analysis reveals that different degrees of ionization could adjust the Co–N sites of the catalysts efficiently, leading to significant changes in their electronic structure, which strongly relate to catalytic performance in oxidation. 20.07% cyclohexane conversion and 13.06% cyclohexanone and cyclohexanol (KA oil) yield can be achieved by metal-based PILs that are better than other commercial catalysts. Compared with CoCl2, metal-based PILs perform well, with superior conversion and KA oil yield. More interestingly, the catalyst created in this study features a malleable Co–N site, which may potentially have an impact on how oxygen species adsorb and desorb from the catalyst. Therefore, the catalyst studied in this work is used as molecular oxygen for the selective oxidation of cyclohexane to produce KA oil, and its application prospect is promising.

Biocatalytic C-H activation has the potential to merge enzymatic and synthetic strategies for bond formation. FeII/αKG-dependent halogenases are particularly distinguished for their ability both to control selective C-H activation as well as to direct group transfer of a bound anion along a reaction axis separate from oxygen rebound, enabling the development of new transformations. In this context, we elucidate the basis for the selectivity of enzymes that perform selective halogenation to yield 4-Cl-lysine (BesD), 5-Cl-lysine (HalB), and 4-Cl-ornithine (HalD), allowing us to probe how site-selectivity and chain length selectivity are achieved. We now report the crystal structure of the HalB and HalD, revealing the key role of the substrate-binding lid in positioning the substrate for C4 vs C5 chlorination and recognition of lysine vs ornithine. Targeted engineering of the substrate-binding lid further demonstrates that these selectivities can be altered or switched, showcasing the potential to develop halogenases for biocatalytic applications.

The present study explores the potential of four NHC-palladium(II) complexes derived from (Z)- or (E)-styryl-N-alkylbenzimidazolium salts, namely trans-dichloro-[(Z)-1-styryl- 3-benzyl-benzimidazol-2-yliden]pyridine palladium(II) (6), trans-dichloro-[(E)-1-styryl-3-benzyl- benzimidazol-2-yliden]pyridine palladium(II) (7), trans-dichloro-[(Z)-1-styryl-3-(3-fluorobenzyl)- benzimidazol-2-yliden]pyridine palladium(II) (8) and trans-dichloro-[(E)-1-styryl-3- (3-fluorobenzyl)-benzimidazol-2-yliden]pyridine palladium(II) (9), to be use as pre-catalysts for the cross-coupling reactions between furanyl or thiofuranyl derivatives and arylbromides via the C–H activation of the heterocycles. The structures of the four Pd(II) complexes have been elucidated through the use of multinuclear NMR, FT-IR and mass spectroscopy. Furthermore, the cis or trans conformation of the styryl substituents and the geometry of two different compounds was substantiated by single-crystal X-ray diffraction, which was carried out on organometallic species 6, 8 and 9. After the optimization of catalytic conditions, which was carried out with 1 mol% of pre-catalyst with KOAc as a base in dimethylacetamide at 120 °C for 3 h, complex 6 proved to be the most effective pre-catalyst agent, with full or quasi full conversions being observed in the cross-coupling of 4-bromoacetophenone with 2-butylfuran, 1-(2-furanyl)-ethanone, furfuryl acetate, furfural, 1-(2-thienyl)-ethanone, thenaldehyde and 2-methylthiophene. [ABSTRACT FROM AUTHOR]

cis-1-amino-2-indanol is an important building block in many areas of chemistry. Indeed, this molecule is currently used as skeleton in many ligands (BOX, PyBOX...), catalysts and chiral auxiliaries. Moreover, it has been incorporated in numerous bioactive structures. The major issues during its synthesis are the control of cis-selectivity, for which various strategies have been devised, and the enantioselectivity of the reaction. This review highlights the various methodologies implemented over the last few decades to access cis-1-amino-2-indanol in racemic and enantioselective manners. In addition, the various substitution patterns on the aromatic ring and their preparations are listed. [ABSTRACT FROM AUTHOR]

Asymmetric catalysis stands at the forefront of modern chemistry, serving as a cornerstone for the efficient creation of enantiopure chiral molecules characterized by their high selectivity. In this review, we delve into the realm of asymmetric catalytic reactions, which spans various methodologies, each contributing to the broader landscape of the enantioselective synthesis of chiral molecules. Transition metals play a central role as catalysts for a wide range of transformations with chiral ligands such as phosphines, N-heterocyclic carbenes (NHCs), etc., facilitating the formation of chiral C-C and C-X bonds, enabling precise control over stereochemistry. Enantioselective photocatalytic reactions leverage the power of light as a driving force for the synthesis of chiral molecules. Asymmetric electrocatalysis has emerged as a sustainable approach, being both atom-efficient and environmentally friendly, while offering a versatile toolkit for enantioselective reductions and oxidations. Biocatalysis relies on nature's most efficient catalysts, i.e., enzymes, to provide exquisite selectivity, as well as a high tolerance for diverse functional groups under mild conditions. Thus, enzymatic optical resolution, kinetic resolution and dynamic kinetic resolution have revolutionized the production of enantiopure compounds. Enantioselective organocatalysis uses metal-free organocatalysts, consisting of modular chiral phosphorus, sulfur and nitrogen components, facilitating remarkably efficient and diverse enantioselective transformations. Additionally, unlocking traditionally unreactive C-H bonds through selective functionalization has expanded the arsenal of catalytic asymmetric synthesis, enabling the efficient and atom-economical construction of enantiopure chiral molecules. Incorporating flow chemistry into asymmetric catalysis has been transformative, as continuous flow systems provide precise control over reaction conditions, enhancing the efficiency and facilitating optimization. Researchers are increasingly adopting hybrid approaches that combine multiple strategies synergistically to tackle complex synthetic challenges. This convergence holds great promise, propelling the field of asymmetric catalysis forward and facilitating the efficient construction of complex molecules in enantiopure form. As these methodologies evolve and complement one another, they push the boundaries of what can be accomplished in catalytic asymmetric synthesis, leading to the discovery of novel, highly selective transformations which may lead to groundbreaking applications across various industries. [ABSTRACT FROM AUTHOR]

Quinazolines are an important class of heterocyclic compounds that have proven their significance, especially in the field of organic synthesis and medicinal chemistry because of their wide range of biological and pharmacological properties. Thus, numerous synthetic methods have been developed for the synthesis of quinazolines and their derivatives. This review article briefly outlines the new synthetic methods for compounds containing the quinazoline scaffold employing transition metal-catalyzed reactions. [ABSTRACT FROM AUTHOR]

Context: The combined use of transition metal-catalyzed C–H activation with aryne annulation reactions has emerged as an important strategy in organic synthesis. In this study, the mechanisms of the palladium(II)-catalyzed annulation reaction of N-methoxy amides and arynes were computationally investigated by density functional theory. The role of methoxy amide as a directing group was elucidated through the calculation of three different pathways for the C–H activation step, showing that the pathway where amide nitrogen acts as a directing group is preferable. At the reductive elimination transition state, an unstable seven-membered ring is formed preventing the lactam formation. A substituent effect study based on an NBO analysis, Hammet, and using a More O'Ferall-Jenks plot indicates that the C–H activation step proceeds via an electrophilic concerted metalation-deprotonation (eCMD) mechanism. The results show that electron-withdrawing groups increase the activation barrier and contribute to an early Pd–C bond formation and a late C–H bond breaking when compared with electron-donating substituents. Our computational results are in agreement with the experimental data provided in the literature. Methods: All calculations were performed using Gaussian 16 software. Geometry optimizations, frequency analyses at 393.15 K, and IRC calculations were conducted at the M06L/Def2-SVP level of theory. Corrected electronic energies, NBO charges, and Wiberg bond indexes were computed at the M06L/Def2-TZVP//M06L/Def2-SVP level of theory. Implicit solvent effects were considered in all calculations using the SMD model, with acetonitrile employed as the solvent. [ABSTRACT FROM AUTHOR]

The construction of N-fused polycyclic compounds at room temperature via the combination of transition-metal catalyst and photocatalyst has been reported. This novel work has successfully realized LED irradiated C-H activation of iodonium ylides. The strategy shows wide substrate scope and ideal functional group tolerance. Our work would be useful for the construction of various heterocyclic compounds. [ABSTRACT FROM AUTHOR]

A strategy of C3/C4 and C5/C4 bis-C–H functionalization of furfural and 5-hydroxymethylfurfural is presented. This task has been accomplished by the initial iridium-catalyzed C–H borylation of furfural, equipped with an appropriate imine function. Depending on the nature of the ligand employed, the borylation takes place selectively at C3 or C5, the products serving in turn as partners in Suzuki-Miyaura cross-couplings. After aldehyde function regeneration, some of the resulting heterobiaryl compounds underwent a, C3- or C5-directed, C4-selective Pd-catalyzed Fujiwara-Moritani olefination. These hitherto unknown serial C3/C4 and C5/C4 bis C–H functionalization strategies allow the straightforward conversion of the bio-sourced platform molecules furfural and 5-hydroxymethylfurfural into tri- and tetra-substituted furaldehyde derivatives.

An efficient Rh(III)-catalyzed C-H activation of azobenzenes and subsequent [4+1] cascade annulation with CF3-imidoyl sulfoxonium ylides was developed, yielding diverse CF3-indazoles. This protocol featured easily available starting materials, excellent functional group tolerance and high efficiency. Moreover, the antitumor activities of selected CF3-indazoles against human cancer cell lines were also studied, and the results indicated that several compounds displayed considerable antiproliferative activities.

Metal-catalyzed cyclization reactions have become a powerful and efficient approach for the stereoselective construction of both carbocyclic and heterocyclic ring systems. Transition metal complexes, with their ability to activate and selectively functionalize organic substrates, have revolutionized various areas of synthetic chemistry. This review highlights recent advancements in metal-catalyzed cyclization reactions, especially in the synthesis of nitrogen-containing heterocycles like imidazoles, pyridines, pyrimidines, and indoles. These advancements have significantly impacted fields such as natural product synthesis, pharmaceuticals, functional materials, and organic electronics. Novel catalytic systems, ligand designs, and reaction conditions continue to expand the capabilities of these reactions, driving further the progress made in synthetic organic chemistry. This review provides a comprehensive overview of recent research.

Methane as the main component in natural gas is a promising chemical raw material for synthesizing value‐added chemicals, but its harsh chemical conversion process often causes severe energy and environment concerns. Photocatalysis provides an attractive path to active and convert methane into various products under mild conditions with clean and sustainable solar energy, although many challenges remain at present. In this review, recent advances in photocatalytic methane conversion are systematically summarized. As the basis of methane conversion, the activation of methane is first elucidated from the structural basis and activation path of methane molecules. The study is committed to categorizing and elucidating the research progress and the laws of the intricate methane conversion reactions according to the target products, including photocatalytic methane partial oxidation, reforming, coupling, combustion, and functionalization. Advanced photocatalytic reactor designs are also designed to enrich the options and reliability of photocatalytic methane conversion performance evaluation. The challenges and prospects of photocatalytic methane conversion are also discussed, which in turn offers guidelines for methane‐conversion‐related photocatalyst exploration, reaction mechanism investigation, and advanced photoreactor design. [ABSTRACT FROM AUTHOR]

In recent years, transition metal-catalyzed C–H activation and site-selective functionalization have been considered to be valuable synthetic tactics to functionalize organic compounds containing multiple C–H bonds. Pyrene is one of the privileged and notorious polycyclic aromatic hydrocarbons. Pyrene and its derivatives have found applications in various branches of chemical sciences, including organic chemistry, chemical biology, supramolecular sciences, and material sciences. Given the importance of pyrene derivatives, several classical methods, including the C–H functionalization method, have been developed for synthesizing modified pyrene scaffolds. This review attempts to cover the recent developments in the area pertaining to the modification of the pyrene motif through the C–H activation process and the functionalization of C–H bonds present in the pyrene motif, leading to functionalized pyrenes.

A single-step method for aniline formation was examined. Using a vanadate catalyst with an iron oxide co-catalyst and hydroxylamine hydrochloride as the amine source, an up to 90% yield of aniline was obtained with high selectivity. Further study showed that the overall reaction was pseudo-second order in terms of hydroxylamine concentration. Regioselective H-D exchange experiments suggest that the C-N bond formation step occurs via an irreversible electrophilic pathway. Based on all of the key observations, a mechanism is proposed.

By exploiting the combined use of a heterogeneous recyclable palladium(II)-bis(N-heterocyclic carbene) catalyst and cyclopentyl methyl ether (CPME) as a convenient recoverable safer reaction medium, an effective waste-minimized approach has been developed for the intramolecular Pd-catalyzed C(sp3)-H activation of methyl pyrrole derivatives. This synthetic tools has allowed to access condensed N-heterocycles generally endowed with biological activities and representatively are the core motif of complex molecules such as Mitomycines and Tylophorines. The heterogeneous catalytic system could be recovered and reused up to representative five runs without any loss in efficiency. The target products (19 examples) have been obtained selectively and with excellent isolated yields up to 93%. The approach leads to the definition of a protocol with a very good E-factor (21) which is much lower (up to 98%) than those of comparable literature examples. Other green metrics have been calculated and the data collected demonstrate that our newly developed protocol is very promising in terms of its environmental impact profile.

Fluorine holds a prominent position within the realm of drug discovery and development, substantiated by its presence in approximately 25% of drugs approved by the US Food and Drug Administration (FDA). Consequently, the advancement of new fluorination reactions stands as a pivotal area in medicinal chemistry. In particular, the monofluoro-, difluoromethyl-, and trifluoromethyl- are three groups that appear most frequently in drug structure. Quinoline, owing to its privileged structural status, plays a crucial role in drug design and synthesis. Various approaches have been documented for the direct difluoromethylation of the C-2 and C-4 positions of the quinoline ring. However, achieving direct C-3 difluoromethylation has remained an elusive objective. In this study, we introduce a novel method for effecting the direct difluoromethylation at the C-3 position of the quinoline ring. Comprehensive characterizations, including 1H-NMR, 13C-NMR, and 19F-NMR for all compounds are performed. We believe that this novel method will open a new way to access the hitherto untapped C-3-difluoromethylation active compounds.

Regioselective rhodium(III)-catalysed C-H activation/annulation of O-pivaloyl benzoylhydroxamates with ortho-alkynylbenzoate esters facilitates the rapid preparation of a novel class of fluorophores based on the isoindolo[2,1-b]isoquinoline-5,7-dione core. The photophysical, electrochemical and coordination properties of these novel structures are investigated. [ABSTRACT FROM AUTHOR]

The naphtholactam scaffold can be found in a lot of natural products or bioactive compounds, with some previous reports highlighting its antibacterial properties. In this context, we report the synthesis of a library of naphtholactams bearing various functional groups and their biological evaluation against the bacterium Pseudomonas aeruginosa. Their synthesis was accomplished through a concise three-step process, from readily available naphthaldehydes, involving a palladium-catalyzed C8-bromination followed by an oxidation/lactam formation sequence. [ABSTRACT FROM AUTHOR]

A rhodium-catalyzed C–H selective amination of 2,4-diarylquinazolines has been developed with the commercially available N -fluorobenzenesulfonimide as the amino source. This approach offers a unique route for direct C–H amidation and demonstrates remarkable functional group tolerance and regioselectivity. [ABSTRACT FROM AUTHOR]

Unreactive C-H bond activation is a new horizon for frustrated Lewis pair (FLP) chemistry. This study provides a systematic assessment of the catalytic reactivity of recently reported intra-molecular FLPs on the activation of typical inert C-H bonds, including 1-methylpyrrole, methane, benzyl, propylene, and benzene, in terms of density functional theory (DFT) calculations. The reactivity of FLPs is evaluated according to the calculated reaction thermodynamic and energy barriers of C-H bond activation processes in the framework of concerted C-H activation mechanisms. As for 1-methylpyrrole, 14 types of N-B-based and 15 types of P-B-based FLPs are proposed to be active. Although none of the evaluated FLPs are able to catalyze the C-H activation of methane, benzyl, or propylene, four types of N-B-based FLPs are suggested to be capable of catalyzing the activation of benzene. Moreover, the influence of the strength of Lewis acid (LA) and Lewis base (LB), and the differences between the influences of LA and LB on the catalytic reactivity of FLPs, are also discussed briefly. This systematic assessment of the catalytic activity of FLPs should provide valuable guidelines to aid the development of efficient FLP-based metal-free catalysts for C-H bond activation. [ABSTRACT FROM AUTHOR]

An efficient method of accessing new CF3-containing spiro-[indene-proline] derivatives has been developed based on a Cp*Rh(III)-catalyzed tandem C-H activation/[3+2]–annulation reaction of 5-aryl-2-(trifluoromethyl)-3,4-dihydro-2H-pyrrole-2-carboxylates with alkynes. An important feature of this spiro annulation process is the feasibility of dehydroproline moiety to act as a directing group in the selective activation of the aromatic C-H bond. [ABSTRACT FROM AUTHOR]

In recent years, transition metal-catalyzed C–H activation and site-selective functionalization have been considered to be valuable synthetic tactics to functionalize organic compounds containing multiple C–H bonds. Pyrene is one of the privileged and notorious polycyclic aromatic hydrocarbons. Pyrene and its derivatives have found applications in various branches of chemical sciences, including organic chemistry, chemical biology, supramolecular sciences, and material sciences. Given the importance of pyrene derivatives, several classical methods, including the C–H functionalization method, have been developed for synthesizing modified pyrene scaffolds. This review attempts to cover the recent developments in the area pertaining to the modification of the pyrene motif through the C–H activation process and the functionalization of C–H bonds present in the pyrene motif, leading to functionalized pyrenes. [ABSTRACT FROM AUTHOR]

A single-step method for aniline formation was examined. Using a vanadate catalyst with an iron oxide co-catalyst and hydroxylamine hydrochloride as the amine source, an up to 90% yield of aniline was obtained with high selectivity. Further study showed that the overall reaction was pseudo-second order in terms of hydroxylamine concentration. Regioselective H-D exchange experiments suggest that the C-N bond formation step occurs via an irreversible electrophilic pathway. Based on all of the key observations, a mechanism is proposed. [ABSTRACT FROM AUTHOR]

The activation of C-H bonds is a potent tool for modifying molecular structures in chemistry. This article details the steps involved in a novel ligand bearing a bicyclic [3.3.1]-nonane framework and bissulfoxide moiety. A palladium catalyzed allylic C-H oxidation method enables a direct benzyl-allylic functionalization with the bissulfoxide ligand. Bissulfoixde ligand possesses a rapidly constructed bicyclic [3.3.1] framework and it proved to be effective for enabling both N- and C-alkylation. A total of 13 C-H activation productions were reported with good to excellent yields. This report validated that it is necessary to include bissulfoxide as a ligand for superior reactivities. Naftifine was produced utilizing developed C-H functionalization methodology in good overall yields.

Disclosed herein is a novel Rh/Ag co-catalyzed SNH directed C–H activation and C–H/N–H bond functionalization protocol of free NH-sulfoximines with hypervalent iodonium ylides. With the aid of AgOTf, these C–H functionalization/cyclization sequences could be achieved at room temperature conditions. The reaction employed EtOH as a “green” solvent and low catalyst loading was required under an oxygen/water-insensitive condition. Under this mild protocol, a wide range of polyheterocyclic sulfoximines bearing fused saturated carbo(hetero)cycles are readily prepared, even toward a complex pharmaceutical Folliculin analog.

The C3-functionalization of furfural using homogeneous ruthenium catalysts requires the preinstallation of an ortho-directing imine group, as well as high temperatures, which did not allow scaling up, at least under batch conditions. In order to design a safer process, we set out to develop a continuous flow process specifically for the C3-alkylation of furfural (Murai reaction). The transposition of a batch process to a continuous flow process is often costly in terms of time and reagents. Therefore, we chose to proceed in two steps: the reaction conditions were first optimized using a laboratory-built pulsed-flow system to save reagents. The optimized conditions in this pulsed-flow mode were then successfully transferred to a continuous flow reactor. In addition, the versatility of this continuous flow device allowed both steps of the reaction to be carried out, namely the formation of the imine directing group and the C3-functionalization with some vinylsilanes and norbonene.

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 CH3OD 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 direct, catalytic arylation of simple arenes in small excess with aryl bromides is disclosed. The developed method does not require the assistance of directing groups and relies on a synergistic catalytic cycle in which phosphine-ligated silver complexes cleave the aryl C-H bond, while palladium catalysts enable the formation of the biaryl products. Mechanistic experiments, including kinetic isotope effects, competition experiments, and hydrogen-deuterium exchange, support a catalytic cycle in which cleavage of the C-H bond by silver is the rate-determining step.

Transition-metal-catalyzed allenes-involved C–H functionalizations demonstrate unique selectivity and undergo exceptional pathways due to the existence of elusive orthogonal cumulative CCC bonds. As a result, it allows for a diverse array of C–H activation reactions, such as allylation, alkenylation, allenylation, dienylation, propargylation, and annulation. In this review, we comprehensively summarize the noteworthy aspects of transition-metal-catalyzed C–H functionalizations involving variously substituted allenes.

Mn-catalysed C–H activation has emerged as a useful sustainable methodology for the formation of new C–C bonds. To date most of the protocols are described in organic solvents. Water as solvent, on the other hand, would be highly advantageous, but is often incompatible with organometallic chemistry. Herein, we describe the C–H activation of indoles using an unmodified, commercially available manganese catalyst in water. Two types of valuable allyl groups can be added and a good substrate scope is described. Substitution at the C-3 group is tolerated, allowing access to medicinally important frameworks, and the reaction works on a gram scale. Finally, harnessing the tolerance of water as the reaction medium, D2O can be used as an inexpensive source of deuterium for the C-2 labelling of indoles.

Selective dehydrogenative silylation is one of the most valuable tools for synthesizing organosilicon compounds. In this study, a regio- and stereoselective ruthenium-catalyzed dehydrogenative intermolecular silylation was firstly developed to access (E)-alkenyl silyl-ether derivatives and silyl-ether heterocycles with good functional group tolerance. Furthermore, two pathways for RuH2(CO)(PPh3)3/NBE-catalyzed dehydrogenative intermolecular silylation of alcohols and alkenes as well as intermolecular silylation of naphthol derivatives were investigated with H2SiEt2 as the hydrosilane reagent. [ABSTRACT FROM AUTHOR]

2-Propargyl-1,3-dicarbonyl compounds have been carbonylated under oxidative conditions and with the catalysis of the PdI2/KI catalytic system to selectively afford previously unreported 2-(4-acylfuran-2-yl)acetamides in fair to good yields (54–81%) over 19 examples. The process takes place under relatively mild conditions and occurs via a mechanistic pathway involving Csp-H activation by oxidative monoamincarbonylation of the terminal triple bond of the substrates with formation of 2-ynamide intermediates, followed by 5-exo-dig O-cyclization (via intramolecular conjugate addition of the in situ formed enolate to the 2-ynamide moiety) and aromative isomerization. [ABSTRACT FROM AUTHOR]