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Solvent-Switched Manganese(I)-Catalyzed Regiodivergent Distal vs Proximal C–H Alkylation of Imidazopyridine with Maleimide
... Patel and co-workers reported the base-assisted and solvent-dependent site-selective alkylation of imidazopyridines with a collection of maleimides ( Figure 8). 64 In particular, with TFE as a solvent, the C−H bond from the C-3 position in the imidazopyridines was activated via an electrophilic distal metalation (supported, among other evidence, by the null reactivity observed with imidazopyridines bearing strong electron-withdrawing substituents), whereas the use of THF led to the well-documented C−H activation of the ortho position at the aryl group by a coordination assistance of the imidazopyridine (the fivemembered manganacycle was later detected by ESI-MS). Different solvents and additives produced lower yields and site selectivities. ...
... It is noteworthy that the solvent-switched protocol presented by Patel et al. 64 corresponds to a unique type of metalation, where the Mn−C bond formation reassembles an electrophilic aromatic substitution pathway, assisted by a resonance effect from the heteroatom at the aryl moiety. Hence, this may correspond to a novel access to C−C bond formations at different aryl positions and/or new further Mncatalyzed methodologies for the incorporation of whole new collections of aryl motifs. ...
In recent years, many manganese-based homogeneous catalytic precursors have been developed as powerful alternatives in organic synthesis. Among these, the hydrofunctionalizations of unsaturated C-C bonds correspond to outstanding ways to afford compounds with more versatile functional groups, which are commonly used as building blocks in the production of fine chemicals and feedstock for the industrial field. Herein, we present an account of the Mn-catalyzed homogeneous hydrofunctionalizations of alkenes and alkynes with the main objective of finding catalytic and mechanistic tendencies that could serve as a platform for the works to come.
... [19][20][21] As a result, many research groups are dedicatedly working towards CÀ H bond functionalization on imidazopyridine, most of which revolve around the active nucleophilic C-3 position. [22,23] Amongst functionalized imidazopyridines, the formation of CÀ S bonds at the C-3 position of imidazopyridine has been particularly useful for attenuating its biological and medicinal properties. [24][25][26][27] For instance, in 3-thiolated imidazopyridines, compound A belongs to a class of protease inhibitors; compound B represents a new class of human rhinovirus inhibitors. ...
An external‐photocatalyst‐free visible light‐induced regioselective C‐3 sulfenylation of imidazo[1,2‐a]pyridines using Bunte salts has been accomplished via C(sp²)−H functionalization. This protocol allows the coupling of a wide range of imidazoheterocycles with alkyl‐, benzyl‐, and aryl Bunte salts under ambient air as the sole oxidant. The radical scavenging, UV–visible spectroscopic studies, and Stern−Volmer experiments revealed that the reaction occurs through energy transfer followed by a radical SET pathway. In this work, the dual role of imidazopyridines as photoexciting species and as energy transfer vehicle is proposed. Activation of the triplet oxygen as a result of energy transfer, which acts on somophlic Bunte salts to generate thiyl radical, eventually resulting in the C(sp²)−H functionalization.
... developed a solvent-switched alkylation of imidazopyridine (101) with maleimide (102) under a Mn(I) catalysis (Scheme 26 and Scheme 27). [37] The protocol displayed a special dependency on solvent to divergently functionalize imidazopyridines with maleimides. In 2,2,2trifluoroethanol (TFE) an electrophilic metalation at the distal position to deliver 104 took place whereas in tetrahydrofuran (THF) a chelation-assisted maleimidation occurs at the proximal position to yield 103. ...
Solvent plays an important role in many chemical reactions. The C−H activation has been one of the most powerful tools in organic synthesis. These reactions are often assisted by solvents which not only provide a medium for the chemical reactions but also facilitate reaching to the product stage. The solvent helps the reaction profile both chemically and energetically to reach the targeted product. Organic transformations via C−H activation from the solvent assistance perspective has been discussed in this review. Various solvents such as tetrahydrofuran (THF), MeCN, dichloromethane (DCM), dimethoxyethane (DME), 1,2‐dichloroethane (1,2‐DCE), dimethylformamide (DMF), dimethylsulfoxide (DMSO), isopropyl nitrile (ⁱPrCN), 1,4‐dioxane, AcOH, trifluoroacetic acid (TFA), Ac2O, PhCF3, chloroform (CHCl3), H2O, N‐methylpyrrolidone (NMP), acetone, methyl tert‐butyl ether (MTBE), toluene, p‐xylene, alcohols, MeOH, 1,1,1‐trifluoroethanol (TFE), 1,1,1,3,3,3‐hexafluoroisopropanol (HFIP), tert‐amyl alcohol and their roles are discussed. The exclusive role of the solvent in various transformations has been deliberated by highlighting the substrate scope, along with the proposed mechanisms. For easy classification, the review has been divided into three parts: (i) solvent‐switched divergent C−H activation; (ii) C−H bond activation with solvent as the coupling reagent, and (iii) C−H activation with solvent caging and solvent‐assisted electron donor acceptor (EDA) complex formation and autocatalysis.
... [24] Besides the catalyst-free conjugate addition, Patel et al. reported the transition-metal catalysed reaction with maleimide using a manganese catalyst (Scheme 1c). [25] However, the alkylation of imidazo[1,2-a]pyridines using α,β-unsaturated ketones remains a challenge. ...
Fluorinated triarylboranes have shown a breadth of reactivity as catalysts for organic transformations, particularly in carbon‐carbon bond forming reactions. Herein we report a facile, metal‐free synthetic route for the addition of 2‐phenylimidazo[1,2‐a]pyridines to α,β‐unsaturated ketones using B(C6F5)3 as a metal‐free catalyst. 25 examples of reactions leading to products in up to 97 % yield are reported. DFT studies show the role of B(C6F5)3 and hydrogen shuttling in the mechanism of this Michael alkylation.
A Rhodium(III)-catalyzed C2-selective C-H activation of indoles bearing a 1,3,5-triazine directing group (DG) and conjugated addition to maleimides under air has been described, furnishing the corresponding products in up to...
Electrochemical oxidative cross-dehydrogenative-coupling (CDC) is an ideal strategy to develop C3-alkoxylation of imidazo[1,2-a]pyridine but still remains a challenge owing to limitation by the use of alkyl alcohols and carboxylic acids....
A cobalt(III)‐catalyzed dual C(sp²)−H/C(sp²)−H activation of 2‐arylimidazopyridines and its annulation with N‐substituted maleimides leads to polycyclic aromatic heterocycles. This sustainable oxidative annulation uses earth‐abundant, less toxic, and cost‐effective cobalt(III) catalyst that complement expensive 2nd and 3rd‐row metals. This oxidative annulation features a broad substrate scope with very good functional group tolerance. These maleimide‐fused imidazopyridines display strong fluorescence in the region of 527− 536 nm with a Stokes shift of 83−87 nm and possess an excited state lifetime of 14.6−16.1 ns. Interestingly, such luminescent compounds show aggregation‐enhanced emission (AEE) behavior in the ⁱPr‐OH/hexane mixed solvent system. Furthermore, field emission scanning microscopy (FESEM) reveals their spherical nano‐aggregates with an average diameter of ~216.8 nm. They can also be used as cellular‐imaging and picric acid‐sensing probes.
Over the past five years, maleimide scaffolds have gained considerable attention in organic synthesis for their role in forming cyclized molecules through annulation and C-H activation. As versatile and reactive coupling agents, maleimides have enabled the efficient synthesis of various cyclized products, including annulation, benzannulation, cycloaddition, and spirocyclization, with applications in medicinal chemistry, drug discovery, and materials science. Despite the extensive study of maleimide chemistry, certain reactions-such as cycloaddition-based annulation, photoannulation, and electrochemical transformations-remain underexplored despite their promising potential in the pharmaceutical and chemical industries. Recent advancements, such as photocatalysis and electrochemical methods, have expanded the utility of maleimides, providing more sustainable and selective approaches for synthesizing complex molecules. This review compiles research published between 2019 and 2024, highlighting the substrate scope, reaction diversity, and industrial relevance of maleimide-based annulation strategies. Additionally, we discuss emerging trends and future directions in maleimide chemistry, exploring opportunities for novel reaction pathways and broader applications in synthetic biology and materials science.
Ru(II)‐catalyzed and solvent‐switched [3+2]‐spiroannulation and [4+n] (n=1, 2, 3) annulations of 2‐aryl quinazolinone or 2‐aryl‐2,3‐dihydrophthalazine‐1,4‐diones with ynones or alkynyl alcohol or 1,3‐diynes under mild reaction conditions have been analyzed. These reactions take place in the presence of the appropriate solvent and features a redox‐neutral pathway. Ynone serves as an ‘atypical one‐carbon unit’ in [4+1] annulation and generates a tetrasubstituted carbon center bearing diverse heterocycles through [3+2] and [4+1] annulation strategies. Post transformations of the synthesized spiro‐products augments the potential of the developed methodology.
A visible light-driven di-functionalization of maleimide with disulfide and in situ-generated singlet oxygen offers selective 1,2-thiohydroxylation under additive-free conditions. Here the disulfide plays the dual role of photo catalyst and...
A Ru(II) catalyzed regioselective Heck-type C-H olefination of isoxazole with unactivated allyl phenyl sulfone is revealed. The solvent DCM offers dual sp2-sp2 C-H activation via an N-directed strategy, leading to ortho-olefinated isoxazoles with exclusive E-selectivity. On the other hand, in DCE solvent, isoxazole serves as the nitrile synthon and leads to o-olefinated benzonitrile. At a higher temperature (110 °C) in DCE, after the ortho-olefination Ru(II) mediated cleavage of isoxazoles delivered the nitrile functionality.
Manganese-catalyzed directed C—H functionalization is an efficient and straightforward approach for the formation of a variety of C—C and C—heteroatom bonds. In this review, we summarize the most significant advances in manganese-catalyzed C(sp2)—H functionalizations, including C—H alkenylation, alkylation, allylation, cyclization, amination, cyanation, borylation, and hydroxymethylation. The chapter is classified based on the type of newly formed chemical bond (C—C, C—N, C—B, and C—D bonds) and the reacting partner.
A Mn(I)-catalyzed site-selective nondirected C3-maleimidation of quinoxaline is established. Herein, the electrophilic C3-metalation precedes over the o-directed strategy to access diversely substituted quinoxaline-appended succinimides. The products undergo PIFA-promoted C(sp2)-C(sp3) spirocyclization via π-electrons drifting from aryls and Selectfluor-mediated dehydrogenation of succinimide at room temperature.
Manganese-catalyzed C–C bond coupling reactions are such an attractive alternative tool for the synthesis of organic functional molecules that they are gained considerable attention in the last decade. This chapter highlights selected examples of the recent advances in the catalytic functionalization of inert Csp2–H bonds through organometallic C–H activation. Reactions involving the hydrocarbofunctionalization of unsaturated C–C bonds leading to C–C bonds formation are also briefly addressed herein.KeywordsC–C bond formationC–H activationC–Mn bondCatalysisHydrocarbofunctionalizationManganese
A regioselective manganese-catalyzed ortho-hydroalkylation of aryl-substituted N-heteroaromatic compounds with a range of maleimides is described. The developed C–H bond functionalization protocol allowed the introduction of succinimide motif at the ortho-position of aryl ring of N-heteroaromatic compounds, such as 2-arylimidazo[1,2-a]pyridines, 2-arylindazoles, 2-phenylpyridine, 2-phenylpyrimidine, 2-phenylimidazo[1,2-a]pyrimidine, 2-phenylimidazo[2,1-b]thiazole, 2-phenylbenzo[d]imidazo[2,1-b]thiazole, 1-phenylindazole, and 1-phenylpyrazole to produce 3-(2-(N-heteroaryl)aryl)-pyrrolidine-2,5-diones in good yields. The protocol exhibited broad substrate scope, good functional group tolerance, and excellent regioselectivity under mild and additive-free reaction conditions.
An efficient PdII- and RhIII-controlled site-selective C-H bond alkynylation of imidazopyridines using (bromoethynyl)triisopropylsilane is disclosed. The divergent methodology allows straightforward access to a wide range of products alkynylated at the C3 and ortho positions. This strategy is suggestive of a practical platform that can be suitable for late-stage diversification and may assist in the design of more selective and complementary catalytic systems.
Imidazopyridine is an important framework that constitutes several pharmaceutical drugs and biologically active molecules. Herein, we present the palladium-catalyzed regioselective C3-allylic alkylation of 2-aryl imidazopyridines with MBH carbonates. This strategy furnishes a broad spectrum of C3-allylated imidazopyridines, and their structures have been unequivocally established using X-ray analysis. Besides, the reaction can be easily scaled up on a gram scale, and the ensuing product can be smoothly manipulated into synthetically useful entities.
A Cu(OTf)2 mediated regioselective de-aromatized aryl-hydroxylation across C(sp2)N bond of 2-aryl quinoxalines and bis-N-arylation of (benz)imidazoles is developed using aryl boronic acids. For dearomative aryl-hydroxylation, the C-center should be electrophilic...
A solvent (2,2,2-trifluoroethanol (TFE) vs ethyl alcohol (EtOH)) switched synthesis of quinolines and pyridines is illustrated from (E)-2-(1,3-diphenylallylidene)malononitriles via a Pd(II)-catalyzed photochemical process. The active catalyst [L2Pd(0)] generated serves as an exogenous photosensitizer. The process offers predominantly Z-alkenylated quinolines and pyridines in TFE and EtOH, respectively. Furthermore, large-scale synthesis and a few interesting post-synthetic modifications have been demonstrated.
The synthesis and chemistry of pyrazoles, imidazoles, 1,2,3-triazoles, 1,2,4-triazoles, and tetrazoles were actively pursued in 2021. No attempt was made to incorporate all the exciting chemistry and biological applications that were published in 2021.
Copper-catalyzed cyclization of alkynes has played a significant role in modern catalytic chemistry. However, the selective cyclization in this transformation is extremely limited by the uncontrolled reactivity of the vinyl-CuII...
A palladium-catalyzed decarboxylative domino reaction of imidazo[1,2- a ]pyridines and coumarin-3-carboxylic acids has been developed, which provides access to dibenzoisochromenoimidazo[1,2- a ]pyridin-6-ones possessing six fused rings.
Herein, we report a cobalt‐catalyzed hydroarylation of maleimides followed by an annulation sequence for the synthesis of polycyclic azaheterocycles in one pot. The reaction proceeds under redox‐neutral conditions and is compatible with various functional groups. Notably, the as‐prepared product exhibits potential photophysical properties.
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The isocyanate group in aryl isocyanates serves as a transformable transient directing group in a Ru(II)-catalyzed ortho olefination leading to o-alkenylanilines. In alcoholic solvents, aryl isocyanates are transformed into carbamates, which initiate the insertion of acrylates via o-C-H activation. In particular, tAmOH serves the dual role of solvent-cum transient directing mediator. The o-alkenylanilines are converted into azacoumarins and subsequently into C-4 aryl-substituted azacoumarins using aryl iodides as coupling partners via Pd(II)-catalyzed C-H functionalizations.
Functionalization of 2-phenylimidazo [1,2-a]pyridine-3-carbaldehydes has been achieved through ruthenium (II) catalysed oxidative C-2′-alkenylation with acrylate ester, leading to the formation of regioselective monoalkenylated products. This protocol can also be utilised for the alkenylation of various 2-phenylbenzo [d]oxazole and 2-phenylbenzo [d]thiazole derivatives. Mechanistic studies revealed that the formation of a five membered cyclic ruthenium complex facilitated the C–H activation. Further, the control experiments including deuterium labelling and 2D NMR suggested the selective aromatic C-2′ activation over C-5/C-8 positions of 2-phenylimidazo [1,2-a]pyridine-3-carbaldehydes.
Transition metal catalysis has contributed immensely to C-C bond formation reactions over the last few decades, and alkylation is no exception. The superiority of such methodologies over traditional alkylation is evident from minimal reaction steps, shorter reaction times, and atom economy while also allowing control over regio- and stereo-selectivity. In particular, hydrocarbonation of alkenes has grabbed increased attention due its fundamental ability to effectively and selectively synthesise a wide range of industrially and pharmaceutically relevant moieties. This review attempts to provide a scientific viewpoint and a systematic analysis of the recent developments in transition-metal-catalyzed alkylation of various C-H bonds using simple and activated olefins. The key features and mechanistic studies involved in these transformations are described briefly.
A convenient and atom-economical rhodium(III)-catalyzed Highly-Selective hydroacylation for the synthesis of spirobenzofuranones and diketones has been successfully developed. Ortho-hydroxyl-group-assisted aldehyde C−H cascade [4+1] annulation makes the formation of spiro compounds...
Earth-abundant and water-tolerant manganese(i) catalyzed alkenylation of 2-arylindazole with alkyl and aryl alkynes through C-H bond activation is described with a unique level of E-selectivity. The reaction proceeds through the control of C3 nucleophilicity of 2-aryl indazoles. This method is applied to the late-stage functionalization of complex molecules including ethinylestradiol, norethisterone, and N-protected amino acid derivatives. The kinetic isotope studies suggest that the C-H bond activation step may not be the rate-determining step.
The structural modification of N-aryl indazolols as tautomers of N-aryl indazolones has been established as a hot topic in pharmaceutics and medicinal chemistry. We herein disclose the rhodium(III)-catalyzed 1,4-addition reaction of maleimides with N-aryl indazol-3-ols, which provides the succinimide-bearing indazol-3-ol scaffolds with complete regioselectivity and a good functional group tolerance. Notably, the versatility of this protocol is demonstrated by the use of drug-molecule-linked and fluorescence-probe-linked maleimides.
Selective C(sp²)−H bond alkylation of indoline, carbazole and (2‐pyridinyl)arenes with unactivated alkyl bromides is achieved using MnBr2 catalyst in the absence of an external ligand. The alkylation uses a simple LiHMDS base and avoids the necessity of Grignard reagent, unlike other Mn‐catalyzed C−H functionalization. This reaction proceeded either through a five‐ or a less‐favored six‐membered metallacycle, and tolerated diverse functionalities, including alkenyl, alkynyl, silyl, aryl ether, pyrrolyl, indolyl, carbazolyl and alkyl bearing fatty alcohol and polycyclic‐steroid moieties. Alkylation follows a single electron transfer (SET) pathway involving 1e oxidative addition of alkyl bromide and a rate‐limiting C−H metalation.
A new rhodium(III)-catalyzed three-component multistep cascade spirocyclization approach was developed to synthesize nolvel N-acetyl chain of spiropyrroloisoquinoline derivatives using oxadiazoles as the directing group. This one-pot reaction also isolates aryloxadiazole...
Imidazo[1,2‐a]pyridine is an important nitrogen‐containing heterocycle from biological as well as pharmaceutical point of view. In recent years, regioselective functionalization of C−H bond of imidazo[1,2‐a]pyridine is extensively carried out using various transition metal‐based catalysts. Alkenylation, arylation, dual dehydrogenative annulations, formylation, thiolation, aminomethylation, dicarbonylation, phosphonylation along with other significant reactions are the progress in the field of functionalization of imidazopyridine. Most of these functionalizations are done at the C‐3 position of imidazo[1,2‐a]pyridine scaffold and in addition to that development towards C‐5 regioselectivity is also available. In this review, our aim is to present the recent advances for the functionalization of imidazo[1,2‐a]pyridine employing transition metal catalysts under significant reaction conditions.
A manganese/NaOPh co-catalyzed C2-selective C-H conjugate addition of indoles to α,β-unsaturated carbonyls has been developed. The reaction features very high atom economy in which no stoichiometric reagents/additives were employed. The crucial role of sodium phenolate (NaOPh) as a synergetic catalyst was revealed in the reaction screening process and mechanistic experiments.
Directing group assistance provided a paradigm for controlling site-selectivity in transition metal-catalyzed C–H functionalization reactions. However, the kinetically and thermodynamically favored formation of 5-membered metallacycles has greatly hampered the selective activation of remote C(sp³)–H bonds via larger-membered metallacycles. Recent development to achieve remote C(sp³)–H functionalization via the C–H metallation process largely relies on employing specific substrates without accessible proximal C–H bonds. Encouragingly, recent advances in this field have enabled the selective functionalization of remote aliphatic C–H bonds in the presence of equally accessible proximal ones by taking advantage of the switch of the regiodetermining step, ring strain of metallacycles, multiple non-covalent interactions, and favourable reductive elimination from larger-membered metallacycles. In this review, we summarize these advancements according to the strategies used, hoping to facilitate further efforts to achieve site- and even enantioselective functionalization of remote C(sp³)–H bonds.
Rhodium(III)‐catalyzed dehydrogenative annulation of 2‐aryl‐imidazo[1,2‐a]pyridines with maleimides is described. The reaction afforded 1H‐benzo[e]pyrido[1′,2′:1,2]imidazo[4,5‐g]isoindole‐1,3(2H)‐diones in high yields with wide range of functional group tolerance. The reaction proceeds through Rh(III)‐catalyzed C−H bond activation, followed by maleimide insertion and intramolecular cyclization. Photophysical properties of 1H‐benzo[e]pyrido[1′,2′:1,2]imidazo[4,5‐g]isoindole‐1,3(2H)‐diones were studied with UV‐visible and fluorescence spectroscopy and validated by quantum chemical calculations. All the annulated products showed large Stokes shift values with emission in the range of 530–618 nm, and moderate to high quantum yields.
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Selective C−H bond functionalization catalyzed by metal complexes have completely revolutionized the way in which chemical synthesis is conceived nowadays. Typically, the reactivity of a transition metal catalyst is the key to control the site‐, regio‐ and/or stereo‐selectivity of a C−H bond functionalization. Of particular interests are molecules that contain multiple C−H bonds prone to undergo C−H bond activations with very similar bond dissociation energies at different positions. This is the case of benzanilides, relevant chemical motifs that are found in many useful fine chemicals, in which two C−H sites are present in chemically different aromatic fragments. In the last years, it has been found that depending on the metal catalyst and the reaction conditions, the amide motif might behave as a directing group towards the metal‐catalyzed C−H bond activation in the benzamide site or in the anilide site. The impact and the consequences of such subtle control of site‐selectivity are herein reviewed with important applications in carbon‐carbon and carbon‐heteroatom bond forming processes. The mechanisms unraveling these unique transformations are discussed in order to provide a better understanding for future developments in the field of site‐selective C−H bond functionalization with transition metal catalysts.
A switchable Rh(III)-catalyzed highly regioselective hydroarylation and oxidative arylation of maleimides with 2-arylindazoles via C−H activation has been demonstrated. The reaction affords 3-(2-(2H-indazol-2-yl)phenyl)succinimide and 3-(2-(2H-indazol-2-yl)phenyl)maleimide derivatives in high yields with...
During the last two decades, impressive advancements have been achieved in transition metal‐ catalyzed chelation‐assisted C—H functionalization reaction. While reactions in this field are still dominated by precious 4d or 5d metals (e.g., Pd, Rh, Ir), the 3d base metals (e.g., Ni, Co, Cu, Fe) have made significant headway partially due to their relatively large abundance, low cost, low toxicity as well as their occasionally occurred novel reactivity when compared to their noble cousins. This review will give a comprehensive summary on Ni‐catalyzed functionalization of inert C—H bonds assisted by chelation groups. For clarity, the content is classified by the newly formed chemical bonds, namely C—C, C—N, C—chalcogen and C—halogen bond formation. image
Among nitrogen‐containing organic compounds, imidazo[1,2‐a]pyridines, and especially C3‐functionalized imidazo[1,2‐a]pyridines, have a wide range of industrial applications in the fields of optics, material science, and organometallics. This scaffolds also have various medicinal uses due to their antiviral, cytotoxic, antibacterial, fungicidal, and antiinflammatory activities as they are found in many commercially available drugs such as Alpidem, Miroprofen, and Zolimidine. In this review, we summarized and classified the latest synthetic methods for the preparation of C3‐functionalized imidazo[1,2‐a]pyridines based on the type of the substituents on the 3‐position of imidazo[1,2‐a]pyridine including C3‐alkylation, C3‐arylation, C3‐carbonylation, C3‐sulfenylation, C3‐selenation, C3‐N‐Substitution, C3‐phosphonation, and C3‐halogenation.
A unique approach to achieve site‐selective C−H olefinations exclusively at the C‐3‐ or C‐8‐positions in the quinoline framework has been developed by catalyst control. Distal C(3)−H functionalization is achieved by using palladium catalysis, whereas proximal C(8)−H functionalization is obtained by employing ruthenium catalysis. Switching the site selectivity within a single substrate directly indicates two diverse pathways, which are operating under the palladium‐ and ruthenium‐catalyzed reaction conditions.
The limitations of arene C–H functionalization of aryl sulfonamides containing strongly coordinating N-heterocycles were overcome using a Rh(III) catalyst. The site-selectivity of C–H carbenoid functionalization at the ortho position relative to either the sulfonamide or N-heterocycle directing groups was elegantly switched using solvent of different polarities and different additive concentrations. Importantly, sulfonamide-group-directed ortho-C–H carbenoid functionalization tolerated strongly coordinating N-heterocycles, including pyridine, pyrrole, thiazole, pyrimidine, and pyrazine. Density functional theory (DFT) calculations were performed to rationalize the reaction mechanisms and the influence of reaction polarity.
Herein we describe an unprecedented RuII-catalyzed site-selective and regiospecific annulation of benzoic acids with propargylic carbonates. The weakly coordinating carboxylic acid moiety outperformed other typically used directing groups in C–H...
Maleimide and succinimide core moieties are present in various natural products and pharmaceuticals. In addition, these derivatives can be readily modified into biologically important organic molecules including pyrrolidines and γ‐lactams. A transition‐metal‐catalyzed chelation‐assisted functionalization of inert C−H bond of organic molecules with electrophiles or nucleophiles is one of the efficient methods to construct chemical bonds in a highly atom‐ and step‐economical manner. The present review describes the recent advances in the reaction involving maleimides with organic molecules by a chelation‐assisted inert C−H bond activation methodology. The reaction involving maleimides with organic molecules having directing groups, such as ketone, acyl, pyridyl, pyrimidyl, oxime, amide, imidate, chromone, azo, N‐sulfonyl ketimine, carboxylic acids, and aldimines, were described. The scope, limitation and mechanistic investigation of the alkylation, annulation and alkenylation reactions were discussed elaborately. This review article includes the entire report on the chemical bond‐forming reaction of maleimides with organic molecules by the C−H bond activation strategy until the end of 2018.
Bioorthogonal late‐stage diversification of structurally complex peptides has enormous potential for drug discovery and molecular imaging. In recent years, transition‐metal‐catalyzed C−H activation has emerged as an increasingly viable tool for peptide modification. Despite major accomplishments, these strategies largely rely on expensive palladium catalysts. We herein report an unprecedented cobalt(III)‐catalyzed peptide C−H activation, which enables the direct C−H functionalization of structurally complex peptides, and sets the stage for a multicatalytic C−H activation/alkene metathesis/hydrogenation strategy for the assembly of novel cyclic peptides.
We herein present a simple methodology to systematically expand the scope of maleimide-based dyes and also provide an insight into the relationship between substitution pattern and optical properties.
A manganese-catalyzed bicyclic annulation of imines with α,β-unsaturated esters via C–H activation is described, which provides an expedient access to fused β-lactams in one-step operation with high efficiency and good functional group tolerance. Of note, both ketimines and aldimines are amenable to this transformation. Mechanistic studies have identified a five-membered azamanganacycle as the key reaction intermediate.
The pyridyl group has been extensively employed to direct transition-metal-catalyzed C−H activation reactions in the past half-century. The typical cyclic transition states involved in these cyclometalation processes have only enabled the activation of ortho-C−H bonds. Here, we report that pyridine is adapted to direct meta-C−H activation of benzyl and phenyl ethyl alcohols through engineering the distance and geometry of a directing template. This template takes advantage of a stronger σ-coordinating pyridine to recruit Pd catalysts to the desired site for functionalization. The Ushaped structure accommodates the otherwise highly strained cyclophane-like transition state. This development illustrates the potential of achieving site selectivity in C−H activation via the recognition of distal and geometric relationship between existing functional groups and multiple C−H bonds in organic molecules.
Ru(II) catalyzed annulation of 2-arylimidazo[1,2-a]pyridines with maleimides has been achieved for the synthesis of a diverse range of benzo[e]pyrido[1',2':1,2]imidazo[4,5-g]isoindole derivatives. The reaction proceeds through a Ru(II)-catalyzed C–H metalation of 2-arylimidazo[1,2-a]pyridine followed by maleimide insertion and intramolecular cyclization. This method is simple and atom-economical to produce the pharmaceutically relevant benzo[e]pyrido[1',2':1,2]imidazo[4,5-g]isoindole derivatives with a wide substitution pattern.
Manganese-catalyzed C-H activation has emerged as a powerful tool in organic synthesis within a few years. These reactions are highly selective, eco-friendly and exhibit wide substrate scope. These strategies have...
In this paper, an efficient and sustainable synthesis of the synthetically and pharmaceutically significant maleimide-fused benzocarbazoles/imidazo[1,2-a]pyridines from the reaction of 2-arylindoles/2-arylimidazo[1,2-a]pyridines with maleimides through rhodium-catalyzed oxidative [4 + 2] annulation is presented. This method features easily obtainable substrates, high atom-efficiency and good functional group tolerance. Notably, by using this method a bioactive agent was smoothly synthesized in an excellent yield.
A Ru(II)-catalyzed bisallylation of imidazopyridines with vinylcyclopropanes or vinyl cyclic carbonate has been successfully realized. Notably, pharmacophore imidazopyridine was utilized as an intrinsic directing group, which gave access to value-added bisallylated products in high yields via double tandem C-H and C-C/C-O activation. The current methodology was featured with broad substrate scope, good functional group compatibility, and operational simplicity.
The regiodivergent catalysis of C-H alkylation with alkenes is of great interest and importance, but has remained hardly explored to date. We report herein the first regiodivergent C-H alkylation of quinolines with alkenes by half-sandwich rare-earth catalysts. The regiodivergence was achieved by fine-tuning the metal/ligand combination or steric and electronic prop-erties of the catalysts. The use of a C5Me5-ligated scandium catalyst Sc-3 for the reaction of quinolines with styrenes and that of a C5Me4H-ligated yttrium catalyst Y-2 for the reaction with aliphatic olefins exclusively afforded the corresponding C8-H alkylation products, thus constituting the first example of direct C8‒H alkylation of neutral quinolines. In contrast, the Sc-3-catalyzed reaction of 2-aryl quinolines with aliphatic olefins and the Y-2-catalyzed reaction with styrenes selective-ly gave the 2-aryl ortho-C‒H alkylation products. Based on the catalyst/substrate-controlled regiodivergence, the sequential regiospecific dialkylation of quinolines with two different alkenes has also been achieved. The DFT studies revealed that the C‒H activation of 2-phenylquinoline at both the C8 position and an ortho-position of the 2-phenyl substituent was possible, and these two types of initially formed C‒H activation products were interconvertible through the coordination and C‒H activation of another molecule of quinoline. The regioselectivity for the C‒H alkylation reactions was governed not only by the easiness of the initial formation of the C‒H activation products but also by the energy barriers for their interconversions, as well as by the energy barriers or steric and electronic influences in the subsequent alkene insertion processes. This work has not only constituted an efficient protocol for the selective synthesis of diversified quinoline derivatives, but also offered unprecedented insights into the C‒H activation and transformation of quinolines, and may help design more efficient, selec-tive or complementary catalysts.
The ability to effectively differentiate between chemically inequivalent, yet highly similar, C–H bonds in a given molecule remains a fundamental challenge in organic chemistry. In particular, the lack of sufficient steric and electronic differences between C–H bonds located distal to functional groups has prevented the development of site-selective catalysts with broad scope. An emerging approach to circumvent this obstacle is to utilize the distance between a target C–H bond and a coordi-nating functional group, along with the geometry of the cyclic transition state in directed C–H activation, as core molecular recognition parameters to differentiate between multiple C–H bonds. In this perspective, we discuss the advent and recent advances of this concept. We cover a wide range of template-directed remote C–H activation reactions of alcohols, carboxylic acids, sulfonates, phosphonates and amines. Additionally, we review examples which take advantage of non-covalent interac-tions, such as reversible heterocycle-metal coordination, hydrogen bonding, and ion pairing, to achieve regiocontrol. The feasibility of directed C–H activation via macrocyclic transition states has also been demonstrated employing Rh(III) and Ir(I) catalysts. Continued advancement of this distance and geometry-based differentiation approach for regioselective remote C–H functionalization reactions may lead to the ultimate realization of molecular editing: the freedom to modify organic mole-cules at any site, in any order.
The first base metal-catalyzed regioselective dehydrogenative alkylation of indolines using readily available alcohols as the alkylating reagent is reported. A single air- and moisture-stable manganese catalyst provides access to either C3- or N-alkylated indoles depending on the solvent used. Mechanistic studies indicate that the reaction takes place through a combined acceptorless dehydrogenation and hydrogen autotransfer strategy.
Transition-metal-catalyzed C-H activation followed by oxidative annulation with alkynes has been an efficient synthetic tool for the assembly of various polyaromatic scaffolds. Despite the substantial progress in this field, it is still a significant challenge to achieve the synthesis of nonsubstituted vinylene-fused compounds. In this contribution, we report a Rh-catalyzed C-H/C-H vinylene cyclization adopting vinylene carbonate as a "vinylene transfer" agent. This protocol achieves the direct annulative π-extension of imidazole- and pyrazole-fused aromatics.
The regioselective Rh(III)-catalyzed C-H amidation of aniline derivatives with dioxazolones as an amidating reagent with a pyrimidine as a directing group leading to the production of 1,2-diaminobenzene derivatives or benzimidazole derivatives is described. The product distribution is controlled by the nature of solvent used. The reaction provides a broad substrate scope for aniline derivatives with various important functional groups including dioxazolones.
An unprecedented synthesis of functionalized naphtho[1',2':4,5]imidazo[1,2-a]pyridines via rhodium-catalyzed cascade reactions of 2-arylimidazo[1,2-a]pyridine-3-carbaldehydes with cyclic α-diazo-1,3-diketones is presented. To our knowledge, this is the first example in which the title compounds were prepared through Rh(III)-catalyzed C−H bond carbenoid insertion and [5+1] annulation by using cyclic α-diazo-1,3-diketones as a C1 synthons featuring with a ring-opening and reannulation. Notably, a wide range of substrates and functional groups were well-tolerated under the optimized reaction conditions to produce products in good to excellent yields.
A Rh(III)-catalyzed directed ortho-amidation of 2-arylimidazoheterocycles using dioxazolone as an amidating reagent has been developed. This protocol is a simple, straightforward, and economic was to afford a variety of N-(2-(imidazo[1,2- a]pyridin-2-yl)phenyl)acetamide derivatives with excellent yields. A mechanistic study reveals that a reversible cleavage of C-H bond might be involved in the reaction.
The efficient couplings of diverse N-arylureas and methyleneoxetanones have been realized via Rh(III)-catalyzed and solvent-controlled chemoselective C-H functionalization, which involved the tunable β-H elimination and β-O elimination processes, thereby giving divergent access to quinolin-2(1 H)-ones and ortho-allylated N-arylureas with broad substrate compatibility and good functional group tolerance. the divergent synthetic utilities of the transformations have also been exemplified by subsequently tandem C-H allylation, unsymmetrical C-H functionalization, alternative reaction mode, as well as removal of the carbamoyl group.
High levels of catalyst control are demonstrated in determining the positional selectivity in C-H alkenylation of isoxazoles. A cationic rhodium-mediated, strong-directing group promotes C(sp ² )-H activation at the proximal aryl ring whereas, the palladium-mediated electrophilic metallation leads to the C(sp ² )-H activation at the distal position of the directing group. Synthetic elaboration of this C-H alkenylation product via ruthenium and copper co-catalysis leads to an efficient method for the assembly of densely substituted pyrroles.
An efficient cobalt-catalyzed ring-opening reaction of bench-stable 1,2-oxazetidines with heteroarenes was unprecedentedly developed. The sustainable Cp *Co(III) catalyst enables a distinctive merger of C-H activation with concomitant N-O and C-C cleavages of 1,2-oxazetidine, leading to site-selective C-H aminomethylation and hydroxymethylation of heteroaromatic compounds containing a broad range of functional groups. Preliminary control experiments unravel some essential mechanistic features of this one-pot transformation.
Carbohydrates play important roles in many physiological and pathological events. The preparation of the derivatives and conjugates of carbohydrates is often needed to help interrogate and exploit their biological properties. Owning to their structural complexity, one major challenge in the derivatization of carbohydrates is to control site-selectivity, that is, to selectively modify one hydroxyl group in the presence of many others. In recent years, ligand controlled transition-metal catalysis has been employed in the site-selective modification of glycosides, resulting in methodologies that enable efficient and direct syntheses of carbohydrates derivatives. In this minireview, we will focus on reactions in which the site-selectivity is controlled by the properties of the ancillary ligands of transition-metals.
C-H activation has surfaced as an increasingly powerful tool for molecular sciences, with notable applications to material sciences, crop protection, drug discovery, and pharmaceutical industries, among others. Despite major advances, the vast majority of these C-H functionalizations required precious 4d or 5d transition metal catalysts. Given the cost-effective and sustainable nature of earth-abundant first row transition metals, the development of less toxic, inexpensive 3d metal catalysts for C-H activation has gained considerable recent momentum as a significantly more environmentally-benign and economically-attractive alternative. Herein, we provide a comprehensive overview on first row transition metal catalysts for C-H activation until summer 2018.
The late‐stage modification of structurally‐complex peptides bears great potential for drug discovery, crop protection and pharmaceutical industries, among others. While traditional approaches had thus far largely relied on prefunctionalizations, C‒H activation catalysis has in recent years emerged as an increasingly powerful tool for post‐translational peptide modifications in a step‐economical manner. Herein, we summarize the recent success in organometallic C‒H activation on peptides until June 2018, featuring inter alia position‐ and chemo‐selective palladium, ruthenium and manganese catalysts.
As a synthetic methodology, C–H activation represents a complimentary protocol to traditional cross-couplings such as the Suzuki–Miyaura and Stille reactions, by avoiding the extra synthetic steps required to install activating groups. C–H activation also often avoids the production of waste associated with B, Sn, halide etc. Pd-catalysed transformations have been most prominent in the C–H activation realm. However, as a society we are over-reliant on transitional metals, cost is increasing, and the accessible supply is dwindling. One potential solution is to develop chemistry using Earth Abundant Metals (EAMs). Manganese (Mn), in particular, demonstrates great promise. Since the publication of an excellent review by Ackermann in 2016 (ACS Catal. 2016, 6, 3743–3652), there has been a flurry of reports on Mn-catalysed C–H activation. We report here an overview of approximately 30 new papers, which include a number of notable advances since April 2016
Dibenzocyclooctadiene lignans are an interesting class of molecules for their unique structure of axially chiral biaryls as well as their significant biological activities. Herein, a Pd-catalyzed atroposelective C‒H alkynylation was developed for the gram-scale, stereocontrolled formal syntheses of (+)-isoschizandrin and (+)-steganone. tert-Leucine was identified as an efficient, catalytic transient chiral auxiliary. The scope of this reaction is also presented and a wide range of enantioenriched biaryls were prepared in good yields (up to 99%) with excellent enantioselectivities (up to >99% ee).
The first total synthesis of conosilane A, a densely oxygenated nonisoprenoid sesquiterpene, has been achieved through stereoselective intramolecular radical cyclization and double utilization of site-selective C-H functionalization as key steps,...
A chiral manganese porphyrin complex with a two-point hydrogen bonding site was prepared and probed in catalytic C-H oxygenation reactions of 3,4-dihydroquinolones. The desired oxygenation occurred with perfect site-selectivity at the C4 methylene group and with high enantioselectivity in favor of the respective (4S)-configured secondary alcohols (12 examples, 66-86% yield, 87-99% ee). Mechanistic studies support a rate and selectivity determining attack of the reactive manganese oxo complex at the hydrogen-bound substrate and an oxygen transfer by a rebound mechanism.
The manganese-catalyzed addition of C-2 position of indoles to maleimides has been achieved under additive-free conditions. The manganese catalyst exhibits excellent chemo- and regioselectivity, good functional group compatibility, and high catalytic efficiency. The substrate scope can also be extended to maleates, ethyl acrylate, 1,4-dihydro-1,4-epoxynaphthalene, pyrroles, and 2-phenylpyridine, which further demonstrates the universality of this straightforward approach.
An efficient Cp*Rh(III)-catalyzed selective bis-cyanation of arylimidazo[1,2-α]pyridines with N-cyano-N-phenyl-p-methylbenzenesulfonamide via N-directed ortho double C–H activation has been developed. The reaction proceeds with broad functional group tolerance to furnish various cyanated imidazopyridines in high yields. The current methodology exhibits unique characteristics, including high bis-cyanation selectivity, operational convenience, and gram-scale production.
Recent advances in transition metal-catalyzed C–H bond functionalization have profoundly impacted synthetic strategy. Since organic substrates typically contain several chemically distinct C–H bonds, controlling the regioselectivity of C–H bond functionalization is imperative to harness its full potential. Moreover, the ability to alter reaction pathways to selectively functionalize different C–H bonds in a substrate represents a greater opportunity and challenge. The choice of catalysts, ligands, solvents, and even more subtle variations of the reaction conditions have been shown to allow the formation of regioisomeric C–H functionalization products starting from the same precursors. This review describes recent advances in transition metal-catalyzed divergent C–H bond functionalization that highlight its potential in organic synthesis.
In chemical syntheses, the activation of carbon-hydrogen (C-H) bonds converts them directly into carbon-carbon or carbon-heteroatom bonds without requiring any prior functionalization. C-H activation can thus substantially reduce the number of steps involved in a synthesis. A single specific C-H bond in a substrate can be activated by using a 'directing' (usually a functional) group to obtain the desired product selectively. The applicability of such a C-H activation reaction can be severely curtailed by the distance of the C-H bond in question from the directing group, and by the shape of the substrate, but several approaches have been developed to overcome these limitations. In one such approach, an understanding of the distal and geometric relationships between the functional groups and C-H bonds of a substrate has been exploited to achieve meta-selective C-H activation by using a covalently attached, U-shaped template. However, stoichiometric installation of this template has not been feasible in the absence of an appropriate functional group on which to attach it. Here we report the design of a catalytic, bifunctional nitrile template that binds a heterocyclic substrate via a reversible coordination instead of a covalent linkage. The two metal centres coordinated to this template have different roles: one reversibly anchors substrates near the catalyst, and the other cleaves remote C-H bonds. Using this strategy, we demonstrate remote, site-selective C-H olefination of heterocyclic substrates that do not have the necessary functional groups for covalently attaching templates.
Direct o-amidation at the phenyl group of 2-phenylimidazo-heterocycles with aryl isocyanates has been achieved via chelation-assisted cationic ruthenium(II) complex-catalyzed mechanism. The methodology provides a straightforward, high-yielding regioselective approach towards the synthesis of an array of o-amidated phenylimidazo-heterocycles without prior activation of C(sp2)-H. This also reports the first method for coupling of aryl isocyanates with imidazo[1,2-a]pyridine system via penta cyclometalated intermediate. The methodology is found to be easily scalable and could be applied towards selective o-amidation of 2-heteroarylimidazo[1,2-a]pyridine frameworks.
The rhodium(III)-catalyzed cross-coupling reaction of 8-methylquinolines and maleimides is described. In contrast to the C(sp(2))-H functionalization, a first catalytic functionalization of sp(3) C-H bonds with maleimides is reported. This protocol provides a facile access to various succinimide scaffolds on 8-methylquinolines via a direct C-H cleavage approach.
Transition metal-catalyzed direct functionalization of C-H bonds has recently emerged as a powerful strategy for the construction of carbon-carbon and carbon-heteroatom bonds. Among various metals employed, base metal copper has attracted significant attention owing to its relatively low cost, abundance, and versatile reactivity. This review aims to comprehensively summarize the recent advances in copper-mediated (both stoichiometric and catalytic) chelation-assisted functionalization of unactivated C-H bonds.
Over the years, various strategies have been reported for the synthesis of imidazo[1,2‐ a ]pyridines due to their importance in different fields. In this account, we represent the methods developed by our group for the synthesis and functionalization of imidazo[1,2‐ a ]pyridines. Different synthetic strategies have been developed using easily accessible reactants for this purpose. We envisage that these newly developed protocols will be very useful for the synthesis of functionalized molecules bearing imidazo[1,2‐ a ]pyridine scaffolds. These strategies will also be attractive for the construction of other pharmaceutically important heterocycles.
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Cyclic imides are commonly encountered structural motifs in natural and synthetic molecules with remarkable pharmacological properties. They are also used widely for further functionalization through various chemical transformations. Currently, renewed focus has been devoted worldwide on this important class of compounds for their potential new applications especially in the area of medicinal / pharmaceutical chemistry as well as in drug discovery. Consequently, their syntheses have attracted considerable interest. Various innovative methodologies have recently been developed in order to access and functionalize this class of compounds. For example, the combination of classical as well as modern reactions allowed synthetic chemists to perform the straight forward and direct synthesis of diversity based library of compounds, often in 1-2 steps. The present report will cover the relevant and recent advances in the field of occurrences, synthesis and chemical reactions of cyclic imides mainly from 1980 to the end of 2015.
Manganese is found in the active center of numerous enzymes that operate by an outer-sphere homolytic C-H cleavage. Thus, a plethora of bioinspired radical-based C-H functionalizations by manganese catalysis have been devised during the past decades. In contrast, organometallic C-H activation by means of manganese catalysis has emerged only recently as an increasingly viable tool in organic synthesis. These manganese(I)-catalyzed processes enabled a variety of C-H functionalizations with ample scope, which very recently set the stage for substitutive C-H functionalizations. The versatile manganese catalysis largely operates by an isohypsic, thus redox-neutral, mode of action through chelation assistance, and provided step-economical access to structurally divers compounds of relevance to inter alia bioorganic, agrochemical, and medicinal chemistry as well as the material sciences.
Pd-catalyzed α-olefinic C-H activation of simple α,β-unsaturated olefins has been developed. 4-imino-β-lactam derivatives were readily synthesized via activation of α-olefinic C-H bonds with excellent cis stereoselectivity. A wide range of heterocycles at the β-position are compatible with this reaction. The product of 4-imino-β-lactam derivatives can be readily converted to 2-aminoquinoline which exists extensively in pharmaceutical drugs and natural products.
A 1,4-addition with the nucleophilic center generated at the ortho carbon atom of an aromatic ketone in the presence of the highly reactive α-C-H bond, using a directing group strategy, is presented. The reaction yields pharmaceutically useful 3-arylated succinimide derivatives. In order to gain understanding of this redox neutral reaction, despite the presence of copper acetate, and to substantiate the lack of Heck-type products, DFT calculations have been carried out.