Direct Arene Research Articles

Recent Advances in C—F Bond Formation from Carbon‐Centered Radicals

Comprehensive SummaryConstruction of C—F bonds is a direct and efficient method for introducing fluorine into pharmaceuticals, agrochemicals, and materials. Strategies such as nucleophilic, electrophilic, radical, and transition‐metal catalyzed fluorination have been developed to meet the demand of diverse C—F bond formation. Among them, radical fluorination has been witnessed with substantial advancement in a recent decade. Herein, we reviewed methods for formation of C—F bonds with carbon‐centered radicals as key intermediates, especially in recent five years. We introduce in the paper with different fluorinating reagents, strategies for radical generation, and application in late‐stage functionalization and synthesis of PET tracers. We also indicate the current limitations and propose the direction of the field for the future development. Key ScientistsRadical fluorination was recognized as an old and uncontrolled reaction that may date back to the time when element fluorine was first mixed with organic compounds by Henri Moissan in 1891. The development of the field was slow in combination with discovery of new fluorinating reagents. Substantial changes took place in 2012, when the first example of carbon radical fluorination with robust and mild fluorinating reagents, such as NFSI and Selectfluor, was reported by the Sammis group. In the same year, Groves, Lectka, Li, and Boger led the pioneering works on aliphatic C—H fluorination, decarboxylative fluorination, and fluorofunctionalization of alkenes in a radical manner. Photoredox catalysis was introduced to radical fluorination in 2013 by the Chen group, which opens up a new avenue for diverse fluorinative transformations. Most of the previous works focus on radical fluorination to form C(sp3)–F bonds. In 2018, the challenging non‐directed aromatic C—H fluorination was solved by Ritter and coworkers. Direct arene fluorination with fluoride ion was later disclosed by the Nicewicz group in 2019. There are many other scientists that have also made tremendous contribution to the development of radical fluorination, with too limited space to list them all. We only list those with first discoveries that may point to the new direction of radical fluorination.

Electrocatalyzed direct arene alkenylations without directing groups for selective late-stage drug diversification

Electrooxidation has emerged as an increasingly viable platform in molecular syntheses that can avoid stoichiometric chemical redox agents. Despite major progress in electrochemical C−H activations, these arene functionalizations generally require directing groups to enable the C−H activation. The installation and removal of these directing groups call for additional synthesis steps, which jeopardizes the inherent efficacy of the electrochemical C−H activation approach, leading to undesired waste with reduced step and atom economy. In sharp contrast, herein we present palladium-electrochemical C−H olefinations of simple arenes devoid of exogenous directing groups. The robust electrocatalysis protocol proved amenable to a wide range of both electron-rich and electron-deficient arenes under exceedingly mild reaction conditions, avoiding chemical oxidants. This study points to an interesting approach of two electrochemical transformations for the success of outstanding levels of position-selectivities in direct olefinations of electron-rich anisoles. A physical organic parameter-based machine learning model was developed to predict position-selectivity in electrochemical C−H olefinations. Furthermore, late-stage functionalizations set the stage for the direct C−H olefinations of structurally complex pharmaceutically relevant compounds, thereby avoiding protection and directing group manipulations.

Direct arene trifluoromethylation enabled by promiscuous activity of fungal laccase.

Laccase from Trametes versicolor was found to oxidize non-phenolic arenes and enable the trifluoromethylation of arenes in the presence of in situ generated CF3 radicals at a catalyst loading as low as 0.0034%. The biocatalytic trifluoromethylation proceeded under mild conditions and could increase the yield by up to 12 fold, compared to the control.

Direct Arene Trifluoromethylation Enabled by a High-Valent CuIII -CF3 Compound.

Direct C-H trifluoromethylation of arenes and heteroarenes poses an important synthetic challenge that is highly desirable. High-valent CuIII -CF3 compounds have often been invoked in copper-mediated trifluoromethylation reactions, but the fundamental reactivity toward arenes is elusive. Herein, direct C-H trifluoromethylation of arenes/heteroarenes by a high-valent CuIII -CF3 compound is disclosed for the first time. The CuIII -CF3 compound serves CF3 radical and a CuII oxidant by homolytic cleavage of a CuIII -CF3 bond, which engage synergistically in a SE Ar type reaction with arenes. The presence of K2 S2 O8 co-oxidant can significantly improve the reaction yields. This reaction shows good efficiency, broad functional group tolerance, and the potential in late-stage functionalization. The reactivity of high-valent CuIII -CF3 compounds disclosed in this study represents an important progress in organofluorine and CuIII chemistry.

Pd-catalyzed Site-selective direct arene C [sbnd] H arylation of Pyrrolo[2,3-d]pyrimidine derivatives with aryl iodides

A simple and efficient methodology was developed for the direct ortho C H arylation of pyrrolo[2,3-d]pyrimidine derivatives. Aryl iodides are chosen as an arylating reagent for C(sp2)−H bond under Pd(II)/Pd(IV) catalysis in the presence of TFA, affording a diverse array of (hetero)biaryls-containing pyrrolo[2,3-d]pyrimidines in moderate to good yields with high regioselectivity and chemoselectivity.

Watching Hydrogens Migrate: Step by Step from [ReI(η6-C6H6)2]+ to [ReIII(η3-C6H9)(η6-C6H6)(NCCH3)2]2.

Arene substitution reactions in [M(η6-arene)2]0/2+ are well documented for Groups 6 and 8 but are essentially unknown for the manganese triad. Aiming to replace benzene in [ReI(η6-C6H6)2]+, we altered the hapticity of one coordinated benzene, which we found to be tunable stepwise from an η6 to an η3-allyl coordination mode. Reduction of [ReI(η6-C6H6)2]+ with hydrides gives [ReI(η5-C6H7)(η6-C6H6)]. Subsequent addition of acid yields [ReIIIH(η5-C6H7)(η6-C6H6)]+, which converts to [ReI(η4-C6H8)(η6-C6H6)NCCH3]+ in acetonitrile. Further protonation gives the title complex [ReIII(η3-C6H9)(η6-C6H6)(NCCH3)2]2+ by a rhenium-mediated, intramolecular hydride shift. Herein, we present a full mechanistic elucidation of these transformations based on NMR studies, isolation of reaction intermediates, and their full characterizations. The structural feature {ReIII(η6-C6H6)} is unprecedented. Direct arene exchange from [ReI(η6-C6H6)2]+ to [ReI(η6-arene)(η6-C6H6)]+ was found only under strongly acidic conditions in neat arene. The analogous chemistry of the lighter homologue technetium (99Tc) is distinctly different. Treatment of [TcI(η5-C6H7)(η6-C6H6)] with acid in acetonitrile yields only mixtures of [TcI(η6-C6H6)2]+ and [TcII(NCCH3)6]2+.

An Earth-abundant cobalt based photocatalyst: visible light induced direct (het)arene C-H arylation and CO2 capture.

In this work, we have reported a noble metal free heterogeneous photocatalyst to carry out direct (het)arene C-H arylation and solvent-free CO2 capture via single-electron transfer processes at room temperature and under pressure. The catalytic system comprises a cobalt(III) complex grafted over the silica coated magnetic support for the efficient recovery of the photocatalytic moiety without hampering its light-harvesting capability. The novel Earth-abundant cobalt(III) based photocatalyst possesses various fascinating properties such as high surface area to volume ratios, large pore volume, crystalline behaviour, high metal loading, excellent stability and reusability. The general efficacy of the highly abundant and low-cost cobalt based heterogeneous nanocatalyst was checked for the selective conversion of aryldiazonium salts into synthetically and pharmaceutically significant biaryl motifs under ambient conditions upon irradiation with visible light. The highly efficient photocatalytic conversion of carbon dioxide (CO2) to a value-added chemical was accomplished under mild reaction conditions with high selectivity, showing the added benefit of operational simplicity.

Ru-catalyzed direct arene C–H amidation of pyrrolo[2,3-d]pyrimidines with sulfonyl azides

Ru-catalyzed direct C–H amidation of pyrrolo[2,3-d]pyrimidine derivatives was developed using sulfonyl azides as the amino source in a mild, efficient and highly chemoselective manner. The promising protocol has good compatibility with diverse functional groups and high regioselectivity, providing various structurally versatile monoamidated pyrrolo[2,3-d]pyrimidines in good to excellent yields with potential biological and therapeutic activity.

Photophysical and electrochemical properties of alternating copolymers consisting of 3,4-ethylenedioxythiophene and 4,4′-diphenylamine/3,6-carbazole

ABSTRACT In the past decades, π-conjugated polymers including polyaniline (PANI), polycarbazole (PCz) and poly(3,4-ethylenedioxythiophene) (PEDOT), have roused much attention and been widely applied in high-performance organic semiconductors on account of their unique electronic, optoelectronic, electrochemical, and mechanical properties. Herein, two kinds of alternating copolymers, poly[(N-(2-ethylhexyl)carbazole-3,6-diyl)-(3,4-ethylenedioxythiophene-2,5-diyl)] (P(3,6-Cz-EDOT)) and poly[(N-(2-ethylhexyl)diphenylamine-4,4′-diyl)-(3,4-ethylenedioxythiophene-2,5-diyl)] (P(4,4′-DPA-EDOT)) were subtly designed and synthesized via direct (hetero)arene polymerization (DHAP) in good yields (up to 88% and 90%, respectively) and high molecular weights (up to 8400 and 24100 Da, respectively). The photophysical, electrochemical, thermal and morphological properties of P(3,6-Cz-EDOT) and P(4,4′-DPA-EDOT) were systematically investigated based on experimental analysis and theoretical simulations. As compared to P(4,4′-DPA-EDOT), P(3,6-Cz-EDOT) exhibited shorter π-conjugation, a higher glass transition temperature (T g), better thermal stability, more porous morphology and a preferably curved or spiral conformation. Moreover, both P(3,6-Cz-EDOT) and P(4,4′-DPA-EDOT) possessed high specific discharge capacities, indicating their potential applications in solution-processed charge-storage devices.

A Metal‐Free Direct Arene C−H Amination

AbstractThe synthesis of aryl amines via the formation of a C−N bond is an essential tool for the preparation of functional materials, active pharmaceutical ingredients and bioactive products. Usually, this chemical connection is only possible by transition metal‐catalyzed reactions, photochemistry or electrochemistry. Here, we report a metal‐free arene C−H amination using hydroxylamine derivatives under benign conditions. A charge transfer interaction between the aminating reagents TsONHR and the arene substrates enables the chemoselective amination of the arene, even in the presence of various functional groups. Oxygen was crucial for an effective conversion and its accelerating role for the electron transfer step was proven experimentally. In addition, this was rationalized by a theoretical study which indicated the involvement of a dioxygen‐bridged complex with a “Sandwich‐like” arrangement of the aromatic starting materials and the aminating agents at the dioxygen molecule.magnified image

Recent Progress towards Organocatalyzed Asymmetric (Hetero)Arene Formation

AbstractOwing to the importance of arene moieties in organic chemistry, methods for arene construction attract great attention. Besides the traditional substitution strategy from pre-existing arenes, the straightforward formation of arene cores can also provide significant shortcuts towards a wide array of target molecules with different substitution patterns. Among direct arene formation reactions, applying environmentally benign organocatalysis to access arene moieties continues to attract increasing attention. This short review provides a brief summary of recent progress on organocatalyzed de novo (hetero)arene formation and applications in enantioselective synthesis.1 Introduction2 Arene Formation with Non-Covalent Organocatalysts2.1 Arene Formation with Acid Organocatalysts2.2 Arene Formation with Base Organocatalysts2.3 Arene Formation with Hydrogen-Bonding Organocatalysts3 Arene Formation with Covalent Organocatalysts3.1 Arene Formation with Lewis Base Organocatalysts3.1.1 Arene Formation with Secondary Amine Organocatalysts3.1.2 Arene Formation with Tertiary Amine, Tertiary Phosphine and Sulfide Organocatalysts3.1.3 Arene Formation with N-Heterocyclic Carbene Organocatalysts3.2 Arene Formation with Lewis Acid Organocatalysts4 Conclusion

Direct Radiofluorination of Arene C-H Bonds via Photoredox Catalysis Using a Peroxide as the Terminal Oxidant.

Herein, we describe an organic photoredox system for direct arene C-H radiofluorination, using a peroxide oxidizing agent and LEDs as the light source. In conjunction with an optimized photocatalyst and a microtubing reactor, this system is applicable to a range of electron-rich aromatics and heteroaromatics. We also demonstrate the feasibility of C-H radiofluorination without an azeotropic drying step, which greatly simplifies the workflow of the labeling process.

Direct arene C-H fluorination with 18F- via organic photoredox catalysis.

Positron emission tomography (PET) plays key roles in drug discovery and development, as well as medical imaging. However, there is a dearth of efficient and simple radiolabeling methods for aromatic C-H bonds, which limits advancements in PET radiotracer development. Here, we disclose a mild method for the fluorine-18 (18F)-fluorination of aromatic C-H bonds by an [18F]F- salt via organic photoredox catalysis under blue light illumination. This strategy was applied to the synthesis of a wide range of 18F-labeled arenes and heteroaromatics, including pharmaceutical compounds. These products can serve as diagnostic agents or provide key information about the in vivo fate of the labeled substrates, as showcased in preliminary tracer studies in mice.

Michael J. Ingleson

Angewandte Chemie International EditionVolume 58, Issue 14 p. 4440-4440 Author ProfileFree Access Michael J. Ingleson First published: 08 November 2018 https://doi.org/10.1002/anie.201812314AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Graphical Abstract “The natural talent I would like to be gifted with is being able to go to sleep on demand. Looking back over my career, I decided the best years are ahead …” Find out more about Michael J. Ingleson in his Author Profile. Michael J. Ingleson The author presented on this page has published more than 10 articles in Angewandte Chemie in the last 10 years, most recently: “Selective Boryl-Anion Migration in a Vinyl sp2–sp3 Diborane Induced by Soft Borane Lewis Acids”: V. Fasano, J. Cid, R. J. Procter, E. Ross, M. J. Ingleson, Angew. Chem. Int. Ed. 2018, 57, 13293; Angew. Chem. 2018, 130, 13477. Date of birth: April 10, 1979 Position: Professor of Chemistry, University of Manchester E-mail: michael.ingleson@manchester.ac.uk Homepage: https://personalpages.manchester.ac.uk/staff/Michael.Ingleson/ ORCID: 0000-0001-9975-8302 Education: 2001 MChem, University of Bath 2004 PhD with Prof. Andrew S. Weller, University of Bath 2004–2005 Postdoctoral research with Prof. Kenneth G. Caulton, Indiana University 2006–2008 Postdoctoral research with Prof. Matthew J. Rosseinsky, University of Liverpool. Awards: 2008 Royal Society University Research Fellowship; 2012 ERC Starting Grant; 2012 RSC Harrison–Meldola Prize; 2017 ERC Consolidator Grant. Current research interests: Main-group chemistry, catalysis, organometallic synthesis, and anything to do with boron chemistry. Hobbies: Playing squash, walking, Welsh rugby (watching not playing) The natural talent I would like to be gifted with is being able to go to sleep on demand Looking back over my career, I decided the best years are ahead, I'm only 39! Last time I went to the pub was after playing squash—a beer after an evening match is essential to help “rehydration” and ease the pain of the muscle aches (or losing!). My favorite drink is a good quality craft ale, currently something from the Verdant or Track breweries. My favorite saying/quote is “in science serendipity and hindsight combined are unstoppable” (I heard it at a conference from someone wittier than me!). My favorite time of day is at 6 a.m. walking the dog through the woods before work (though not in the winter) My favorite named reaction is the Suzuki–Miyaura reaction, not only is it super useful but it helps justify a lot of my research activity in making C−B bonds! The most important thing I learned from my students is to listen and let them speak first as they often have better ideas than I do. My favorite book is tough to choose as a bookworm, possibly the Wind-up Bird Chronicle by Haruki Murakami, or the Player of Games by Iain M. Banks (though this answer would change week to week). My 5 top papers: 1“[(PPh3)Ag(HCB11Me11)]: A Complex with Intermolecular Ag⋅⋅⋅H3C Interactions”: M. J. Ingleson, M. F. Mahon, N. J. Patmore, G. D. Ruggiero, A. S. Weller, Angew. Chem. Int. Ed. 2002, 41, 3694; Angew. Chem. 2002, 114, 3846. (The first paper from my PhD studies, which includes my first “crystal structure” and the first new (well unreported at least) compound I had made.) 2Pinacol Boronates by Direct Arene Borylation with Borenium Cations: A. Del Grosso, P. J. Singleton, C. A. Muryn, M. J. Ingleson, Angew. Chem. Int. Ed. 2011, 50, 2102; Angew. Chem. 2011, 123, 2150. (The first “big” paper from my independent career that confirmed we were onto something using borenium cations.) 3“Formation of C(sp2)–Boronate Esters by Borylative Cyclization of Alkynes Using BCl3”: A. J. Warner, J. R. Lawson, V. Fasano, M. J. Ingleson, Angew. Chem. Int. Ed. 2015, 54, 11245; Angew. Chem. 2015, 127, 11397. (We knew the title conversion worked with borocations, but wanted to check that BCl3 did not do it—instead it does it and is better than the borocation.) 4“Direct C(sp2)–C(sp3) Cross-Coupling of Diaryl Zinc Reagents with Benzylic, Primary, Secondary, and Tertiary Alkyl Halides: J. J. Dunsford, E. R. Clark, M. J. Ingleson, Angew. Chem. Int. Ed. 2015, 54, 5688; Angew. Chem. 2015, 127, 5780. (Started our interest in the chemistry of zinc electrophiles for C−C and C−B bond formation.) 5“A modular route to boron doped PAHs by combining borylative cyclisation and electrophilic C−H borylation”: D. L. Crossley et al., Chem. Sci. 2017, 8, 7969. (Several of our electrophilic borylation methods can be used in sequence to generate well-defined B-doped polyaromatic hydrocarbons.) Volume58, Issue14March 26, 2019Pages 4440-4440 ReferencesRelatedInformation

Palladium-Catalyzed Late-Stage Direct Arene Cyanation

Summary Methods for direct benzonitrile synthesis are sparse, despite the versatility of cyano groups in organic synthesis and the importance of benzonitriles for the dye, agrochemical, and pharmaceutical industries. We report the first general late-stage aryl C–H cyanation with broad substrate scope and functional-group tolerance. The reaction is enabled by a dual-ligand combination of quinoxaline and an amino acid-derived ligand. The method is applicable to direct cyanation of several marketed small-molecule drugs, common pharmacophores, and organic dyes.

Highly Selective Palladium-Catalyzed Arene C-H Acyloxylation with Benzothiadiazole as a Modifiable Directing Group.

An efficient protocol for the palladium-catalyzed direct arene C-H acyloxylation of benzothiadiazole-arene derivatives is reported for the first time. The key strategy is the employment of benzothiadiazole as a modifiable directing group. The highly selective mono- or bis-acyloxylation can be achieved by tuning the reaction conditions, affording various acyloxylated benzothiadiazole derivatives, which could offer a rational tailoring of their electronic properties and be applied in organic electronic and optoelectronic materials. Finally, by diversity-oriented modification of the benzothiadiazole directing group, the acyloxylated products can be readily converted into various valuable functionalized (hetero)biaryls.

Synthesis of Enantiomerically Pure and Racemic Benzyl-Tethered Ru(II)/TsDPEN Complexes by Direct Arene Substitution: Further Complexes and Applications

The use of a direct arene-exchange method for the synthesis of benzyl-tethered arene/Ru/TsDPEN complexes for use in asymmetric transfer hydrogenation is reported. A series of complexes tethered through a three-carbon linear chain was also prepared. The arene-exchange approach significantly simplifies the synthetic approach to this class of catalyst and permits the ready formation of modified analogues. The approach also provides a route to racemic catalysts for use in general reductions with either hydrogen or transfer hydrogenation.

Toward an Ideal Synthesis of (Bio)molecules through Direct Arene Assembling Reactions

Abstract C–H (hetero)arylation of aromatic compounds using transition-metal catalysts has garnered much attention from the synthetic chemistry community as a next-generation coupling method for constructing (hetero)biaryl motifs. This account describes our recent achievements in transition-metal-catalyzed aromatic C–H arylation and its applications to the synthesis of bioactive molecules.

Mechanistic Studies on Gold-Catalyzed Direct Arene C–H Bond Functionalization by Carbene Insertion: The Coinage-Metal Effect

The catalytic functionalization of the Csp2–H bond of benzene by means of the insertion of the CHCO2Et group from ethyl diazoacetate (N2═CHCO2Et) has been studied with the series of coinage-metal complexes IPrMCl (IPr = 1,3-bis(diisopropylphenyl)imidazol-2-ylidene) and NaBArF4 (BArF4 = tetrakis(3,5-bis(trifluoromethyl)phenyl)borate). For Cu and Ag, these examples constitute the first use of such metals toward this transformation, which also provides ethyl cyclohepta-2,4,6-trienecarboxylate as a byproduct from the so-called Buchner reaction. In the case of methyl-substituted benzenes, the reaction exclusively proceeds onto the aromatic ring, the Csp3–H bond remaining unreacted. A significant coinage-metal effect has been observed, since the gold catalyst favors the formation of the insertion product into the Csp2–H bond whereas copper and silver preferentially induce the formation of the cycloheptatriene derivative. Experimental studies and theoretical calculations have explained the observed selectivity i...

Iridium-Catalyzed Direct C–H Amination with Alkylamines: Facile Oxidative Insertion of Amino Group into Iridacycle

Described herein is the development of Cp*Ir(III)-catalyzed direct arene C–H amination using alkylamines as an amino source. This C–N bond formation showcases a notable example of cross-dehydrogenative coupling to install an amino functionality at the ortho-position of benzamide substrates. Mechanistic studies including the isolation of an amine-bound iridacyclic intermediate along with a set of chemical oxidations demonstrated the Ir-catalyzed inner-sphere C–H amination with primary alkylamines for the first time.