CF₃-substituted carbocations: underexploited intermediates with great potential in modern synthetic chemistry

• Anthony J. Fernandes,
• Armen Panossian,
• Bastien Michelet,
• Agnès Martin-Mingot,
• Frédéric R. Leroux and
• Sébastien Thibaudeau

Beilstein J. Org. Chem. 2021, 17, 343–378, doi:10.3762/bjoc.17.32

• formation of the corresponding α-(trifluoromethyl)allylcarbenium ion 103↔103’, the resonance form 103 of which could be trapped with arenes to afford (trifluoromethyl)vinyl-substituted derivatives 102 (Scheme 29) [79][80]. It was also suggested that the resonance form 103’ has a nonnegligible contribution

• as this α-(trifluoromethyl)allylcarbenium ion could be trapped by some electron rich arenes (i.e., xylene, cumene, etc.). The products 104 further react to afford indanes 105 after hydroarylation. A closely related study on dibrominated allylic α-(trifluoromethyl) alcohols also invoked the transient

• (hetero)arenes [104][105] and alkenes [106] under Lewis acid activation but also with electron-rich arenes under thermal activation [107][108][109]. CF3-substituted hemiacetal 168 can react with amines to furnish the corresponding hemiaminal ethers, which can be further activated by a Lewis acid to

The preparation and properties of 1,1-difluorocyclopropane derivatives

• Kymbat S. Adekenova,
• Peter B. Wyatt and
• Sergazy M. Adekenov

Beilstein J. Org. Chem. 2021, 17, 245–272, doi:10.3762/bjoc.17.25

• mediated by strong acids led to the cleavage of the proximal bond by the generation of fluorine-stabilized carbocations (SN1 mechanism) [114]. The Friedel–Crafts reaction of 2,2-difluorocyclopropanecarbonyl chloride (148) with arenes 149a–c was accompanied by a proximal bond scission promoted by the strong

Total synthesis of decarboxyaltenusin

• Lucas Warmuth,
• Aaron Weiß,
• Marco Reinhardt,
• Anna Meschkov,
• Ute Schepers and
• Joachim Podlech

Beilstein J. Org. Chem. 2021, 17, 224–228, doi:10.3762/bjoc.17.22

• analysis, we envisioned a Suzuki coupling of two suitably substituted arenes. Silyl protecting groups like the tert-butyldimethylsilyl group (TBS) were considered appropriate for all projected reaction steps. The boronate moiety 6a was prepared starting with 4-methylcatechol (2), which was initially

Synthesis of aryl 2-bromo-2-chloro-1,1-difluoroethyl ethers through the base-mediated reaction between phenols and halothane

• Yukiko Karuo,
• Ayaka Kametani,
• Atsushi Tarui,
• Kazuyuki Sato,
• Kentaro Kawai and
• Masaaki Omote

Beilstein J. Org. Chem. 2021, 17, 89–96, doi:10.3762/bjoc.17.9

• as monofluorinated and trifluoromethylated arenes or aliphatics [1][2][3][4]. Recent progress in difluoromethylene chemistry successfully led to the finding of bioactive compounds such as pantoprazole, a proton pump inhibitor [5], and AFP-07, a prostaglandin I2 receptor-selective agonist [6][7][8

Metal-free synthesis of biarenes via photoextrusion in di(tri)aryl phosphates

• Hisham Qrareya,
• Lorenzo Meazza,
• Stefano Protti and
• Maurizio Fagnoni

Beilstein J. Org. Chem. 2020, 16, 3008–3014, doi:10.3762/bjoc.16.250

• iodides) [30][31] or by the direct photolysis of arylazo sulfones [38][39][40] and employed for the desired arylations. These reactions have the advantage of being applied to non-functionalized arenes but have the drawback to require a large excess of the nucleophilic reagent (the arene Ar–H) in up to 10

• these cases, the expected phenylated arenes 2j–l were isolated in the 50–64% range. We were then intrigued to extend the scope of the reaction by focusing on a few ethyl diaryl phosphates 3a–e. Gratifyingly, the formation of the symmetric biaryls 4 took place efficiently with the substrates bearing

Chiral anion recognition using calix[4]arene-based ureido receptors in a 1,3-alternate conformation

• Tereza Horáčková,
• Jan Budka,
• Vaclav Eigner,
• Wen-Sheng Chung,
• Petra Cuřínová and
• Pavel Lhoták

Beilstein J. Org. Chem. 2020, 16, 2999–3007, doi:10.3762/bjoc.16.249

• triazole functional groups (to name at least some of them) has appeared during the last two decades [19][20][21]. Due to well-established functionalisation approaches, calix[4]arenes [22][23][24] are frequently used as molecular platform in the design of more complex receptor systems. The existence of four

• basic conformations (cone, partial cone, 1,3-alternate, and 1,2-alternate) offers the combination of a precisely defined 3D structure, with functional groups being introduced at exactly defined mutual positions. This makes calix[4]arenes an ideal molecular scaffold [25][26] for the construction of

• different conformations. Although the overwhelming majority of calixarene-based receptors makes use of the cone conformer A (Figure 1), the corresponding diureidocalix[4]arenes in the 1,3-alternate conformation B showed [42][43] surprisingly good complexation abilities towards selected anions. Especially

Construction of pillar[4]arene[1]quinone–1,10-dibromodecane pseudorotaxanes in solution and in the solid state

• Xinru Sheng,
• Errui Li and
• Feihe Huang

Beilstein J. Org. Chem. 2020, 16, 2954–2959, doi:10.3762/bjoc.16.245

• different substituents on the alkyl chains have been used to prepare pseudorotaxanes with pillar[5]arenes and have opened potential applications in different fields [38][39][40][41][42][43]. So far, fabricating pseudorotaxanes containing more than two components is still a difficult task. Herein, we report

Synthesis of imidazo[1,5-a]pyridines via cyclocondensation of 2-(aminomethyl)pyridines with electrophilically activated nitroalkanes

• Dmitrii A. Aksenov,
• Nikolai A. Arutiunov,
• Vladimir V. Maliuga,
• Alexander V. Aksenov and
• Michael Rubin

Beilstein J. Org. Chem. 2020, 16, 2903–2910, doi:10.3762/bjoc.16.239

• heating in polyphosphoric acid, the nitroalkanes 1 convert into the phosphorylated nitronates 2, which exhibit strong electrophilic properties. This allowed for the employment of these species in reactions wherein electron-rich arenes serve as carbon-based nucleophilies [38][39][40]. It was also

NMR Spectroscopy of supramolecular chemistry on protein surfaces

• Peter Bayer,
• Anja Matena and
• Christine Beuck

Beilstein J. Org. Chem. 2020, 16, 2505–2522, doi:10.3762/bjoc.16.203

• phosphonate groups. While sulfonato-calix[4]arenes can bind unmodified Lys and Arg residues, their strength lies in the recognition and even tighter binding of methylated lysines [29]. Their binding affinity increases 70-fold from unmethylated over mono- and di- to trimethylated lysine, as every methyl group

• epigenetic reader proteins [30][31][32]. Negatively charged calixarene ligands have further been used to inhibit enzymatic activity [33][34][35] and amyloid fibril formation [36][37][38]. Calix[4]arenes with positively charged substituents like guanidinium groups lining the top of their bowl-shaped core have

• phosphonato-calix[n]arenes of different ring sizes (n = 4, 6 or 8) to Cyt c [20][23][24][26][27][28] and the antifungal protein PAF [25] as model proteins. These studies combined 15N-HSQC titrations with X-ray crystallography, isothermal titration calorimetry (ITC) and size exclusion with light scattering

Recent developments in enantioselective photocatalysis

• Callum Prentice,
• James Morrisson,
• Andrew D. Smith and
• Eli Zysman-Colman

Beilstein J. Org. Chem. 2020, 16, 2363–2441, doi:10.3762/bjoc.16.197

• ], electron-deficient arenes [24], and nitriles [25]. Additionally, Cozzi recently applied a novel aluminium-based photocatalyst 9 to this reaction, as an earth-abundant metal alternative albeit with slightly reduced enantioselectivities (8 examples, up to 96:4 er) [26]. Interestingly, as with some other

The biomimetic synthesis of balsaminone A and ellagic acid via oxidative dimerization

• Sharna-kay Daley and
• Nadale Downer-Riley

Beilstein J. Org. Chem. 2020, 16, 2026–2031, doi:10.3762/bjoc.16.169

• ], and chromium trioxide (CrO3), which, based on its Cr(VI) oxidation state, should be able to facilitate single-electron transfer in the presence of electron-rich arenes. The dimerization of 1,2,4-trimethoxynaphthalene (17) in the presence of the metal oxidants CAN, V2O5, and CrO3, afforded binaphthyl

When metal-catalyzed C–H functionalization meets visible-light photocatalysis

• Lucas Guillemard and
• Joanna Wencel-Delord

Beilstein J. Org. Chem. 2020, 16, 1754–1804, doi:10.3762/bjoc.16.147

• electron transfer to complete the catalytic cycle and regenerate the active catalytic species. The classical Fujiwara–Moritani reaction promoting the addition of arenes to olefins illustrates a general mechanism for such traditional C–H functionalization (Figure 4, left) [70][71][72]. The insertion of a

• -functionalization viewpoint, thus furnishing a large panel of compounds in excellent to good yields. This C–H olefination of arenes was performed under aerobic conditions in order to reoxidize the photocatalyst (Figure 8). Interestingly, the desired products were also delivered while using a stoichiometric amount

• alkylation of arenes. The ruthenium-catalyzed meta-selective C–H functionalization through arene σ-activation was already well established yet limited by harsh reaction conditions and elevated reaction temperatures. Both research groups hence hypothesized that the Ru-metallacyclic intermediate, generated via

Clickable azide-functionalized bromoarylaldehydes – synthesis and photophysical characterization

• Dominik Göbel,
• Marius Friedrich,
• Enno Lork and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2020, 16, 1683–1692, doi:10.3762/bjoc.16.139

• alkynes, exhibiting different degrees of steric demand, was performed in high efficiency. Finally, we investigated the photophysical properties of the azide-functionalized arenes and their covalently linked triazole derivatives to gain deeper insight towards the effect of these covalent linkers on the

• azide functionalities, similar to para- and ortho-bromobenzaldehydes. Conclusion In summary, azide-functionalized ortho- and para-bromobenzaldehydes and fluorene derivatives were successfully synthesized. The azide bearing arenes were efficiently linked with even sterically highly demanding alkynes in

Pauson–Khand reaction of fluorinated compounds

• Jorge Escorihuela,
• Daniel M. Sedgwick,
• Alberto Llobat,
• Mercedes Medio-Simón,
• Pablo Barrio and
• Santos Fustero

Beilstein J. Org. Chem. 2020, 16, 1662–1682, doi:10.3762/bjoc.16.138

• -withdrawing para-substituted arenes were obtained in good yields and demonstrate excellent functional group compatibility; MeO– (36e, 65%), −CN (36f, 72%), −CO2Me (36g, 76%) and fluorinated groups such as p-CF3C6H4 (36h, 77%) (Scheme 17). Concerning the intramolecular PKR with fluorine atoms or fluorinated

In silico rationalisation of selectivity and reactivity in Pd-catalysed C–H activation reactions

• Liwei Cao,
• Mikhail Kabeshov,
• Steven V. Ley and
• Alexei A. Lapkin

Beilstein J. Org. Chem. 2020, 16, 1465–1475, doi:10.3762/bjoc.16.122

• mild conditions [13]. In particular, reactions involving palladium-catalysed activation of sp2 or sp3 C–H bonds of arenes or alkanes have been extensively investigated due to their wide scope and functional group tolerance [14]. A number of different mechanisms are proposed in the literature

Photocatalytic trifluoromethoxylation of arenes and heteroarenes in continuous-flow

• Alexander V. Nyuchev,
• Ting Wan,
• Borja Cendón,
• Carlo Sambiagio,
• Job J. C. Struijs,
• Michelle Ho,
• Moisés Gulías,
• Ying Wang and
• Timothy Noël

Beilstein J. Org. Chem. 2020, 16, 1305–1312, doi:10.3762/bjoc.16.111

• , Road, North Chicago, Illinois 60064, United States of America 10.3762/bjoc.16.111 Abstract The first example of photocatalytic trifluoromethoxylation of arenes and heteroarenes under continuous-flow conditions is described. Application of continuous-flow microreactor technology allowed to reduce the

• photoredox protocols for the radical trifluoromethoxylation of unfunctionalized (hetero)arenes by using specifically designed CF3O radical-releasing agents (Scheme 1B). Following our long-standing interest in the development of continuous-flow approaches for C–H functionalization [18][26] and photochemical

• methodologies [27][28][29][30][31], herein we report the first application of flow methods for the direct trifluoromethoxylation of arenes and heteroarenes. Results and Discussion Among the three reagents shown in Scheme 1B, we decided to use the “second” Ngai reagent (1, Scheme 1C) for our investigation, as

Photocatalysis with organic dyes: facile access to reactive intermediates for synthesis

• Stephanie G. E. Amos,
• Marion Garreau,
• Luca Buzzetti and
• Jerome Waser

Beilstein J. Org. Chem. 2020, 16, 1163–1187, doi:10.3762/bjoc.16.103

• )) radicals are important reactive intermediates for the construction of C–C and C–heteroatom bonds [31]. Their addition onto unsaturated systems, such as olefins and arenes, is particularly efficient. Additionally, alkyl radicals can undergo translocations, abstracting atoms from different sites. Recently

• (DHP) 5.1 in a metallaphotoredox protocol for the synthesis of alkylated (hetero)arenes (Scheme 5a) [49]. These substrates, easily synthesized from the corresponding aldehydes, can undergo a facile SET oxidation with the excited state of 4CzIPN. The ensuing fragmentation of the pyridyl group releases

• : a biradical capable of abstracting an H atom from C–H bonds. Recently, Martin exploited this feature in a nickel-catalyzed process for the alkylation of arenes (Scheme 8) [57]. In this report, the excited state of a push–pull benzophenone OD10 can abstract an H atom from the substrate

Copper-based fluorinated reagents for the synthesis of CF₂R-containing molecules (R ≠ F)

• Louise Ruyet and
• Tatiana Besset

Beilstein J. Org. Chem. 2020, 16, 1051–1065, doi:10.3762/bjoc.16.92

• )aryldiazonium salts, a panel of difluoromethylated arenes and heteroarenes was obtained (26 examples, up to 84% yield). Note that the transformation was also carried out starting from 4-methoxyaniline followed by the in situ formation of the corresponding diazonium salt. In the same vein, the authors used this

• functionalization of alkyl bromides, alkyl mesylates, aryldiazonium salts [43] as well as electron-rich arenes [44] (Scheme 4). In 2015, the group of Qing investigated the oxidative difluoromethylation reaction of terminal alkynes with TMSCF2H via a copper-mediated reaction [45]. Using a stoichiometric amount of

• ][53][54]. The active species was prepared from TMSCF2PO(OEt)2, a copper salt and an activator. Note that the TMSCF2PO(OEt)2 was easily prepared from the commercially available BrCF2PO(OEt)2 and TMSCl under basic conditions [49]. The access to CF2PO(OEt)2-containing arenes was obtained after a

Recent advances in Cu-catalyzed C(sp³)–Si and C(sp³)–B bond formation

• Balaram S. Takale,
• Ruchita R. Thakore,
• Elham Etemadi-Davan and
• Bruce H. Lipshutz

Beilstein J. Org. Chem. 2020, 16, 691–737, doi:10.3762/bjoc.16.67

• the details of the mechanism for the hydrofunctionalization of internal alkenes and vinyl arenes (Scheme 55) [100]. Unlike acyclic alkenes, Tortosa et al. utilized cyclobutenes as well as bicyclic cyclobutenes as educts using (R)-DM-Segphos for Cu-catalyzed enantioselective borylation, affording

• developed by Suginome [125], or B2pin2, along with various N-hydroxylamine derivatives (400) under ligand-influenced Cu catalysis, high regioselectivities were typically obtained [126]. A year later, Popp et al. reported a Cu-catalyzed regiospecific boracarboxylation of vinyl arenes using 1 atm CO2 and

Cascade trifluoromethylthiolation and cyclization of N-[(3-aryl)propioloyl]indoles

• Ming-Xi Bi,
• Shuai Liu,
• Yangen Huang,
• Xiu-Hua Xu and
• Feng-Ling Qing

Beilstein J. Org. Chem. 2020, 16, 657–662, doi:10.3762/bjoc.16.62

• the direct incorporation of the SCF3 group into organic compounds [9][10][11][12][13][14][15][16], such as alkynes, alkenes, arenes, and alkanes. Despite these impressive advances, there is a continued strong demand for new methods that enable the efficient synthesis of SCF3-containing compounds

Recent developments in photoredox-catalyzed remote ortho and para C–H bond functionalizations

• Rafia Siddiqui and
• Rashid Ali

Beilstein J. Org. Chem. 2020, 16, 248–280, doi:10.3762/bjoc.16.26

• catalyst for the oxidation of the arenes. The reaction is initiated by the oxidation of 100 through the excited photocatalyst to generate the arene radical cation 102. Here, P(OEt)3 acts as a nucleophile, capturing the radical cation of 102 and generating 103. Concomitant to the reduction of the Co(III

• hydroxylation of arenes (Scheme 18) [157]. They realized that the photoredox catalyst 8 possesses a great oxidizing ability (Ered vs SCE = 2.72 V) at ambient conditions. The mechanism of the reaction was studied by fluorescence quenching and transient absorption spectroscopy. They observed that the one-electron

• benzene are difficult to oxidize with nonphotochemical processes, whereas with photoredox catalyst 5 and TBN in the presence of oxygen, benzene can be easily be oxidized (Scheme 19) [158]. Remarkably, photoredox catalyst 5 offered a one-step oxygenation of arenes to phenol with high quantum yields. It was

Extension of the 5-alkynyluridine side chain via C–C-bond formation in modified organometallic nucleosides using the Nicholas reaction

• Renata Kaczmarek,
• Dariusz Korczyński,
• James R. Green and
• Roman Dembinski

Beilstein J. Org. Chem. 2020, 16, 1–8, doi:10.3762/bjoc.16.1

• diverse products via formation of C–C bonds. Nucleophiles as diverse as electron-rich arenes or heteroarenes [41][42], alkenes [43], allylmetalloids [44][45][46], enol derivatives [47][48], and organometallics [49] are suitable for the Nicholas reaction. Allenic byproducts are rarely seen, and

• electron-rich arenes, π-excessive heterocycles, enol derivatives, and allylmetalloids. Specifically, the reactivity of 1,3,5-trimethoxybenzene, N-methylindole, acetophenone trimethylsilyl enol ether, and allyltrimethylsilane was investigated (Table 1). The Nicholas reaction products 6 and 7 (Figure 1) were

An improved, scalable synthesis of Notum inhibitor LP-922056 using 1-chloro-1,2-benziodoxol-3-one as a superior electrophilic chlorinating agent

• Nicky J. Willis,
• Elliott D. Bayle,
• George Papageorgiou,
• David Steadman,
• Benjamin N. Atkinson,
• William Mahy and
• Paul V. Fish

Beilstein J. Org. Chem. 2019, 15, 2790–2797, doi:10.3762/bjoc.15.271

• et al. described the electrophilic chlorination of arenes and heterocycles by 1-chloro-1,2-benziodoxol-3-one (12) [18][19]. The hypervalent iodine(III) reagent 12 is reported to be a mild and effective reagent for the chlorination of nitrogen containing heterocycles which is easy to prepare and is

Acid-catalyzed rearrangements in arenes: interconversions in the quaterphenyl series

• Sarah L. Skraba-Joiner,
• Carter J. Holt and
• Richard P. Johnson

Beilstein J. Org. Chem. 2019, 15, 2655–2663, doi:10.3762/bjoc.15.258

• Sarah L. Skraba-Joiner Carter J. Holt Richard P. Johnson Department of Chemistry and Materials Science Program, University of New Hampshire, Durham, NH 03824, USA 10.3762/bjoc.15.258 Abstract Arenes undergo rearrangement of phenyl, alkyl, halogen and other groups through the intermediacy of ipso

• . Relative free energies are given in kcal/mol. Pathways for 1,2-biphenyl shifts in quaterphenyl isomers calculated with IEFPCM(DCE)/B3LYP/6-31+G(d,p) theory. Relative free energies are given in kcal/mol. Acid-catalyzed rearrangements of arenes. Rearrangement of quaterphenyl isomers by phenyl shifts

Anion-driven encapsulation of cationic guests inside pyridine[4]arene dimers

• Anniina Kiesilä,
• Jani O. Moilanen,
• Anneli Kruve,
• Christoph A. Schalley,
• Perdita Barran and
• Elina Kalenius

Beilstein J. Org. Chem. 2019, 15, 2486–2492, doi:10.3762/bjoc.15.241

• Berlin, Germany Michael Barber Centre for Collaborative Mass Spectrometry, Manchester Institute of Biotechnology, School of Chemistry, The University of Manchester, Princess Street, Manchester, UK 10.3762/bjoc.15.241 Abstract Pyridine[4]arenes have previously been considered as anion binding hosts due

• dimeric and hexameric capsules, which can encapsulate cationic and neutral guests [1][2][3]. Pyridine[4]arenes [4] are analogous macrocycles to resorcin[4]arenes. Whereas resorcinarenes are cyclic tetramers of resorcinol, pyridinearenes are formed from 2,6-dihydroxypyridine (see Scheme 1). Although the

• synthesis of pyridine[4]arenes dates back to 2001 [4], their host–guest chemistry is still under-explored. Both macrocycles are concave and are known to form capsular assemblies via intermolecular hydrogen bonding [5][6]. Pyridine is significantly less electron-rich than benzene. Consequently, pyridinearene