Nickel-catalyzed cross-coupling of 2-fluorobenzofurans with arylboronic acids via aromatic C–F bond activation

• Takeshi Fujita,
• Haruna Yabuki,
• Ryutaro Morioka,
• Kohei Fuchibe and
• Junji Ichikawa

Beilstein J. Org. Chem. 2025, 21, 146–154, doi:10.3762/bjoc.21.8

• coupling reactions of aromatic C–F and C–Br bonds with arylboronic acids. Keywords: arylboronic acid; benzofuran; C–F bond activation; cross-coupling; nickel; Introduction The metal-catalyzed activation of aromatic carbon–fluorine (C–F) bonds is widely recognized as a challenging task in synthetic

• -(trifluoromethyl)-1-alkenes strongly interact with electron-rich zero-valent nickel species to form nickelacyclopropanes C [15][16][17]. These intermediates enable C–F bond activation through the formation of nickelacyclopentenes D with alkynes, followed by β-fluorine elimination, leading to defluorinative

• coupling between these components (Scheme 1b). Among aromatic fluorides, we have targeted 2-fluorobenzofurans 1 for C–F bond activation [19]. These compounds, which we prepared efficiently via 5-endo-trig cyclization of β,β-difluoro-o-hydroxystyrenes [20][21], possess a C–C double bond with an electron

Efficient synthesis of fluorinated triphenylenes with enhanced arene–perfluoroarene interactions in columnar mesophases

• Yang Chen,
• Jiao He,
• Hang Lin,
• Hai-Feng Wang,
• Ping Hu,
• Bi-Qin Wang,
• Ke-Qing Zhao and
• Bertrand Donnio

Beilstein J. Org. Chem. 2024, 20, 3263–3273, doi:10.3762/bjoc.20.270

• commercial perfluoroarene chemical blocks and reagents, involving catalyzed C–F-bond activation and cross-coupling reactions, usually requiring precious transition-metal catalysts and tedious synthetic routes [28][29][30][31][32][33][34]. Therefore, low-cost and facile synthetic strategies are desired to

Hypervalent iodine-mediated intramolecular alkene halocyclisation

• Charu Bansal,
• Oliver Ruggles,
• Albert C. Rowett and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 3113–3133, doi:10.3762/bjoc.20.258

• C‒F bond to give predominantly the trans product, but this pathway competes with a less favourable SN2 nucleophilic attack by fluorine to form the cis product. However, a mechanism entirely mediated by the I(III) HVI reagent, with the Pd(OAc)2 only acting as a Lewis acid to activate the HVI reagent

A review of recent advances in electrochemical and photoelectrochemical late-stage functionalization classified by anodic oxidation, cathodic reduction, and paired electrolysis

• Nian Li,
• Ruzal Sitdikov,
• Ajit Prabhakar Kale,
• Joost Steverlynck,
• Bo Li and
• Magnus Rueping

Beilstein J. Org. Chem. 2024, 20, 2500–2566, doi:10.3762/bjoc.20.214

• oxidized to a carbocation, which is subsequently attacked by the alkoxide to furnish the final product (Scheme 17). The Lei group also demonstrated C–F-bond formations, particularly developing an electrochemical method for the cleavage of C–C bonds and the 1,3-difunctionalization of arylcyclopropanes [26

Synthesis and conformational analysis of pyran inter-halide analogues of ᴅ-talose

• Olivier Lessard,
• Mathilde Grosset-Magagne,
• Paul A. Johnson and
• Denis Giguère

Beilstein J. Org. Chem. 2024, 20, 2442–2454, doi:10.3762/bjoc.20.208

• analogues (Table 1, entries 7 and 8). Also, the exocyclic C1–O1 bond lengths of compounds 13–15 and 17 are in average 0.033 Å longer than native talose (18). As expected, all the C–F bond lengths are shorter than the corresponding C–OH bond lengths (Table 1, entries 10–12) [48]. The C2–F2 bond lengths are

1,2-Difluoroethylene (HFO-1132): synthesis and chemistry

• Liubov V. Sokolenko,
• Taras M. Sokolenko and
• Yurii L. Yagupolskii

Beilstein J. Org. Chem. 2024, 20, 1955–1966, doi:10.3762/bjoc.20.171

• case was predominant over [2 + 2]-cycloadducts. Reactions involving C–F bonds It was shown by Liu and co-workers that SiF2 was able to insert into the C–F bond of 1,2-difluoroethylene, as well as into the emerging Si–F bond, leading to a mixture of fluoropolysilanes with a low combined yield (Scheme 24

Oxidative fluorination with Selectfluor: A convenient procedure for preparing hypervalent iodine(V) fluorides

• Samuel M. G. Dearman,
• Xiang Li,
• Yang Li,
• Kuldip Singh and
• Alison M. Stuart

Beilstein J. Org. Chem. 2024, 20, 1785–1793, doi:10.3762/bjoc.20.157

• -molecule drugs contain at least one fluorine atom [2]. Hypervalent iodine(III) fluorides, such as difluoroiodotoluene 1 and fluoroiodane 2, have been key to the development of numerous, new synthetic procedures for C–F bond formation over the last decade. Since difluoroiodotoluene 1 has low chemical

Regio- and stereochemical stability induced by anomeric and gauche effects in difluorinated pyrrolidines

• Ana Flávia Candida Silva,
• Francisco A. Martins and
• Matheus P. Freitas

Beilstein J. Org. Chem. 2024, 20, 1572–1579, doi:10.3762/bjoc.20.140

• stereochemical behavior. Consequently, various molecular properties, such as polarity, viscosity, and intra- and intermolecular interactions, are impacted by the C‒F bond. These features underlie the important role of selective fluorination in pharmaceuticals and agrochemicals development [1]. For instance

• pyrrolidinium salt [11] with the CCSD/DGTZVP geometry of the pyrrolidinium cation (with an exclusively axial C–F bond) and the energy of 3-fluoropyrrolidine conformations. Various combinations of DFT methods (B3LYP-D3BJ, ωB97XD, and PBEPBE) and basis sets (DGTZVP and 6-311++G**) were evaluated. The selection of

• Figure 5 and Table 2. This disparity in stability was largely attributed to the relative orientation of the nitrogen electron lone pair and the adjacent C–F bond, facilitating an anomeric interaction characterized by nN→σ*CF electron delocalization. Isomer 2 also demonstrated such an orientation, but the

Benzylic C(sp³)–H fluorination

• Alexander P. Atkins,
• Alice C. Dean and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 1527–1547, doi:10.3762/bjoc.20.137

• benzylic radical furnishing the desired product and regenerating I. Photochemical methods Photochemical methods that make use of fluoride to quench benzylic carbocations in order to form a new C–F bond have proved effective for functionalising a broad range of benzylic substrates. Two concurrent

Direct synthesis of acyl fluorides from carboxylic acids using benzothiazolium reagents

• Lilian M. Maas,
• Alex Haswell,
• Rory Hughes and
• Matthew N. Hopkinson

Beilstein J. Org. Chem. 2024, 20, 921–930, doi:10.3762/bjoc.20.82

• employed as acylation reagents [1][2][3]. The strong C–F bond makes acyl fluorides relatively stable towards hydrolysis and easier to handle than other acyl halides [4][5][6][7][8]. Their reactions with nucleophiles are typically less violent than for the corresponding acyl chlorides with acyl fluorides

(E,Z)-1,1,1,4,4,4-Hexafluorobut-2-enes: hydrofluoroolefins halogenation/dehydrohalogenation cascade to reach new fluorinated allene

• Nataliia V. Kirij,
• Andrey A. Filatov,
• Yurii L. Yagupolskii,
• Sheng Peng and
• Lee Sprague

Beilstein J. Org. Chem. 2024, 20, 452–459, doi:10.3762/bjoc.20.40

• 1b. Wherein various alkyl and aryl olefins, including those that contain Lewis basic esters, carbamates and amines or α-branched moieties, may be used in efficient and exceptionally Z-selective cross-metathesis reactions [6][7][8]. A few years ago, some publications devoted to the cleavage of the C–F

• bond in butenes 1a,b have been presented in the literature. First, Crimmin et al. investigated the reaction of an aluminum(I) complex with fluoroalkenes. Unlike all the presented fluoroolefins, the reaction of the Al(I) complex with (Z)-butene 1b did not allow isolating the intermediate organoaluminum

Transition-metal-catalyzed C–H bond activation as a sustainable strategy for the synthesis of fluorinated molecules: an overview

• Louis Monsigny,
• Floriane Doche and
• Tatiana Besset

Beilstein J. Org. Chem. 2023, 19, 448–473, doi:10.3762/bjoc.19.35

• . Note that, in this process, Selectfluor® is playing a key role. Indeed, using this electrophilic fluorinating source as oxidant generates a Pd(IV)(ppy)F(OAc)2 (ppy = 2-phenylpyridine) complex as intermediate. As the competitive C–F bond formation was disfavored (slow reductive elimination step), the

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

• Renato L. Carvalho,
• Amanda S. de Miranda,
• Mateus P. Nunes,
• Roberto S. Gomes,
• Guilherme A. M. Jardim and
• Eufrânio N. da Silva Júnior

Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126

•  19D). In carbocyclic substrates the displacement of a C–F bond or ionization with a Lewis acid is difficult, but mesylates are stable and suitable for AlMe3 activation. As already mentioned, indoles are an important class of molecules with potential antidiabetic properties since they can act as GPR40

Iodine-catalyzed electrophilic substitution of indoles: Synthesis of (un)symmetrical diindolylmethanes with a quaternary carbon center

• Thanigaimalai Pillaiyar,
• Masoud Sedaghati,
• Andhika B. Mahardhika,
• Lukas L. Wendt and
• Christa E. Müller

Beilstein J. Org. Chem. 2021, 17, 1464–1475, doi:10.3762/bjoc.17.102

• interest due to fluorine’s unique physical and chemical properties, such as its small size, high electronegativity, and high C–F bond dissociation energy [22][23][24]. Organofluoro compounds developed as drug molecules often display increased metabolic stability and bioavailability compared to non

Metal-free glycosylation with glycosyl fluorides in liquid SO₂

• Krista Gulbe,
• Jevgeņija Lugiņina,
• Edijs Jansons,
• Artis Kinens and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 964–976, doi:10.3762/bjoc.17.78

• groups, promoter, solvent and temperature has to be applied. In 1981, Mukaiyama et al. introduced glycosyl fluorides [5] as a new class of glycosyl donors [6]. The C–F bond is one of the strongest single bonds in the realm of organic compounds with a bond dissociation energy (BDE) of 570 kJ/mol [7]. Thus

• reaction was observed and mannosyl fluoride α-1a was fully recovered. Recently, Pedersen et al. have studied the vessel effect on the C–F bond activation of glucosyl fluorides [63]. They have proposed an autocatalytic glycosylation by SiF4 generated in situ form initially released HF that reacts with

• performed on the model reaction α-11 + MeOH → α-13c to elucidate the influence of SO2 on the dissociation of the glycosidic C–F bond [78] (Figure 2). Indeed, it was found that the coordination of the Lewis acidic SO2 to the fluoride (transition state TS-A≠ versus TS-A(SO2)≠) decreases the C–F bond

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

• Letcka et al., which can be seen as a strong nF→2pC interaction (Wiberg bond order of 0.53 for each C–F bond), gave additional credit to these calculations (Figure 1, bottom) [26][27][28]. The thermochemical data can also provide information on the effect of the CF3 group on the stability of the

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

• disrotation at C2 and C3 during stereomutation in 1,1-difluorocyclopropanes [85]. An important feature in the fluorinated system was the stabilization of the intermediate 2,2-difluorotrimethylene radicals due to the conjugation of the radical centers with the σ*-orbital of C–F bond, which can be represented

Fluorine effect in nucleophilic fluorination at C4 of 1,6-anhydro-2,3-dideoxy-2,3-difluoro-β-D-hexopyranose

• Danny Lainé,
• Vincent Denavit,
• Olivier Lessard,
• Laurie Carrier,
• Charles-Émile Fecteau,
• Paul A. Johnson and
• Denis Giguère

Beilstein J. Org. Chem. 2020, 16, 2880–2887, doi:10.3762/bjoc.16.237

• destabilize the adjacent carbocation center [41][42][43], avoiding 1,2-alkyl shift, and thus formation of byproduct 20. Similarly, the large dipole moment of the C–F bond at C2 influences the outcome of the deoxyfluorination at C4 [3]. For triflates 16 and 17, both dipoles (green arrows, Figure 3a) are

Vicinal difluorination as a C=C surrogate: an analog of piperine with enhanced solubility, photostability, and acetylcholinesterase inhibitory activity

• Yuvixza Lizarme-Salas,
• Alexandra Daryl Ariawan,
• Ranjala Ratnayake,
• Hendrik Luesch,
• Angela Finch and
• Luke Hunter

Beilstein J. Org. Chem. 2020, 16, 2663–2670, doi:10.3762/bjoc.16.216

• . Stereoselective fluorination is an emerging strategy for controlling the conformations of organic molecules. The highly polarized C–F bond tends to align in predictable ways with adjacent functional groups, due to a combination of hyperconjugative and/or dipolar interactions [18][19][20][21]. This knowledge led

Activation of pentafluoropropane isomers at a nanoscopic aluminum chlorofluoride: hydrodefluorination versus dehydrofluorination

• Maëva-Charlotte Kervarec,
• Thomas Braun,
• Mike Ahrens and
• Erhard Kemnitz

Beilstein J. Org. Chem. 2020, 16, 2623–2635, doi:10.3762/bjoc.16.213

• 1,1,1,2,3-pentafluoropropane (HFC-245fa, HFC-245cb, and HFC-245eb) were activated through C–F bond activations using aluminium chlorofluoride (ACF) as a catalyst. The addition of the hydrogen source Et3SiH is necessary for the activation of the secondary and tertiary C–F bonds. Multiple C–F bond activations

• such as hydrodefluorinations and dehydrofluorinations were observed, followed by hydroarylation and Friedel–Crafts-type reactions under mild conditions. Keywords: aluminum fluoride; C–F bond activation; dehydrofluorination; hydrodefluorination; hydrofluorocarbons; Introduction Hydrofluorocarbons

• in part needed due to the high dissociation energy of C–F bonds, and in general, C–F activation steps are considered to be challenging [20][21][22][23][24][25][26][27]. Solid Lewis acids with a high fluoride ion affinity as catalysts are useful tools for C–F bond activation reactions since the Lewis

Conformational preferences of fluorine-containing agrochemicals and their implications for lipophilicity prediction

• Daniela Rodrigues Silva,
• Joyce K. Daré and
• Matheus P. Freitas

Beilstein J. Org. Chem. 2020, 16, 2469–2476, doi:10.3762/bjoc.16.200

• soil sorption and bioconcentration of organic compounds. Since the C–F bond is the most polar in organic chemistry, the orientation of fluorine substituents originating from the rotation around C–C(F) bonds should affect the polarity and, consequently, the physicochemical and biological properties of

• on conformation, membrane permeation, pharmacokinetic properties, among other parameters [7]. From a conformational analysis point of view, the fluorine atom presents minimal steric effects; on the other hand, due to its high electronegativity, the C–F bond is highly polarized, which characterizes it

• conformations along the 1,2-disubstituted ethane motif, the C–C(F) bond was rotated to additionally obtain conformers Igg and Iga, and the corresponding geometries were then optimized. The resulting geometries and relative conformational energies are summarized in Figure 2. At first, we observe that the overall

Photosensitized direct C–H fluorination and trifluoromethylation in organic synthesis

• Shahboz Yakubov and
• Joshua P. Barham

Beilstein J. Org. Chem. 2020, 16, 2151–2192, doi:10.3762/bjoc.16.183

• . One exciting development in C–F bond formation is the use of small-molecule photosensitizers, allowing the reactions i) to proceed under mild conditions, ii) to be user-friendly, iii) to be cost-effective and iv) to be more amenable to scalability than typical photoredox-catalyzed methods. In this

• fluorinated agrochemicals (Figure 2) [7][8]. Fluorine possesses some unique properties, such as the highest atomic electronegativity [9] and, in its molecular form (F2), the most positive standard reduction potential (E0) of +2.87 V [10], as predictable from its position in the periodic table. The C–F bond

• ][119][120][121][122]. There are many approaches to photosensitized fluorination that do not involve direct C–H activation, which are reviewed elsewhere [123][124][125], such as C–C bond fragmentation/C–F bond formation [126], aminofluorination of cyclopropanes [127] and decarboxylative fluorination

Lipophilicity trends upon fluorination of isopropyl, cyclopropyl and 3-oxetanyl groups

• Benjamin Jeffries,
• Zhong Wang,
• Robert I. Troup,
• Anaïs Goupille,
• Jean-Yves Le Questel,
• Charlene Fallan,
• James S. Scott,
• Elisabetta Chiarparin,
• Jérôme Graton and
• Bruno Linclau

Beilstein J. Org. Chem. 2020, 16, 2141–2150, doi:10.3762/bjoc.16.182

• polarizability of the oxygen lone pairs due to the fluorine electronegativity. However, while D2 is a β-fluorohydrin, its fluorine is substituted at a tertiary position, with the C–F bond able to polarize the six C–H bonds of the methyl groups, which has a lipophilicity lowering effect. The electron-withdrawing

• cases, for the same fluorination motif, the cyclopropane derivatives have a lower lipophilicity compared to their acyclic equivalents. It is also useful to compare lipophilicities of acyclic and cyclopropane derivatives in which the isosterism represents conversion of a C–H and C–F bond into a C–C bond

Reactions of 3-aryl-1-(trifluoromethyl)prop-2-yn-1-iminium salts with 1,3-dienes and styrenes

• Thomas Schneider,
• Michael Keim,
• Bianca Seitz and
• Gerhard Maas

Beilstein J. Org. Chem. 2020, 16, 2064–2072, doi:10.3762/bjoc.16.173

• characteristics of the C‒F bond [6][7] are the basis for the electronic and steric properties of the CF3 group, such as a strong electron-withdrawing (−I) effect, the accumulation of negative charge density in a relatively small volume and the low polarizability of the fluoro atoms. These and other substituent

Polarity effects in 4-fluoro- and 4-(trifluoromethyl)prolines

• Vladimir Kubyshkin

Beilstein J. Org. Chem. 2020, 16, 1837–1852, doi:10.3762/bjoc.16.151

• fluorination usually increases polarity of a molecule due the newly introduced polar C–F bond. A CF3 group introduces a dipole of a similar size (see Figure 2), however, due to its high molar volume it increases the hydrophobicity of a molecule [75]. The overall outcome may appear paradoxical: a CF3 group can

• diastereomers exhibited some differences. The cis-diastereomer 1 with the C–F bond pointing in the same direction as the carboxymethyl group, appeared more polar compared to the trans-isomer 2, where the direction was opposite (ΔlogPcis/trans ≈ −0.18). The same effect was observed in 4-hydroxyprolines as well