Photoredox catalysis harvesting multiple photon or electrochemical energies

• Mattia Lepori,
• Simon Schmid and
• Joshua P. Barham

Beilstein J. Org. Chem. 2023, 19, 1055–1145, doi:10.3762/bjoc.19.81

Synthesis, structure, and properties of switchable cross-conjugated 1,4-diaryl-1,3-butadiynes based on 1,8-bis(dimethylamino)naphthalene

• Semyon V. Tsybulin,
• Ekaterina A. Filatova,
• Alexander F. Pozharskii,
• Valery A. Ozeryanskii and
• Anna V. Gulevskaya

Beilstein J. Org. Chem. 2023, 19, 674–686, doi:10.3762/bjoc.19.49

• trifluoromethyl group of one independent molecule is disordered with an occupancy of fluorine atoms of 0.54/0.46, which makes the molecule asymmetric. The second independent molecule has an inversion center. Compared to the free bases 5 discussed above, the protonated form 11с demonstrates almost complete

Direct C2–H alkylation of indoles driven by the photochemical activity of halogen-bonded complexes

• Martina Mamone,
• Giuseppe Gentile,
• Jacopo Dosso,
• Maurizio Prato and
• Giacomo Filippini

Beilstein J. Org. Chem. 2023, 19, 575–581, doi:10.3762/bjoc.19.42

• presents a difluoromethylene group (–CF2–) in the alpha position to the iodine, was performed (see Figure S3 in Supporting Information File 1). Even in this case, an important shift of the fluorine signal was observed. Thus, from a mechanistic point of view, the reaction is driven by the formation of a

Access to cyclopropanes with geminal trifluoromethyl and difluoromethylphosphonate groups

• Ita Hajdin,
• Romana Pajkert,
• Mira Keßler,
• Jianlin Han,
• Haibo Mei and
• Gerd-Volker Röschenthaler

Beilstein J. Org. Chem. 2023, 19, 541–549, doi:10.3762/bjoc.19.39

• them, trifluoromethyl- and difluoromethyl-substituted cyclopropanes are of great interest in pharmaceutical, materials and agricultural chemistry [3]. Due to the unique properties of fluorine, such as highest electronegativity, small atomic radius, or low polarizability, the strategic placement of

• . Phosphonates containing CF2 groups can sterically and electronically mimic oxygen, enabling the second dissociation constant, pKa2, to closer mirror those of the phosphates due to the electron-withdrawing effect of fluorine [39]. As a result, improved lipophilicity, metabolic stability or bioavailability of

• stereochemistry of the main isomer, the 19F,1H-HOESY NMR spectrum of compound 6c was recorded. The spectrum shows direct correlation of one fluorine nucleus of the difluoromethyl phosphonate group with two cyclopropane protons at 1.75 and 2.91 ppm, respectively. Thus, it is conceivable that the major

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

• ; palladium; synthetic method; Introduction Nowadays, fluorinated molecules represent an indispensable class of molecules in chemistry and in chemical biology. Thanks to the unique properties of the fluorine atom or fluorinated groups to modulate biological and physicochemical properties of the parent non

• pharmaceuticals and 30–40% of agrochemicals [3][4][5] contain at least one fluorine atom. Because of the exceptional features of fluorinated derivatives, tremendous developments and discoveries have been made in this blossoming research area, with a high interest for fundamental research as well as the industry

• largely underexplored to date. Furthermore, the development of enantioselective transformations allowing the synthesis of enantioenriched fluorine-containing compounds by transition-metal-catalyzed C–H bond activation will have a significant impact as for instance an access to pharmaceutically relevant

Dipeptide analogues of fluorinated aminophosphonic acid sodium salts as moderate competitive inhibitors of cathepsin C

• Karolina Wątroba,
• Małgorzata Pawełczak and
• Marcin Kaźmierczak

Beilstein J. Org. Chem. 2023, 19, 434–439, doi:10.3762/bjoc.19.33

• development of fluorinated aminophosphonate-based inhibitors. Keywords: aminophosphonates; cathepsin C; dipeptide; fluorine; solvolysis; Introduction Cathepsin C, also known as dipeptidyl peptidase I (DPPI) belongs to the family of lysosomal cysteine proteases encompassing 11 human enzymes (cathepsins B, C

• the catalytic cysteine Cys234 [10]. Phosphonates, as well as their analogues phosphonic acids, can be modified in a number of ways, one of which is the introduction of a fluorine atom into their molecules by fluorination or alkylfluorination [11][12][13][14]. However, the reaction of β-aminoalcohols

• with nucleophilic deoxyfluorinating reagents often does not lead to the expected products with a fluorine atom in place of the –OH group. They usually undergo rearrangement, and intramolecular cyclization leading to products that are constitutional isomers [15]. The solvolysis reaction of phosphonates

Synthesis and characterisation of new antimalarial fluorinated triazolopyrazine compounds

• Kah Yean Lum,
• Jonathan M. White,
• Daniel J. G. Johnson,
• Vicky M. Avery and
• Rohan A. Davis

Beilstein J. Org. Chem. 2023, 19, 107–114, doi:10.3762/bjoc.19.11

• . Antimalarial activity was significantly reduced when C-8 of the triazolopyrazine scaffold was substituted with CF3 and CF2H moieties, whereas incorporation of a CF2Me group at the same position completely abolished antiplasmodial effects. Keywords: antimalarial; characterisation; DiversinateTM; fluorine

• promising leads within the OSM project [14]. Fluorine-containing compounds have exhibited wide applications in pharmaceuticals and agrochemicals – approximately 20% of marketed drugs are fluoro-pharmaceuticals, while for agrochemicals, 53% are fluoro-compounds [17][18]. In recent decades, the introduction

• of fluorine or a fluorinated functional group into organic compounds has become increasingly prevalent in drug design and development, as fluorine substitution can greatly influence drug potency, pharmacokinetic and pharmacodynamic properties [19]. Therefore, in this study we undertook additional LSF

Simple synthesis of multi-halogenated alkenes from 2-bromo-2-chloro-1,1,1-trifluoroethane (halothane)

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

Beilstein J. Org. Chem. 2022, 18, 1567–1574, doi:10.3762/bjoc.18.167

• fluorine atoms were prepared in moderate to good yields via the reactions of phenols and 2-bromo-2-chloro-1,1,1-trifluoroethane (halothane) in the presence of KOH. This simple reaction enabled the construction of highly halogenated compounds with the potential for further functionalization. The reaction

• ) has been used as a fluorine-containing building block for the construction of trifluoromethyl and difluoromethylene motifs [1][2]. Such structures have been found in several multifunctional materials and biologically important molecules (Figure 1) [3][4][5][6][7]. The halothane structure contains two

On drug discovery against infectious diseases and academic medicinal chemistry contributions

• Yves L. Janin

Beilstein J. Org. Chem. 2022, 18, 1355–1378, doi:10.3762/bjoc.18.141

• drug vinorelbine (45). This provided in one step vinflunine (46) which, from 2009, became another anticancer drug. Past the historical case of fluoroquinolones [295], many more examples of the possible advantages of introducing fluorine(s) in a drug are provided in recent reviews [289][296]. Another

Heterogeneous metallaphotoredox catalysis in a continuous-flow packed-bed reactor

• Wei-Hsin Hsu,
• Susanne Reischauer,
• Peter H. Seeberger,
• Bartholomäus Pieber and
• Dario Cambié

Beilstein J. Org. Chem. 2022, 18, 1123–1130, doi:10.3762/bjoc.18.115

• peaks were detected in the fluorine spectra. The product yield calculated from the relative ratio of the product to the total integral area was comparable with the NMR yield calculated with hexafluorobenzene as internal standard in the high-field spectrometer (see Supporting Information File 1, Table S1

Electrochemical formal homocoupling of sec-alcohols

• Kosuke Yamamoto,
• Kazuhisa Arita,
• Masashi Shiota,
• Masami Kuriyama and
• Osamu Onomura

Beilstein J. Org. Chem. 2022, 18, 1062–1069, doi:10.3762/bjoc.18.108

• transformation was investigated as shown in Scheme 2. Various 1-arylethanol derivatives were firstly examined. Substrates bearing p-methyl (1b) or p-tert-butyl (1c) groups afforded the desired products 2b and 2c in moderate yields. Halogen substituents such as fluorine (1d) and chlorine (1e) atoms were tolerated

Post-synthesis from Lewis acid–base interaction: an alternative way to generate light and harvest triplet excitons

• Hengjia Liu and
• Guohua Xie

Beilstein J. Org. Chem. 2022, 18, 825–836, doi:10.3762/bjoc.18.83

• acids B(C6F5)3 and B(C6H5)3 as electron acceptors, respectively [29]. B(C6F5)3 displays high chemical stability and Lewis acidity [30]. Moreover, its good solubility endows the possibility to form Lewis acid–base adducts in films by solution processing. The strong electron attraction of the fluorine

• spectrum (see Figure 9b), which were different from the same chemical environment of fluorine atoms in the original B(C6F5)3. To further explore the interaction of the Lewis acid–base pairs, Huang et al. added B(C6F5)3 to pyridine group-capped diketopyrrolopyrrole (DPP) molecules, i.e., DPPPy-Py-F (16

• , Figure 5) [29][39]. As illustrated in Figure 12a, BCF can narrow down the bandgap of the exciplex because of the stronger electrophilicity of the fluorine atoms. Similarly, Yamaguchi et al. used molecular modifications to introduce stronger electron donors to luminescent molecules and obtained stronger

Synthesis of α-(perfluoroalkylsulfonyl)propiophenones: a new set of reagents for the light-mediated perfluoroalkylation of aromatics

• Durbis J. Castillo-Pazos,
• Juan D. Lasso and
• Chao-Jun Li

Beilstein J. Org. Chem. 2022, 18, 788–795, doi:10.3762/bjoc.18.79

• bonds have been substituted with fluorine atoms. Within this family of molecules, perfluoroalkyl groups represent an industrially relevant moiety, capable of modifying the physicochemical properties of the scaffold that they are attached to. Such properties and a distinctive reactivity – or inert

Cholyl 1,3,4-oxadiazole hybrid compounds: design, synthesis and antimicrobial assessment

• Anas J. Rasras,
• Mohamed El-Naggar,
• Nesreen A. Safwat and
• Raed A. Al-Qawasmeh

Beilstein J. Org. Chem. 2022, 18, 631–638, doi:10.3762/bjoc.18.63

• observed in most of the compounds except for derivatives 4b, 4d, 4p, and 4u. All aromatic compounds showed resonances at δ = 6.50–8.00 ppm. Compounds 4b and 4c indicated the fluorine coupling effect on the aromatic protons. The carbaldehyde proton in compound 4h resonates at δ = 8.00 ppm, while compound 4k

Multi-faceted reactivity of N-fluorobenzenesulfonimide (NFSI) under mechanochemical conditions: fluorination, fluorodemethylation, sulfonylation, and amidation reactions

• José G. Hernández,
• Karen J. Ardila-Fierro,
• Dajana Barišić and
• Hervé Geneste

Beilstein J. Org. Chem. 2022, 18, 182–189, doi:10.3762/bjoc.18.20

• spectroscopy (Scheme 3h). Formation of 4a could have occurred from the direct reaction of the N–H nitrogen of 3a with NFSI, which would agree with the propensity for NFSI to react with some hard oxygen and nitrogen nucleophiles at the sulfur atom instead of at the fluorine atom [39][40]. Similarly, NFSI has

Silica gel and microwave-promoted synthesis of dihydropyrrolizines and tetrahydroindolizines from enaminones

• Robin Klintworth,
• Garreth L. Morgans,
• Stefania M. Scalzullo,
• Charles B. de Koning,
• Willem A. L. van Otterlo and
• Joseph P. Michael

Beilstein J. Org. Chem. 2021, 17, 2543–2552, doi:10.3762/bjoc.17.170

• enaminone 15r, which was prepared in situ prior to cyclization. The pyrrolizine 19r was obtained within 90 seconds of microwave heating, and in 99% yield over the two steps. The rapidity of the condensation probably reflects both the inductive electron-withdrawing effect of fluorine and the minimal steric

Enantioselective PCCP Brønsted acid-catalyzed aminalization of aldehydes

• Martin Kamlar,
• Robert Reiberger,
• Martin Nigríni,
• Ivana Císařová and
• Jan Veselý

Beilstein J. Org. Chem. 2021, 17, 2433–2440, doi:10.3762/bjoc.17.160

• example, when benzaldehydes substituted with fluorine or chlorine in the para-position were employed in catalytic reaction with anthranilamide (1a), the corresponding derivatives 3i,j were isolated in 58 and 69% yield, respectively. The rates of enantioselectivity for both reactions were lower and

Synthesis and antimicrobial activity of 1H-1,2,3-triazole and carboxylate analogues of metronidazole

• Satya Kumar Avula,
• Syed Raza Shah,
• Khdija Al-Hosni,
• Muhammad U. Anwar,
• Rene Csuk,
• Biswanath Das and
• Ahmed Al-Harrasi

Beilstein J. Org. Chem. 2021, 17, 2377–2384, doi:10.3762/bjoc.17.154

• protons of –N–CH2-CH2–Ph. A singlet peak at δ 1.86 is attributed to methyl protons on the imidazole ring. The 19F NMR spectrum of 1H-1,2,3-triazole compound 5c showed a singlet at δ −113.61 corresponding to one fluorine atom of the phenyl ring. The high-resolution mass spectrometric data at 317.1141 (M

• . Crystal structure of compound 3. Colour codes: carbon = grey, mitrogen = blue, oxygen = red, hydrogen = white. Crystal structure of 1H-1,2,3-triazole compound 5c: Colour codes: carbon = grey, nitrogen = blue, oxygen = red, fluorine = yellow, hydrogen = white. Crystal structures of compound 7b. Colour

A study on selective transformation of norbornadiene into fluorinated cyclopentane-fused isoxazolines

• Zsanett Benke,
• Attila M. Remete and
• Loránd Kiss

Beilstein J. Org. Chem. 2021, 17, 2051–2066, doi:10.3762/bjoc.17.132

• the CM transformations with the goal of exploring substrate and steric effects, catalyst influence and chemodifferentiation of the olefin bonds furnishing the corresponding functionalized, fluorine-containing isoxazoline derivatives. Keywords: functionalization; metathesis; nitrile oxide

• are considered as to be of type II, only a handful of literature data are available on the behavior of fluorine-containing olefins or perfluorinated alkenes. The incorporation of fluoroalkyl moieties (such as difluoromethyl, trifluoromethyl and perfluoroalkyl groups) into an organic molecule can often

• ) late-stage fluorination, when the fluorine atom is incorporated in the final step of the synthetic protocol (e.g., deoxofluorinations) or ii) application of various commercial fluorine-containing scaffolds (e.g., fluorine-containing amines, fluorine-containing alkenes etc.) [49][50][51][52][53][54][55

Recent advances in the syntheses of anthracene derivatives

• Giovanni S. Baviera and
• Paulo M. Donate

Beilstein J. Org. Chem. 2021, 17, 2028–2050, doi:10.3762/bjoc.17.131

• introduction of highly electronegative halides, such as fluorine or chlorine, on the phenyl ring afforded the substituted 9-methylanthracenes in lower yields. In addition, the method proposed by Lee and co-workers presented advantages that included shorter reaction times and milder reaction conditions [37

Progress and challenges in the synthesis of sequence controlled polysaccharides

• Giulio Fittolani,
• Theodore Tyrikos-Ergas,
• Denisa Vargová,
• Manishkumar A. Chaube and
• Martina Delbianco

Beilstein J. Org. Chem. 2021, 17, 1981–2025, doi:10.3762/bjoc.17.129

• ]. Mimicking the natural cellulose synthases machinery can be foreseen to provide synthetic Cellulose I. Some enzymes offer the flexibility to produce modified cellulose structures. Cellulose oligomers with fluorine substitution at C-2, C-3 or C-6 position were prepared by cellodextrin phosphorylases [78

• , fluorine, and carboxymethyl groups, prevented the formation of insoluble aggregates by disrupting hydrogen-bond networks. Dramatic differences in the conformation (e.g., radius of gyration and glycosidic bond conformation) and aggregation behaviour (i.e., crystallinity and solubility) were observed for

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

• to oxidize ethylbenzene without significant loss of activity and metal leaching. The authors have suggested a mechanism for the reaction involving radical species bearing a benzylic carbon–vanadium bond. Fluorine presents unique features and may lead to essential changes in the structural and

• also been reported for the direct C(sp3)–H fluorination. Chen and co-workers [94] described a fluorination method employing Selectfluor as fluorine source and the commercially available V2O3 to give fluorine-containing compounds under mild conditions and with moderate to good yields (Scheme 10B,C). The

• /hemiacetal avoiding undesirable elimination to the enamine, or attack at other electrophilic sites in complex substrates. The presence of a fluorine source like diethylaminosulfur trifluoride (DAST) or the Lewis acid boron trifluoride diethyl etherate (BF3·OEt2) result in the formation of reactive iminium or

Development of N-F fluorinating agents and their fluorinations: Historical perspective

• Teruo Umemoto,
• Yuhao Yang and
• Gerald B. Hammond

Beilstein J. Org. Chem. 2021, 17, 1752–1813, doi:10.3762/bjoc.17.123

• Teruo Umemoto Yuhao Yang Gerald B. Hammond Department Chemistry, University of Louisville, Lousiville, Kentucky 40292, USA 10.3762/bjoc.17.123 Abstract This review deals with the historical development of all N-F fluorinating agents developed so far. The unique properties of fluorine make

• salt; fluoropyridinium salt; fluorosulfonimide; Introduction Fluorinated organic compounds occupy an important position in pharmaceuticals [1], agrochemicals [2], and materials [3]. Especially, in the first two areas, the presence of fluorine has attracted attention during the last decades. Nowadays

• , a considerable number of medicines [4][5] and agrochemicals [6] contain at least one fluorine atom in their structures. The fluorine atom has unique properties such as the highest electronegativity, extremely low polarization, strong C–F bonds, and the smallest size after a hydrogen atom [7]. Thus

Sustainable manganese catalysis for late-stage C–H functionalization of bioactive structural motifs

• Jongwoo Son

Beilstein J. Org. Chem. 2021, 17, 1733–1751, doi:10.3762/bjoc.17.122

• . Additionally, difluorination was observed with negligible amounts because the monofluorinated product is rendered more electronically deficient by the first fluorine atom. Based on an analysis by DFT calculations, the postulated reaction pathway of manganese-catalyzed C–H fluorination is described in Figure 1

• fluorine activation (see 22i–j), and the oxygen-containing natural terpenoid ambroxide was methylated at the methylene position next to the O atom on the tetrahydrofuran ring (see 22k). This manganese-catalyzed late-stage approach enables the direct methylation of unactivated C–H bonds with excellent site

Chemical approaches to discover the full potential of peptide nucleic acids in biomedical applications

• Nikita Brodyagin,
• Martins Katkevics,
• Venubabu Kotikam,
• Christopher A. Ryan and
• Eriks Rozners

Beilstein J. Org. Chem. 2021, 17, 1641–1688, doi:10.3762/bjoc.17.116

• uracil with fluorine or trifluoromethyl improved PNA binding affinity for complementary DNA and RNA [127]. Moreover, fluorination increased the cellular uptake of PNAs [127]. Fluorinated uracil derivatives are also useful probes for studying different binding modes of PNA using 19F NMR [128]. PNA