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

• two equivalents of NFSI afforded 4,4-difluoro-3,5-dimethoxy-2,5-cyclohexadienone (2c'') as the major product in 80% yield (Scheme 2a). Mechanistically, formation of 2c'' from 1,3,5-trimethoxybenzene (1c) requires a fluorodemethylation pathway to be operational under the ball-milling conditions, for

A novel methodology for the efficient synthesis of 3-monohalooxindoles by acidolysis of 3-phosphate-substituted oxindoles with haloid acids

• Li Liu,
• Yue Li,
• Tiao Huang,
• Dulin Kong and
• Mingshu Wu

Beilstein J. Org. Chem. 2021, 17, 2321–2328, doi:10.3762/bjoc.17.150

• or methoxy substituent gave a better yield (see 3b and 3c) than starting materials with an electron-withdrawing group, such as a NO2, CF3, Cl, Br, or F substituent (see 3d–g, 3j, 3k, and 3o). Surprisingly, a phosphate possessing two electron-withdrawing substituents in the form of a 4,6-difluoro

• appeared that the position of the residue R1 on the aryl ring exerted a pronounced effect on the reactivity. For instance, 4-bromo-, 4-chloro-, 4,6-difluoro-, 7-fluoro-, and 7-chloro-substituted phosphates afforded the corresponding products 3h, 3i, and 3l–n in a higher yield than the 5-fluoro-, 5-bromo

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

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

• ’-difluorobipyridinium salts and N,N’-difluoro-1,4-diazoniabicyclo[2.2.2]octane salts, and their many derivatives and analogs, including chiral N-F reagents such as optically active N-fluoro-sultam derivatives, N-fluoro-alkaloid derivatives, DABCO-based N-F derivatives, and N-F binaphthyldisulfonimides. The synthesis

• -rich substrates such as sodium diethyl (phenyl)malonate, 1-morpholinocyclohexene, phenol, and anisole (Scheme 47). The fluorination power of the carboxamide 21-2 was less than that of its N-F sulfonamide analog 11-2. 1-22. N,N’-Difluoro-1,4-diazoniabicyclo[2.2.2]octane salts In 1996, Umemoto and co

• -worker reported the successful synthesis of various N,N’-difluoro-1,4-diazoniabicyclo[2.2.2]octane salts 22-1a–f in a pure form and in good to excellent yields (Scheme 48) [83]. All the salts were fully identified by elemental analysis and spectral analysis. Previously, in 1992, Banks and co-workers

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

• . Initially, resting Mn(TMP)F undergoes oxidation, generating oxomanganese(V) complex O=Mn(TMP)F (5A), followed by H-abstraction of the substrate 1 or 3, providing HO–Mn(TMP)F (5B) and a C-centered radical. The trans-difluoro-substituted Mn(TMP) intermediate 5C, generated by an excess of the fluoride source

• was observed at the less sterically hindered benzylic position. The proposed reaction mechanism for radiofluorination is depicted in Figure 2. Although the trans-difluoro-substituted Mn(IV) complex is the reactive F-transfer intermediate in 19F chemistry, the formation of a trans-18F-difluoro

Synthesis of multiply fluorinated N-acetyl-D-glucosamine and D-galactosamine analogs via the corresponding deoxyfluorinated glucosazide and galactosazide phenyl thioglycosides

• Vojtěch Hamala,
• Lucie Červenková Šťastná,
• Martin Kurfiřt,
• Petra Cuřínová,
• Martin Dračínský and
• Jindřich Karban

Beilstein J. Org. Chem. 2021, 17, 1086–1095, doi:10.3762/bjoc.17.85

• ]. Unprotected multiply-deoxyfluorinated N-acetyl-ᴅ-glucosamine (GlcNAc) and N-acetyl-ᴅ-galactosamine (GalNAc) have not yet been described except for a 4,6-difluoro-GalNAc analog [22], although GlcNAc is the most abundant monosaccharide component of mammalian glycans [23], and GalNAc occurs in important glycan

• thioglycosides 27–31 (Scheme 3). As the 3,4-difluorinated thiogalactoside could not be accessed from compound 13 by reaction with PhSTMS/ZnI2 (Scheme 2), it was necessary to obtain 3,4-difluoro and 3,4,6-trifluoro analogs of GalNAc from 3-fluoro-4,6-diol 18. According to precedents in the literature [53

Beyond ribose and phosphate: Selected nucleic acid modifications for structure–function investigations and therapeutic applications

• Christopher Liczner,
• Kieran Duke,
• Gabrielle Juneau,
• Martin Egli and
• Christopher J. Wilds

Beilstein J. Org. Chem. 2021, 17, 908–931, doi:10.3762/bjoc.17.76

¹⁹F NMR as a tool in chemical biology

• Diana Gimenez,
• Aoife Phelan,
• Cormac D. Murphy and
• Steven L. Cobb

Beilstein J. Org. Chem. 2021, 17, 293–318, doi:10.3762/bjoc.17.28

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

• of fluorinated cyclopropanes was described by Atkinson in 1952 [9], followed by Tarrant [10], and Misani [11]. Tarrant, Lovelace and Lilyquist synthesized 1,1-difluoro-2,3-dimethylcyclopropane (2) by a reductive debromination using zinc metal (Scheme 1) [10]. After 1960 further methods of generating

• ]. Methyl 2,2-difluorosulfonyldifluoroacetate as a source of difluorocarbene: Eusterwiemann et al. devised a method for the generation of difluorocyclopropanes using methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (MDFA, 30) as a source of difluorocarbene (Scheme 14) [38]. The difluorocyclopropanation of α

• reagent was also used for the synthesis of organic spiro compounds, containing selectively fluorinated cyclopropanes 38a,b [45], for the preparation of 6,6-difluoro-3-azabicyclo[3.1.0]hexane (39) (on a 10 g scale) [46], and of the epothilone B analog 40 [47] (Table 2). The reagents (chlorodifluoromethyl

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

• , without byproduct formation from a Michael reaction (Table 2, entry 14). When o-aminophenol (1p) was used as the substrate, the coupling reaction occurred on the hydroxy group exclusively to give 2p (Table 2, entry 15). To show the synthetic advantages of the obtained gem-difluoro ethers 2, we examined

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

• approach using Et3N·3HF as an alternative to the DAST reagent. We controlled the stereochemistry of the nucleophilic fluorination at C4 of 1,6-anhydro-2,3-dideoxy-2,3-difluoro-4-O-triflate-β-ᴅ-talopyranose using Et3N·3HF or in situ generated Et3N·1HF. The influence of the fluorine atom at C2 on reactivity

• -difluoro-β-ᴅ-hexopyranoses 2–5 were prepared as pivotal intermediates to access compounds 6–9. We initially supposed that C4 deoxyfluorination of intermediates 2–5 could provide the corresponding trifluorinated product with inversion of configuration. Although that holds true for intermediates 2–4 (leading

• . Nevertheless, we investigated the preparation of 1,6-anhydro-2,3,4-trideoxy-2,3,4-trifluoro-β-ᴅ-hexopyranose analogues from previously described 1,6-anhydro-2,3-dideoxy-2,3-difluoro-β-ᴅ-hexopyranoses 2–5 using DAST (Table 1). We thus used 2 equivalents of DAST at 100 °C under microwave heating for 1 h and

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

• . This was achieved by performing a DFT study in the Gaussian software, using the M06-2X level of theory with the 6-311+G(d,p) basis set, parameters similar to those employed by Linclau and co-workers for their studies of vicinal difluoro systems [22]. A set of starting structures of 2 was generated by

The B & B approach: Ball-milling conjugation of dextran with phenylboronic acid (PBA)-functionalized BODIPY

• Patrizia Andreozzi,
• Lorenza Tamberi,
• Elisamaria Tasca,
• Gina Elena Giacomazzo,
• Marta Martinez,
• Mirko Severi,
• Marco Marradi,
• Stefano Cicchi,
• Sergio Moya,
• Giacomo Biagiotti and
• Barbara Richichi

Beilstein J. Org. Chem. 2020, 16, 2272–2281, doi:10.3762/bjoc.16.188

• mitochondrial activity was determined by the following formula: (Absorbance of treated cells/ Absorbance of control cells) × 100 (%). Synthesis of 3,5-dichloro-4,4-difluoro-8-(4-boronophenyl)-4-bora-3a,4a-diaza-s-indacene (PBA-BODIPY, 1) PBA-BODIPY (1) was prepared following the synthetic strategy reported in

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

• ). In contrast, the one-carbon introduction of a cyclopropyl group in H2 to give E2 leads to a lipophilicity increase. Replacing the fluorine substituent by a cyclopropyl carbon (compare H2 with E1) also leads to a lipophilicity increase, but not when starting from a geminal difluoro motif (compare C4

Natural dolomitic limestone-catalyzed synthesis of benzimidazoles, dihydropyrimidinones, and highly substituted pyridines under ultrasound irradiation

• Kumar Godugu,
• Venkata Divya Sri Yadala,
• Mohammad Khaja Mohinuddin Pinjari,
• Trivikram Reddy Gundala,
• Lakshmi Reddy Sanapareddy and
• Chinna Gangi Reddy Nallagondu

Beilstein J. Org. Chem. 2020, 16, 1881–1900, doi:10.3762/bjoc.16.156

• -withdrawing group (4-NO2: 2l), and halogen atoms (4-F: 2m, 4-Cl: 2n, and 3,4-difluoro: 2t), respectively, at different positions on the aromatic ring showed a good reactivity with the said reactants and afforded the corresponding products 11b–h that ranged from 90 to 96% (Table 7, entries 2–8). Further, the

On the hydrolysis of diethyl 2-(perfluorophenyl)malonate

• Ilya V. Taydakov and
• Mikhail A. Kiskin

Beilstein J. Org. Chem. 2020, 16, 1863–1868, doi:10.3762/bjoc.16.153

• aqueous or mixed water–EtOH solutions [29] or in biphasic water–Et2O mixtures [30] under reflux conditions. An exhaustive analysis of the literature revealed that virtually the same conditions were suitable for the hydrolysis of diethyl 2‐(2,6‐difluoro‐4‐methoxyphenyl)malonate (8) [31], dimethyl 2-(2

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

• isomerism were examined for diastereomeric 4-fluoroprolines, 4-(trifluoromethyl)prolines, and 1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylates. The preferred conformation on the proline ring originated from a preferential axial positioning for a single fluorine atom, and an equatorial positioning for a

• the examination of 1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylate based models, which showed similar trends in properties. Finally, the study provides a set of experimental evidences that reveal details of the transition state for the cis/trans amide rotation. Namely, it follows from the presented

Recent synthesis of thietanes

• Jiaxi Xu

Beilstein J. Org. Chem. 2020, 16, 1357–1410, doi:10.3762/bjoc.16.116

• [4.2.1.02,5]non-7-ene (366) in 11% yield with a trans:cis ratio of 55:45 [99] (Scheme 74). The reaction of 2,2,4,4-tetrafluoro-1,3-dithietane (367) and quadricyclane (218) generated the difluoro-bridged thietane 368 in 13% yield and two other byproducts 369 and 370 [99] (Scheme 75). The reaction of 2,2,4,4

Fluorinated phenylalanines: synthesis and pharmaceutical applications

• Laila F. Awad and
• Mohammed Salah Ayoup

Beilstein J. Org. Chem. 2020, 16, 1022–1050, doi:10.3762/bjoc.16.91

• tetrafluoro-Phe derivatives via chiral auxiliary 31. Synthesis of 2,5-difluoro-Phe and 2,4,5-trifluoro-Phe via Schöllkopf reagent 34. Synthesis of 2-fluoro- and 2,6-difluoro Fmoc-Phe derivatives starting from chiral auxiliary 39. Synthesis of 2-[18F]FPhe via chiral auxiliary 43. Synthesis of FPhe 49a via

• photooxidative cyanation. Synthesis of FPhe derivatives via Erlenmeyer azalactone synthesis. Synthesis of (R)- and (S)-2,5-difluoro Phe via the azalactone method. Synthesis of 3-bromo-4-fluoro-(S)-Phe (65). Synthesis of [18F]FPhe via radiofluorination of phenylalanine with [18F]F2 or [18F]AcOF. Synthesis of 4

Reaction of indoles with aromatic fluoromethyl ketones: an efficient synthesis of trifluoromethyl(indolyl)phenylmethanols using K₂CO₃/n-Bu₄PBr in water

• Thanigaimalai Pillaiyar,
• Masoud Sedaghati and
• Gregor Schnakenburg

Beilstein J. Org. Chem. 2020, 16, 778–790, doi:10.3762/bjoc.16.71

• the reactants was explored by subjecting the reaction of 2,2-difluoro-1-phenylethan-1-one (2i) with 1a. The desired product 3i was obtained in 63% yield. However, no product was formed when the reaction was carried out with 2-fluoro-1-phenylethan-1-one (2j) or acetophenone (2k). The reason could be

• scope of ketones was further extended with mixed halogen-substituted, pentafluoro or heptafluoro ketones such as 2-chloro-2,2-difluoro-1-phenylethan-1-one (2m), 2,2,3,3,3-pentafluoro-1-phenylpropan-1-one (2n) and 2,2,3,3,4,4,4-heptafluoro-1-phenylbutan-1-one (2o). All these reactions provided the

Chemical tuning of photoswitchable azobenzenes: a photopharmacological case study using nicotinic transmission

• Lorenzo Sansalone,
• Jun Zhao,
• Matthew T. Richers and
• Graham C. R. Ellis-Davies

Beilstein J. Org. Chem. 2019, 15, 2812–2821, doi:10.3762/bjoc.15.274

• . Since the latter has an oxygen atom para to the azo group we tested the feasibility of adding such a strong electron donor to an analog of a difluoro-(2F)AB Hecht photochrome [13] by making "MeO-2FAB" (Figure 1, see Supporting Information File 1 for synthesis). Since 2FAB and 4FAB photochromes with

• absorption spectra of these compounds (left). Note, the analogous difluoro-ABs have similar spectra to 4FABs [13]. Effect of electron donation on the fluoro-AB absorption spectra, the cis-MeO-2FAB (pink dots) is the green photostationary state of the photochrome (right). Structure of the photochrome core of

Recent advances in transition-metal-catalyzed incorporation of fluorine-containing groups

• Xiaowei Li,
• Xiaolin Shi,
• Xiangqian Li and
• Dayong Shi

Beilstein J. Org. Chem. 2019, 15, 2213–2270, doi:10.3762/bjoc.15.218

• fluorination of α,α-difluoro- and α-fluoroarylacetic acids with a wide functional group compatibility in the presence of AgNO3 as catalyst in good yields (Scheme 40). Further, this approach was efficiently applied to the preparation of [18F]-labelled tri- and difluoromethylarenes using [18F]Selectfluor bis

Cyclopropanation–ring expansion of 3-chloroindoles with α-halodiazoacetates: novel synthesis of 4-quinolone-3-carboxylic acid and norfloxacin

• Sara Peeters,
• Linn Neerbye Berntsen,
• Pål Rongved and
• Tore Bonge-Hansen

Beilstein J. Org. Chem. 2019, 15, 2156–2160, doi:10.3762/bjoc.15.212

• 6,7-difluoro-4-quinolone-3-carboxylate building block 10 was accessed in high yield in only three steps from commercially available substrates. The nature of the cyclopropanation–ring expansion makes the 4-chloro-3-carboxy-quinoline structure with perfect positioning of the carboxylate and chlorine

• substituents for the subsequent reaction to form the quinolone. The current work shows that the key cyclopropanation–ring expansion reaction works well with 3-chloroindole and 6,7-difluoro-3-chloro-indole, consistent with our previous work where substituents in positions 3–7 are well tolerated. Experimental

Synthesis of dipolar molecular rotors as linkers for metal-organic frameworks

• Sebastian Hamer,
• Fynn Röhricht,
• Marius Jakoby,
• Ian A. Howard,
• Xianghui Zhang,
• Christian Näther and
• Rainer Herges

Beilstein J. Org. Chem. 2019, 15, 1331–1338, doi:10.3762/bjoc.15.132

• leave rotational freedom in solids with confined free volumes. The dipole moments are generated by electron-donating substituents (benzo-1,3-dioxole, benzo-1,4-dioxane, or benzo-2,1,3-thiadiazole annelation) and withdrawing substituents (difluoro, or dicyano substitution) at the opposite positions of

• cross coupling. Using this method, dicarboxylic acids could be obtained from simple aqueous work-up and extraction. Difluoro compound 1 Difluorobenzenes have been employed as dipolar rotors by Garcia-Garibay in crystals [10], as an elongated MOF linker by Blight and Forgan [25] and for the investigation

• acid 1 using cesium fluoride under a carbon dioxide atmosphere. Difluoro- and dicyanobenzothiadiazole compounds 2 and 3 Substituted benzothiadiazole derivatives are well studied in the literature and are of great interest in organic photovoltaics and electronics. As there are no reports of such

Conformational signature of Ishikawa´s reagent using NMR information from diastereotopic fluorines

• Laize A. F. Andrade,
• Lucas A. Zeoly,
• Rodrigo A. Cormanich and
• Matheus P. Freitas

Beilstein J. Org. Chem. 2019, 15, 506–512, doi:10.3762/bjoc.15.44

• NMR spin–spin coupling constants (SSCCs), such as in methyl 2-fluoroesters [2], 3-fluoro-1,2-propanediol [3], 1-halo-2-propanols [4], enflurane [5], and 1-chloro-1,1-difluoro-2-pentanol [6]. This is possible due to an analogy with the Karplus curve that correlates the magnitude of vicinal 3JH,H SSCCs