Benzothiazolium salts as reagents for the deoxygenative perfluoroalkylthiolation of alcohols

• Armin Ariamajd,
• Nils J. Gerwien,
• Benjamin Schwabe,
• Stefan Dix and
• Matthew N. Hopkinson

Beilstein J. Org. Chem. 2021, 17, 83–88, doi:10.3762/bjoc.17.8

• fluoride species, which can subsequently react with the alcohol, delivering thionoester 4. β-Fluoride elimination is a known decomposition pathway of −SCF3 and has even been exploited in synthetic trifluoromethylthiolation and fluorination processes [32][33][34]. The formation of the side-product 4a could

Synthesis of tetrafluorinated piperidines from nitrones via a visible-light-promoted annelation reaction

• Vyacheslav I. Supranovich,
• Igor A. Dmitriev and
• Alexander D. Dilman

Beilstein J. Org. Chem. 2020, 16, 3104–3108, doi:10.3762/bjoc.16.260

• typically introduced into a saturated cycle by nucleophilic fluorination reactions [10][11][12][13][14][15][16][17]. For compounds bearing gem-difluorinated fragments, an alternative pathway based on the construction of the cycle from building blocks may be considered [18]. However, the latter frequently

Deoxyfluorination of acyl fluorides to trifluoromethyl compounds by FLUOLEAD^®/Olah’s reagent under solvent-free conditions

• Yumeng Liang,
• Akihito Taya,
• Zhengyu Zhao,
• Norimichi Saito and
• Norio Shibata

Beilstein J. Org. Chem. 2020, 16, 3052–3058, doi:10.3762/bjoc.16.254

• and not as fluorination of acyl fluorides. Thus, the acyl fluoride moiety is commonly sacrificed as a “leaving group” in reactions. On the other hand, the transformation to CF3 derivatives from carboxylic acids are traditionally examined. In 1960, Engelhardt [27] performed the deoxyfluorination of

Controlled decomposition of SF₆ by electrochemical reduction

• Sébastien Bouvet,
• Bruce Pégot,
• Stéphane Sengmany,
• Erwan Le Gall,
• Eric Léonel,
• Anne-Marie Goncalves and
• Emmanuel Magnier

Beilstein J. Org. Chem. 2020, 16, 2948–2953, doi:10.3762/bjoc.16.244

• degradation of SF6 [17][18]. Other elegant approaches have described the use of SF6 as precursor of reagent for fluorination or pentafluorosulfanylation. Very interestingly, the photochemical activation of this gas was described and allowed the in situ transformation of alcohols into alkyl fluorides [19][20

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

• various deoxyfluorination reaction conditions. In our specific case, we were able to modulate the stereoselectivity of the nucleophilic fluorination at C4 with the use of Et3N·3HF. As proposed by the group of Linclau [20], we support the involvement of an oxiranium intermediate (results reinforced by

• elimination byproduct. These results suggest that addition of Et3N dictates the selectivity for the C4 fluorination. With the optimized conditions in hand, we investigated the use of other triflate analogues (Figure 3a). Under optimized conditions (Table 2, entry 2), triflate analogues 16–18 [19] gave

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

• products. We were forced to conclude that the rather complex structure of 3 was incompatible with the Jacobsen catalytic system. Since the one-step difluorination method (Scheme 1) was unsuccessful, we decided to pursue a stepwise fluorination approach [26][27] (Scheme 2). Thus, the allylic alcohol 7 [28

• obtained with DeoxoFluor at elevated temperature (Scheme 2). A side-product in this fluorination reaction was the tricyclic compound 12, which presumably formed through an electrophilic aromatic substitution reaction of the activated alcohol intermediate. The inclusion of TMS-morpholine [29] reduced the

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

• ACF itself consists of the fluorination of AlCl3 by chlorofluoroalkanes [40][41]. Nevertheless, in C6D6, the formation of 5 and 6 and the Friedel–Crafts product CF2=CHCH2C6D5 (9) was observed from 14. Based on these findings, a general scheme can be drafted to illustrate the sequential generation of

Synthesis of novel fluorinated building blocks via halofluorination and related reactions

• Attila Márió Remete,
• Tamás T. Novák,
• Melinda Nonn,
• Matti Haukka,
• Ferenc Fülöp and
• Loránd Kiss

Beilstein J. Org. Chem. 2020, 16, 2562–2575, doi:10.3762/bjoc.16.208

• cyclic olefins, such as diesters, imides, and lactams with varied functionalization patterns and different structural architectures is described. The synthetic methodologies were based on electrophilic activation through halonium ions of the ring olefin bonds, followed by nucleophilic fluorination with

• transformation, and COOH→CF3 transformation), is also an important nucleophilic fluorination method [2][3][4][5][10][11][18]. The synthesis of fluorinated compounds via deoxyfluorination [21][22][23][24][25][26][27][28][29][30] or utilizing sulfur fluoride deoxyfluorinating reagents [31][32] is a highlighted

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

• expensive and time-consuming procedure [2]. Fluorination is a common strategy employed as part of the optimization process during the design of new chemical compounds, which includes the modulation of a variety of properties such as lipophilicity, biological half-life, and biosorption [3][4]. This role

• helps in explaining the expressive amount of fluorine-containing agrochemical candidates (around 30%) as well as pharmaceuticals (around 20%) [5][6]. In this sense, the chemistry of fluorine-containing compounds has been extensively investigated in order to better understand the effects of fluorination

• and their unusual physicochemical properties. Lastly, Müller [11] explained that these features along with fluorine’s strict monovalent binding mode and little polarizability, when covalently bound, guarantee fluorination the well-known ability of modulating physicochemical properties. Although the

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

• fluorination methods, of which direct C–H fluorination is among the most powerful. Despite the challenges and limitations associated with the direct fluorination of unactivated C–H bonds, appreciable advancements in manipulating the selectivity and reactivity have been made, especially via transition metal

• catalysis and photochemistry. Where transition metal catalysis provides one strategy for C–H bond activation, transition-metal-free photochemical C–H fluorination can provide a complementary selectivity via a radical mechanism that proceeds under milder conditions than thermal radical activation methods

• review, we highlight photosensitized C–H fluorination as a recent strategy for the direct and remote activation of C–H (especially C(sp3)–H) bonds. To guide the readers, we present the developing mechanistic understandings of these reactions and exemplify concepts to assist the future planning of

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

• Nantes, France Medicinal Chemistry, Oncology R&D, AstraZeneca, Cambridge CB4 0WG, UK 10.3762/bjoc.16.182 Abstract A systematic comparison of lipophilicity modulations upon fluorination of isopropyl, cyclopropyl and 3-oxetanyl substituents, at a single carbon atom, is provided using directly comparable

• , and easily accessible model compounds. In addition, comparison with relevant linear chain derivatives is provided, as well as lipophilicity changes occurring upon chain extension of acyclic precursors to give cyclopropyl containing compounds. For the compounds investigated, fluorination of the

• isopropyl substituent led to larger lipophilicity modulation compared to fluorination of the cyclopropyl substituent. Keywords: aliphatic fluorination; cyclopropane; isopropyl; isostere; lipophilicity; oxetane; Introduction The introduction of small alkyl groups onto bioactive compounds as space filling

Synthesis of 6,13-difluoropentacene

• Matthias W. Tripp and
• Ulrich Koert

Beilstein J. Org. Chem. 2020, 16, 2136–2140, doi:10.3762/bjoc.16.181

• significant effect on the molecular shape, is fluorination [5]. Suzuki et al. showed in 2004 the strong effect of perfluorination on the electronic properties [6]. While unsubstituted pentacene (1, PEN, Figure 1) is known to be a p-type semiconductor, the perfluorinated counterpart perfluoropentacene (2, PFP

• ) showed an n-type behavior. In their synthesis and structural as well as electronic characterization of F4PEN 3, Bettinger et al. showed that the electronic properties of pentacenes are not a simple linear function of the degree of fluorination [7][8]. They reported that the fluorination in the 2,3,9,10

• herringbone structure of 1–3. Here, the synthesis and characterization of 6,13-difluoropentacene (5, F2PEN) is reported. Since the central ring of pentacenes is known to be a weak spot (because of light-induced dimerization or oxidation) [2] the effects of fluorination in these positions are of interest

Controlling the stereochemistry in 2-oxo-aldehyde-derived Ugi adducts through the cinchona alkaloid-promoted electrophilic fluorination

• Yuqing Wang,
• Gaigai Wang,
• Anatoly A. Peshkov,
• Ruwei Yao,
• Muhammad Hasan,
• Manzoor Zaman,
• Chao Liu,
• Stepan Kashtanov,
• Olga P. Pereshivko and
• Vsevolod A. Peshkov

Beilstein J. Org. Chem. 2020, 16, 1963–1973, doi:10.3762/bjoc.16.163

• alkaloid-promoted electrophilic fluorination producing enantioenriched post-Ugi adducts fluorinated at the peptidyl position. Keywords: cinchona alkaloids; electrophilic fluorination; enantioselective synthesis; 2-oxo-aldehydes; Ugi reaction; Introduction Multicomponent reactions (MCRs) [1][2][3][4][5][6

• previously tested the reactivity of 8 in the intermolecular aldol addition to ethyl glyoxalate [62]. As these attempts met with failure, we have turned our attention to enantioselective fluorination reactions [63][64][65]. Specifically, we decided to explore the enantioselective electrophilic fluorination of

• was successfully utilized for the synthesis of several bioactive molecules [79][80][81]. Herein we present its adaptation for the enantioselective fluorination of 2-oxo-aldehyde-derived Ugi adducts 8 leading to the installment of a fluorine-bound quaternary stereocenter at the peptidyl position. It

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

• range by fluorination (directly or indirectly) of initial organic molecules. In the ongoing project, we are interested in synthesizing 2-(perfluorophenyl)malonic acid (2, Figure 1) as a new ligand for the preparation of 3d and 4f heterometallic coordination compounds. Results and Discussion To our

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

• compounds 5 and 6 follow generally similar chiral bias to 3 and 4. The pKa data for the free amino acids shows that there is an identical reduction of the pKa values from fluorination (Figure 10B and C). It was then found that neither the side-chain conformation markers (J coupling at 2-CH) nor the trans

• between the diastereomeric species. Indeed, this conclusion was further corroborated by the rotation barrier data, which showed higher Δwater/benzene for the less lipophilic diastereomer, 6 (Table 4). Overall, the effects from fluorination in both diastereomeric compounds, 5 and 6, were found to be weak

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

• most profound influence [10][11][12]. Regarding the development of new synthetic methodologies for the preparation of such molecules, these can be divided in two main categories: fluorination reactions [13][14][15][16] and the use of fluorinated building blocks [17]. The difference between them is that

Fluorohydration of alkynes via I(I)/I(III) catalysis

• Jessica Neufeld,
• Constantin G. Daniliuc and
• Ryan Gilmour

Beilstein J. Org. Chem. 2020, 16, 1627–1635, doi:10.3762/bjoc.16.135

• suppressed catalysis. The prerequisite for this substructure was established by molecular editing and was complemented with a physical organic investigation of possible determinants. Keywords: α-fluoroketone; alkyne; fluorination; hypervalent iodine; organocatalysis; Introduction The venerable role of

• non-covalent interactions [8][9][10]. These collective attributes render fluorination a valuable strategy in drug discovery [11] and agrochemical development [12]. In the conception of enabling fluorination technologies, the α-fluorocarbonyl motif has emerged as a prominent target scaffold [13

• ]. Remarkable advances in the direct fluorination (F2/N2) of carbonyl compounds by Sandford and co-workers [14][15] are noteworthy in this regard, and mitigate the expense and poor atom economy associated with stoichiometric approaches. Moreover, this substructure provides a versatile entry point for subsequent

Heterogeneous photocatalysis in flow chemical reactors

• Christopher G. Thomson,
• Ai-Lan Lee and
• Filipe Vilela

Beilstein J. Org. Chem. 2020, 16, 1495–1549, doi:10.3762/bjoc.16.125

Synthesis of new fluorescent molecules having an aggregation-induced emission property derived from 4-fluoroisoxazoles

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

Beilstein J. Org. Chem. 2020, 16, 1411–1417, doi:10.3762/bjoc.16.117

• heteroaromatic systems, especially those comprising two heteroatoms such as pyrazoles [28][29], isoxazoles [30], and thiazoles [31][32]. Recently, we reported the selective fluorination of isoxazoles, to give monofluorinated isoxazoles 3 or trifluorinated isoxazolines 4 in moderate to good yields (Scheme 1) [33

• fluorinated diketone, 2-fluoro-1,3-diphenylpropane-1,3-dione (7a), the corresponding enaminoketone 8a was obtained in only low yield (Scheme 4, entry 4) and we did not attempt the conversion of 8a towards the α-fluorinated boron ketoiminate 9a. Next, we attempted the selective fluorination of 6b to obtain the

• desired fluorinated analog 9b. However, in the synthesis of F-BKIs through the selective fluorination of the corresponding BKIs, the use of 1 equiv of Selectfluor did not give any product and performing the reaction with excess amounts of Selectfluor gave rise to the corresponding α,α-difluorinated

Oxime radicals: generation, properties and application in organic synthesis

• Igor B. Krylov,
• Stanislav A. Paveliev,
• Alexander S. Budnikov and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2020, 16, 1234–1276, doi:10.3762/bjoc.16.107

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

• CF2RF reagents Due to the importance of perfluorinated moieties [2] and since their synthesis could not be achieved from the fluorination of the corresponding alkyl chains like in case of perfluoroalkyl arenes, several research groups investigated the synthesis of CF2RF-containing molecules via the use

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

• -phenylalanine (70) was prepared by direct fluorination of 4-borono-ʟ-phenylalanine (BPA, 69) with [18F]AcOF or [18F]F2. The reaction was followed by a HPLC separation using a Delta-Pak Cl8 cartridge 0.1% acetic acid as the mobile phase at a flow rate of 10 mL/min. The product was isolated in radiochemical

• the esters 83 with boronic acids 84a,b afforded the substituted phenylalanine derivatives 85a,b, respectively [58]. Deprotection of the hydroxy group was achieved by treatment with TBAF in THF to give 86a,b. Finally, fluorination of the alcohols 86a,b with DAST followed by deprotection gave the

• of type III 2.1. Fluorination of protected (1R,2R)-2-amino-ʟ-phenylpropane-1,3-diol Recently, Okuda et al. reported the synthesis of (3R)-3-fluoro-ʟ-phenylalanine (121) from (1R,2R)-2-amino-ʟ-phenylpropane-1,3-diol (116). Thus, Boc-protection of the amine group in 116 followed by the protection of

Efficient synthesis of dipeptide analogues of α-fluorinated β-aminophosphonates

• Marcin Kaźmierczak and
• Henryk Koroniak

Beilstein J. Org. Chem. 2020, 16, 756–762, doi:10.3762/bjoc.16.69

• that was proposed based on NMR studies. Keywords: dipeptide analogues; fluorinated aminophosphonates; fluorine; nucleophilic fluorination; phosphorus; Introduction The chemistry of fluorinated aminophosphonates is constantly being developed, mainly due to their wide spectra of applications. What is

• enzyme binding may depend on the C–F stereochemistry, the synthesis of such compounds with a specific configuration is very important [9][10][11]. α-Fluorinated phosphonates can be prepared by many different protocols [12][13][14][15][16]. Nucleophilic fluorination is one of the fundamental reactions in

• shown that the regioselectivity of the nucleophilic fluorination of amino alcohols can be controlled depending on the fluorinating reagent used [30][31]. This work presents the optimization of nucleophilic fluorination conditions. What is more, we discuss the effect of the base used on the

Synthesis of 4-amino-5-fluoropyrimidines and 5-amino-4-fluoropyrazoles from a β-fluoroenolate salt

• Tobias Lucas,
• Jule-Philipp Dietz and
• Till Opatz

Beilstein J. Org. Chem. 2020, 16, 445–450, doi:10.3762/bjoc.16.41

• modern pharmaceuticals [1][2][3][4][5][6] and agrochemicals [7] contain at least one fluorine atom [8][9][10][11][12][13][14][15]. One of the approaches for their synthesis is the use of small fluorinated building blocks which avoids the often cumbersome regioselective fluorination at a later synthetic

• ) of potassium formate, which could not easily be removed without risking the decomposition of the enolate salt (Scheme 1). As the fluorine atom is part of a building block, harsh conditions for a late-stage fluorination can be avoided, and even products with sensitive functionalities are accessible

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

• tracers. In this context, Li’s group has recently developed an effective and mild technique for C–H 18F fluorination with the aid of visible-light photoredox catalysis (Scheme 25) [169]. Using this approach, several pharmaceutical compounds were generated, which were found to be useful as diagnostic

• (5a). Monofluorination using QuCN-ClO4 (8). Fluorination with fluorine-18. Aerobic amination with acridinium catalyst 3a. Aerobic aminations with semiconductor photoredox catalyst 18. Perfluoroalkylation of arenes. Synthesis of benzonitriles in the presence of 3a. Acknowledgments We are grateful to