Regioselective cobalt(II)-catalyzed [2 + 3] cycloaddition reaction of fluoroalkylated alkynes with 2-formylphenylboronic acids: easy access to 2-fluoroalkylated indenols

• Tatsuya Kumon,
• Miroku Shimada,
• Jianyan Wu,
• Shigeyuki Yamada and
• Tsutomu Konno

Beilstein J. Org. Chem. 2020, 16, 2193–2200, doi:10.3762/bjoc.16.184

• -fluoroalkylated indenols, together with a very small amount of 3-fluoroalkylated indanones as side products. Keywords: [2 + 3] cycloaddition; cobalt catalyst; fluorine-containing; indenols; regioselective; Introduction 2,3-Disubstituted indenol derivatives are important compounds possessing high potential due

• to the insecticidal, myorelaxation, and antiproliferative properties (Figure 1) [1][2][3][4][5][6][7][8][9][10][11][12]. Thus, enormous attention has been paid to 2- or 3-fluoroalkylated indenol derivatives in the field of medicinal and agrochemical drug design since a fluorine atom can very often

• bring about an increasing effect on the pharmacological activity owing to the unique nature of the fluorine atom(s) [13][14][15][16][17][18]. However, reports on a synthetic protocol for 2- or 3-fluoroalkylated indenols are very limited [19][20][21][22]. Recently, Yamazaki et al. have reported 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

• reactions. Keywords: C–H activation; energy transfer; fluorination; photocatalysis; photosensitization; visible light; Review 1 Introduction 1.1 Importance of direct C–H fluorination/trifluoromethylation and photosensitization in organic synthesis 1.1.1 Importance of fluorine atoms in organic molecules

• : Here, we briefly summarize the importance of fluorine atoms in organic molecules in the context of medicinal chemistry, materials chemistry, analytical chemistry and in the mechanistic studies of synthetic reactions. The importance of fluorination reactions in organic synthesis is reviewed exhaustively

• elsewhere, and the readers are referred to the relevant reviews [1][2][3][4][5]. Over the last two decades, introducing fluorine atoms into molecules has become a crucial aspect in contemporary synthesis of pharmaceuticals. Extraordinarily, about half of the so-called “blockbuster drugs” contain fluorine

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

• effect of the fluorine is evident from the 1H NMR chemical shift values of the CH3 groups in D1 (0.91 ppm) [29], D3 (0.98 ppm), and D2 (1.37 ppm) [30]. Compared to the monofluorinated D3, difluorination (D4) and trifluorination (D5) at the same carbon atom increases lipophilicity. There is a notable

•  6, with the bold red bond emphasizing the structural change (cf D1 vs E1). For completion, the change observed from the corresponding linear 1-butanol equivalents with equidistant alcohol and fluorine groups, by connecting C2 and C4 as shown (cf G1 to E1), is also considered (see Supporting

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

• two fluorine substituents was investigated. The retrosynthetic analysis for this strategy is shown in Scheme 1. The formation of the C5,5a-bond colored in red could be accomplished by an intramolecular Friedel–Crafts type acylation with the acylium-cation intermediate 6. The corresponding carboxylic

• phthalic anhydride in THF precooled to –100 °C [16]. Using these conditions, the carboxylic acid 12 was isolated in 82% yield. The subsequent Friedel–Crafts acylation proofed to be challenging. Using reagents like PCl5 resulted in a quantitative substitution of the fluorine substituents in the

• . Comparison with the values of PEN (ΔE = 2.13 eV) [9] and PFP (ΔE = 1.99 eV) [9] shows that the electronic structure of F2PEN 5 lies in between these two. While fluorine substituents in 2,3,9,10-positions (F4PEN 3) result in a larger HOMO–LUMO gap compared to PEN [7][8], substitution in the 6,13-positions

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

• reaction of propyn-1-iminium salt 1a with styrene in acetonitrile was considered first and was monitored by 19F NMR spectroscopy. Whereas no reaction appeared to occur at room temperature, a slow transformation into two fluorine-containing products was observed at 70 °C, which after neutralization and work

• signals. Assuming that some of the signals represented products that would easily undergo further thermal reactions, the solution was additionally heated at 70 °C for 40 hours. The resulting reaction mixture still contained several products, of which only the major fluorine-containing component (δF

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

• 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

• should be stressed that the exploration of methods for the enantioselective fluorination continues to be an important topic considering the ever-growing role of fluorine derivatives in drug design and development [82][83]. An alternative strategy to prepare related quaternary carbon-containing adducts

• bearing fluorine and nitrogen atoms involves the asymmetric addition of α-fluoro-β-ketoesters or α-fluoro-α-nitro esters to appropriate electrophiles [84][85][86][87][88][89]. Results and Discussion Initially, we prepared a series of Ugi adducts 8 by varying acid, 2-oxo-aldehyde, amine, and isocyanide

Selective preparation of tetrasubstituted fluoroalkenes by fluorine-directed oxetane ring-opening reactions

• Clément Q. Fontenelle,
• Thibault Thierry,
• Romain Laporte,
• Emmanuel Pfund and
• Thierry Lequeux

Beilstein J. Org. Chem. 2020, 16, 1936–1946, doi:10.3762/bjoc.16.160

• reaction of fluoroalkylidene-oxetanes was directed by the presence of the fluorine atom, enabling a two-step access to tetrasubstituted fluoroalkenes with excellent geometry control. Despite its small van der Waals radii electronic, rather than steric influences of the fluorine atom governed the ring

• -opening reaction with bromide ions, even in the presence of bulky substituents. Keywords: acyclonucleotide; fluorine; monofluoroalkene; oxetane; selective ring-opening reaction; tetrasubstituted alkene; Introduction The introduction of fluorine atoms into organic compounds is known to modify their

• antiviral agents, respectively (Figure 1) [5][6]. The field of acyclonucleotides (ACN) has been explored less, however, the introduction of fluorine atoms showed remarkable effects. The most representative examples are phosphate analogues such as the nucleoside phosphorylase inhibitor III and acyclic

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

• ., pharmacologically active substances [1][2][3][4][5], in asymmetric synthesis and catalysis [6][7][8], as precursors of heterocyclic compounds [9][10][11], as ligands in coordination chemistry [12][13][14][15][16] and for other applications [17][18]. Incorporation of fluorine atoms into an organic molecule is known

• -fluorophenyl)-2-methylmalonate (9) [32], diethyl 2-(3-fluorophenyl)-2-methylmalonate (10) [33], and diethyl 2-(4-fluorophenyl)malonate (11) [6][32] (Figure 2) with minor variations in the alkali concentration and temperature. No nucleophilic substitution of activated fluorine atoms or other side reactions were

• with the formation of acid 12. The nature of these byproducts was not analyzed. Probably, they are formed by nucleophilic substitution of fluorine atoms in the perfluorophenyl moiety. Acid 12 is fairly soluble in water and the separation of reaction products is cumbersome (see Supporting Information

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

• Vladimir Kubyshkin University of Manitoba, Dysart Rd. 144, Winnipeg, R3T 2N2, Canada 10.3762/bjoc.16.151 Abstract Fluorine-containing analogues of proline are valuable tools in engineering and NMR spectroscopic studies of peptides and proteins. Their use relies on the fundamental understanding of

• 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

• C4-exo conformation of the pyrrolidine ring. Keywords: amino acids; cis–trans isomerism; fluorine; polarity; proline; Introduction Polarity is among the key features essential for understanding the behavior of organic molecules of biological origin. In particular, there is a set of polarity-related

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

• transformations to yield more complex biologically active molecules. Despite the increasing availability of fluorinated building blocks and methodologies to incorporate fluorine in compounds with biological interest, there have been few significant advances focused on the fluoro-Pauson–Khand reaction, both in the

• the PKR of enynes containing a fluoride moiety. Keywords: alkene; alkyne; enyne; fluorine; Pauson–Khand; Introduction The prevalence of fluorine-containing molecules in drug-discovery programs is nowadays unquestionable [1][2][3]. The presence of fluorine atoms or fluorine-containing units at

• , preferred conformation or hydrogen bond forming ability, among others, may result in a dramatic effect in the therapeutic potential of a drug candidate [5][6]. All these properties may be fine-tuned by the selective incorporation of fluorine into the structure of the molecule [7]. In addition to therapeutic

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

• fluorine as a powerful physicochemical modulator in small-molecule drug discovery is a compelling argument for the importance of sustained innovation to facilitate this form of structural editing [1][2][3][4]. Routinely employed as a bioisostere of hydrogen or hydroxy [5][6], substitution may enable

• C(sp3)–C(sp3) bond-forming reactions [16][17], and closely resembles one of the very few biological blueprints for the preparation of fluorine-containing materials [18][19][20][21]. However, in translating the fluoroacetate-like building blocks to a laboratory paradigm, the intrinsic toxicity of

One-pot synthesis of 1,3,5-triazine-2,4-dithione derivatives via three-component reactions

• Gui-Feng Kang and
• Gang Zhang

Beilstein J. Org. Chem. 2020, 16, 1447–1455, doi:10.3762/bjoc.16.120

• , and trifluoromethyl they smoothly took part in the three-component reaction and provided the desired products 6ja–na in moderate yields. It is noteworthy that benzaldehydes containing a halogen atom such as fluorine, chlorine, bromine, and iodine in the para and meta-positions were also compatible

An overview on disulfide-catalyzed and -cocatalyzed photoreactions

• Yeersen Patehebieke

Beilstein J. Org. Chem. 2020, 16, 1418–1435, doi:10.3762/bjoc.16.118

• fluorine-containing groups can effectively change the physical and chemical properties and biological activities of organic molecules [21][22]. The addition reaction using disulfide as the visible-light catalyst is an effective and atom-economic method for introducing fluorine-containing groups. In 2016

• . In 1996, Burton and co-workers reported the stereoselective synthesis of cis-1,2-difluorotriethylsilyethylene and its conversion to a variety of cis-1,2-difluoroethylene synthons, which are important building blocks in the preparation of fluorine-containing pharmaceuticals, polymers, and bioactive

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

• synthesized and investigated for their photochemical properties. The introduction of a fluorine substituent into 3,5-diarylisoxazoles led to an increase of fluorescence intensity and exhibited a redshift in the emission intensity. α-Fluorinated boron ketoiminates (F-BKIs) were also synthesized via a ring

• fluorescent properties by irradiation with a UV lamp. Among the non-fluorinated isoxazoles, only 2c demonstrated fluorescent emission, although it was very weak. Thus, we decided to further investigate the photochemical properties and the results were summarized in Figure 1 and Table 1. Introducing a fluorine

• substituent into the isoxazole scaffold led to an increasing fluorescent intensity and exhibited a redshift in the emission intensity. Interestingly, the excitation maximum of 3 showed a redshift of approximately 20 nm with the incorporation of a single fluorine atom into the isoxazole scaffold in comparison

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

• catalysis; trifluoromethoxylation; Introduction The number of fluorine-containing compounds and their influence in medicine and agrochemistry are increasing every year [1][2]. The introduction in a drug (or a bioactive compound in general) of single fluorine atoms, or multiple fluorine-containing

• substituents, such as -CF3, -SCF3, -CF2H/-CF2-, has a range of effects on the pharmacokinetics and pharmacodynamics of the molecule [3]. Among other fluorine-based substituents, the trifluoromethoxy group (-OCF3) has until recently remained less explored and understood [4]. Nonetheless, it possesses unique

Development of fluorinated benzils and bisbenzils as room-temperature phosphorescent molecules

• Shigeyuki Yamada,
• Takuya Higashida,
• Yizhou Wang,
• Masato Morita,
• Takuya Hosokai,
• Kaveendra Maduwantha,
• Kaveenga Rasika Koswattage and
• Tsutomu Konno

Beilstein J. Org. Chem. 2020, 16, 1154–1162, doi:10.3762/bjoc.16.102

• effects of structural modification (i.e., the benzil structure with a tolane vs bisbenzil moiety) and incorporation of fluorine atoms on the phosphorescence, the ratio between the peak intensities at ≈395 and ≈560 nm (I560/I395) was quantitatively calculated, and the results are summarized in Table 1. The

• , although the PL intensity of nonfluorinated 3c increases by approximately three times. Judging from these comprehensive observations, the benzil structure promotes ISC from S1 to T1, causing increment phosphorescence, unlike the corresponding bisbenzil scaffold. Moreover, fluorine substituents on the

• corresponding bis-oxidized bisbenzil derivatives. Based on theoretical calculations, the selective formation of the fluorinated analogues stemmed from the slight modulation of the charge distribution at the alkyne moiety of the reactant induced by the electron-withdrawing fluorine atoms. Evaluation of the

Synthesis of esters of diaminotruxillic bis-amino acids by Pd-mediated photocycloaddition of analogs of the Kaede protein chromophore

• Esteban P. Urriolabeitia,
• Pablo Sánchez,
• Alexandra Pop,
• Cristian Silvestru,
• Eduardo Laga,
• Ana I. Jiménez and
• Carlos Cativiela

Beilstein J. Org. Chem. 2020, 16, 1111–1123, doi:10.3762/bjoc.16.98

• -palladated ring on the other side of the plane, shows that the compound obtained is the epsilon (ε) isomer, according to the classification of Stoermer [61][62]. The non-bonding intramolecular distance between the ortho-fluorine F1 and the cyclobutane proton H4 is d(F1...H4) = 2.286(3) Å, which is much

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

• of fluorine-containing molecules in the pharmaceutical and agrochemical industries. In a world eager to eco-friendlier tools, the need for innovative methods has been growing. To address these two challenges, copper-based reagents were developed to introduce CF2H, CF2RF, CF2CH3, CF2PO(OEt)2 and

• molecules using copper-based fluorinated reagents will be given. Keywords: copper; difluoromethylation; fluorinated reagents; fluorine chemistry; synthetic methodologies; Introduction In a society in which fluorinated molecules are playing a pivotal role in pharmaceutical and agrochemical industries as

• fluorine atom or a fluorinated moiety of unique properties [15]. Despite the tremendous advances made in that field, key synthetic challenges remain to synthesize fluorinated scaffolds. Among the different developed strategies to ravel synthetic issues, the use of inexpensive and readily available copper

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

• pharmaceutical applications with a focus on published synthetic methods that introduce fluorine into the phenyl, the β-carbon or the α-carbon of ᴅ-or ʟ-phenylalanines. Keywords: α-fluorophenylalanine; β- and β,β-difluorophenylalanine; fluorinated phenylalanines; PET; pharmaceuticals application; Introduction

• Major efforts have been focused on the synthesis of fluorinated organic molecules particularly for drug development. The replacement of hydrogen by fluorine has been used in the development to improve the biophysical and chemical properties of bioactives. Such tuning in properties arises from the small

• size of fluorine, the next in size to hydrogen. However, the high electronegativity of the fluorine leads to low polarizability and a strong covalent bond to carbon [1][2][3][4]. Therefore, the introduction of fluorine into phenylalanine (Phe) can modulate the acidity, basicity, hydrophobicity

Aryl-substituted acridanes as hosts for TADF-based OLEDs

• Naveen Masimukku,
• Dalius Gudeika,
• Oleksandr Bezvikonnyi,
• Ihor Syvorotka,
• Rasa Keruckiene,
• Dmytro Volyniuk and
• Juozas V. Grazulevicius

Beilstein J. Org. Chem. 2020, 16, 989–1000, doi:10.3762/bjoc.16.88

• , Figure 4b, and Table 2). The IPPES values were further used for constructing OLED structures. The highest IPPES of 5.62 eV was obtained for compound 6 which contains electron-accepting fluorine atoms. The other compounds (3–5) demonstrated similar IPPES values mainly attributed to removing an electron

Accelerating fragment-based library generation by coupling high-performance photoreactors with benchtop analysis

• Quentin Lefebvre,
• Christophe Salomé and
• Thomas C. Fessard

Beilstein J. Org. Chem. 2020, 16, 982–988, doi:10.3762/bjoc.16.87

• of complex amines: bicyclopentanamines, azetidines, spiroazetidines, spiropyrrolidines and spiropiperidines. Functional group tolerance was probed by using functionalized building blocks bearing esters, carbamates, alcohols, tertiary amines, ethers, sulfones and fluorine atoms (Scheme 2 and Scheme 3

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

• into organic molecules can dramatically influence their physiochemical and biological properties in comparison with non-fluorinated analogs [18] (see compounds I and II in Figure 1). Many pharmaceuticals and agrochemicals developed in recent decades have either a fluorine atom or a trifluoromethyl

• group [19][20][21][22]. Given this, the development of a method for the incorporation of fluorine or trifluoromethyl group into organic molecules perhaps remains a current challenge in organic chemistry methodology. For example, trifluoromethyl-substituted (1H-indol-3-yl)methanol derivatives were

• trifluoroacetophenones did not significantly influence the yield of the reaction. The trifluoromethyl ketones having electron-rich heteroaromatics such as 2-(trifluoroacetyl)furan (2g) and 2-(trifluoroacetyl)thiophene (2h) gave the desired products 3g (97%) and 3h (98%) in excellent yields. Next, the role of fluorine in

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

• -Chloro-N-tosylbenzene-1-sulfonimidoyl fluoride (SulfoxFluor, 3, Figure 1) may be an interesting alternative to 1 or 2. It is not commercially available yet, however, it can be obtained from inexpensive materials [24]. Very often small organic molecules containing a fluorine atom are transformed into

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

Synthesis of organic liquid crystals containing selectively fluorinated cyclopropanes

• Zeguo Fang,
• Nawaf Al-Maharik,
• Peer Kirsch,
• Matthias Bremer,
• Alexandra M. Z. Slawin and
• David O’Hagan

Beilstein J. Org. Chem. 2020, 16, 674–680, doi:10.3762/bjoc.16.65

• vertical alignment (VA) LCD technology, liquid crystals with negative dielectric anisotropy are required [3]. Fluorine, as the most electronegative atom, forms stable bonds to carbon and can thus induce polarity. It is also attractive as a design feature due to the low polarizability of the C–F bond

• which contain axial fluorine substituents (Figure 1, 1 and 2), however, due to the propensity for HF elimination from these molecules over time, these liquid crystals have not been adopted as commercial products [6][7]. 2,3-Difluoroaryl motifs such as 3 have proven to be a successful class of negative

• explore the cyclopropane motif containing fluorine atoms. Selectively fluorinated cyclopropanes have been widely used in pharmaceutical research [11], however, the introduction of fluorinated cyclopropanes into liquid crystal scaffolds has not received much attention. Haufe et al. [12], reported