Oxidative radical ring-opening/cyclization of cyclopropane derivatives

• Yu Liu,
• Qiao-Lin Wang,
• Zan Chen,
• Cong-Shan Zhou,
• Bi-Quan Xiong,
• Pan-Liang Zhang,
• Chang-An Yang and
• Quan Zhou

Beilstein J. Org. Chem. 2019, 15, 256–278, doi:10.3762/bjoc.15.23

• using AgF2 as both oxidant and fluorine atom source via the silver(II)-mediated ring-opening and fluorination of cyclopropanols 91 (Scheme 32) [112]. Through this method, a fluorine atom could easily be introduced in the β-position of a ketone. The mechanism is outlined in Scheme 32, the Ag-alkoxide

Synthesis, biophysical properties, and RNase H activity of 6’-difluoro[4.3.0]bicyclo-DNA

• Sibylle Frei,
• Adam K. Katolik and
• Christian J. Leumann

Beilstein J. Org. Chem. 2019, 15, 79–88, doi:10.3762/bjoc.15.9

• ; Introduction The fluorine atom is a very attractive substituent in medicinal chemistry due to the beneficial biological effects induced by this atom on the overall drug behaviour [1][2][3][4][5]. The positive influences on the drug behaviour is not limited to small molecules but is also valid for antisense

• oligonucleotides (AONs) [6]. An effective way to tune the properties of antisense oligonucleotides is by the insertion of the fluorine atom in the sugar moiety of the nucleoside. In this way, the sugar pucker can be controlled which ideally results in an increased affinity towards complementary RNA [7]. An

• . The reason for the stabilization is an increased strength of the Watson–Crick base pairing and base stacking interactions due to the electronic effects of the axially oriented 2’-fluorine atom [11][12]. Additionally, FC–H···O hydrogen bonds between the 2’-fluorine and the 4’-oxygen or 5’-oxygen of the

N-Arylphenothiazines as strong donors for photoredox catalysis – pushing the frontiers of nucleophilic addition of alcohols to alkenes

• Fabienne Speck,
• David Rombach and
• Hans-Achim Wagenknecht

Beilstein J. Org. Chem. 2019, 15, 52–59, doi:10.3762/bjoc.15.5

• found to occur at E(1+·/1) = 0.75 V (vs SCE). The substitution of the arene moiety by one (see 7) or two fluorine substituents (see 8) only leads to a shift in the reduction potential of about 0.06 V. This trend was expected due to the lower electron density of these two N-phenylphenothiazines at the

• arene moiety. However, the effect by the pure σ-acceptor fluorine is not very pronounced. In the case of the 4-NO2 substituted derivative 6 the pronounced influence of the π-acceptor shifts the reduction potential to a value of up to E(6+·/6) = 0.89 V (vs SCE). Substitution of the N-aryl moiety by

6’-Fluoro[4.3.0]bicyclo nucleic acid: synthesis, biophysical properties and molecular dynamics simulations

• Sibylle Frei,
• Andrei Istrate and
• Christian J. Leumann

Beilstein J. Org. Chem. 2018, 14, 3088–3097, doi:10.3762/bjoc.14.288

• , Figure 1) [23]. Another strategy to overcome some of the limitations deals with the insertion of one or several fluorine atom(s) in the sugar moiety of the nucleic acid analog. The polar hydrophobic nature [24] of the fluorine atom can positively alter the furanose conformation, basicity and/or

• systematically analyzed the effect of the fluorine atom on the bc-DNA and the tc-DNA scaffold. 6’-β-Fluorination of [3.3.0]bicyclo-DNA led to a pseudohydrogen bond interaction between the fluorine atom and the C(6) hydrogen atom of the thymine base, fixing the torsion angle χ. As a consequence, an increased

• affinity to complementary RNA targets was observed [42]. In the case of tc-DNA, C(6’) fluorination resulted in a similar affinity to RNA as standard tc-DNA suggesting no contribution of a fluorine pseudohydrogen bond as in bc-DNA [43]. Also a similar affinity to complementary DNA or RNA than the non

Targeting the Pseudomonas quinolone signal quorum sensing system for the discovery of novel anti-infective pathoblockers

• Christian Schütz and
• Martin Empting

Beilstein J. Org. Chem. 2018, 14, 2627–2645, doi:10.3762/bjoc.14.241

• anthraniloyl-AMP. The reason why the fluorinated anthraniloyl-AMP shows good affinity is the formation of a hydrogen bond of the fluorine with the G279 backbone amide hydrogen and furthermore an interaction with the N7 position of the adenine moiety. Additionally a very typical fluorine/main-chain interaction

Synthesis of 3-aminocoumarin-N-benzylpyridinium conjugates with nanomolar inhibitory activity against acetylcholinesterase

• Nisachon Khunnawutmanotham,
• Cherdchai Laongthipparos,
• Patchreenart Saparpakorn,
• Nitirat Chimnoi and
• Supanna Techasakul

Beilstein J. Org. Chem. 2018, 14, 2545–2552, doi:10.3762/bjoc.14.231

• 12.48 ± 0.71 nM), further modifications by introducing chlorine or fluorine substituents at the ortho-, meta-, or para-positions on the benzyl group were investigated. The results showed that the type and the position of the substituents on the benzyl group influenced the inhibitory activity against

• diminished inhibitory activities, respectively. For fluorine as a substituent, the activity also followed the order of ortho > meta ≈ para. The AChE inhibitory activities of all fluorine analogs were superior to those of the chlorine analogs and the unsubstituted benzylpyridinium salt 9a. In detail, a

• fluorine substituent at the ortho-position (9e) increased the inhibitory activity with an IC50 value of 3.05 ± 0.28 nM, whereas the m- and p-fluoro-substituted analogs 9f and 9g provided comparable IC50 values of 5.04 ± 0.26 and 5.31 ± 0.38 nM, respectively. Difluorinated benzylpyridinium salts were also

Efficient catalytic alkyne metathesis with a fluoroalkoxy-supported ditungsten(III) complex

• Henrike Ehrhorn,
• Janin Schlösser,
• Dirk Bockfeld and
• Matthias Tamm

Beilstein J. Org. Chem. 2018, 14, 2425–2434, doi:10.3762/bjoc.14.220

• the metal tungsten, terminal alkynes at room temperature [54]. Our studies clearly display a strong dependency of the catalytic alkyne metathesis activity on the metal-alkoxide combination. The electrophilicity of the metal sites can be controlled by the number of fluorine atoms of the ancillary

Practical tetrafluoroethylene fragment installation through a coupling reaction of (1,1,2,2-tetrafluorobut-3-en-1-yl)zinc bromide with various electrophiles

• Ken Tamamoto,
• Shigeyuki Yamada and
• Tsutomu Konno

Beilstein J. Org. Chem. 2018, 14, 2375–2383, doi:10.3762/bjoc.14.213

• ., –(CF2)n–, in various fields, such as medicine and materials sciences [1][2][3][4], because incorporation of multiple fluorine atoms into organic substances causes dramatic alterations in the chemical and physical properties of substances, which may significantly enhance their potential functionality [5

Bioinspired cobalt cubanes with tunable redox potentials for photocatalytic water oxidation and CO₂ reduction

• Zhishan Luo,
• Yidong Hou,
• Jinshui Zhang,
• Sibo Wang and
• Xinchen Wang

Beilstein J. Org. Chem. 2018, 14, 2331–2339, doi:10.3762/bjoc.14.208

• ample choice of organic ligand architectures to tailor the electronic properties of the “Co4O4” unit for catalysis. In this regard, Nocera et al. selected an organic ligand bearing an electron-withdrawing group (fluorine) to optimize the “Co4O4” cubane unit for electrocatalytic water oxidation [52]. As

• expected, the resultant catalyst exhibited a larger catalytic current and an earlier onset potential with respect to its analogs without a fluorine functional group. Thus, the control of catalytic properties via molecular design by tunable ligand substitution is essential in the development of Co4O4-based

Cobalt-catalyzed peri-selective alkoxylation of 1-naphthylamine derivatives

• Jiao-Na Han,
• Cong Du,
• Xinju Zhu,
• Zheng-Long Wang,
• Yue Zhu,
• Zhao-Yang Chu,
• Jun-Long Niu and
• Mao-Ping Song

Beilstein J. Org. Chem. 2018, 14, 2090–2097, doi:10.3762/bjoc.14.183

• system. Moreover, a series of biologically relevant fluorine-aryl ethers were easily obtained under mild reaction conditions after the removal of the directing group. Keywords: alkoxylation; C–H activation; cobalt catalysis; 1-naphthylamines; secondary alcohols; Introduction Aryl ethers are common

• alkoxylation of naphthylamine derivatives with both primary and secondary alcohols was developed. This protocol is characterized by mild reaction conditions, broad substrate scope, and good functional group tolerance. Moreover, the excellent compatibility of fluorine-substituted alcohols (for instance, HFIP

• , trifluoroethanol, and 3-fluoropropanol etc.) shows that this strategy is highly valuable for the syntheses of biologically relevant fluorine-aryl ethers after the removal of the directing group. The above studies of the mechanism indicate that this reaction undergoes a SET process and cobalt salt is the actual

Rational design of boron-dipyrromethene (BODIPY) reporter dyes for cucurbit[7]uril

• Mohammad A. Alnajjar,
• Jürgen Bartelmeß,
• Robert Hein,
• Pichandi Ashokkumar,
• Mohamed Nilam,
• Werner M. Nau,
• Knut Rurack and
• Andreas Hennig

Beilstein J. Org. Chem. 2018, 14, 1961–1971, doi:10.3762/bjoc.14.171

• the carbonyl-fringed CB7 rim and the fluorine atoms in the tetrafluoroaniline, which are slightly larger than the hydrogen atoms [57]. The data obtained with 3 could not be fitted satisfactorily, which is presumably due to the more complex photophysics of this dye (see above) and the exchange of 5 was

• specific host–guest binding of 5 to CB7 on the surface, which suggests the use of 5 for straightforward surface functionalization to create nanophotonic devices as well as for multimodal surface group quantifications, e.g., using their optical properties for fluorescence and their fluorine heteroatom for X

Diazirine-functionalized mannosides for photoaffinity labeling: trouble with FimH

• Femke Beiroth,
• Tomas Koudelka,
• Thorsten Overath,
• Stefan D. Knight,
• Andreas Tholey and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2018, 14, 1890–1900, doi:10.3762/bjoc.14.163

• ]), we could not observe labeled products by fluorine NMR. This is presumably due to the low labeling efficiency as in the literature 19F NMR spectra were obtained with proteins having 19F-labeled amino acids incorporated [30]. Disappointingly, instead of crosslinking, we observed two different other

Anomeric modification of carbohydrates using the Mitsunobu reaction

• Julia Hain,
• Patrick Rollin,
• Werner Klaffke and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2018, 14, 1619–1636, doi:10.3762/bjoc.14.138

• also applied for other anomeric modifications, such as fluorination, reported by Kunz et al. for the synthesis of the α-D-mannofuranosyl fluoride 126, however, in moderate yield (Scheme 27) [118]. The advantage of this approach lies in the mild fluorine source, triethyloxonium tetrafluoroborate, which

A survey of chiral hypervalent iodine reagents in asymmetric synthesis

• Soumen Ghosh,
• Suman Pradhan and
• Indranil Chatterjee

Beilstein J. Org. Chem. 2018, 14, 1244–1262, doi:10.3762/bjoc.14.107

• attack of the nitrogen atom onto the alkene (intermediate 67) to generate aziridinium ion 68 is the crucial step in this transformation. Recently, Jacobsen et al. developed a highly stereoselective difunctionalization method for the synthesis of chiral fluorine-containing molecules and the 1,2

London dispersion as important factor for the stabilization of (Z)-azobenzenes in the presence of hydrogen bonding

• Andreas H. Heindl,
• Raffael C. Wende and
• Hermann A. Wegner

Beilstein J. Org. Chem. 2018, 14, 1238–1243, doi:10.3762/bjoc.14.106

• )-azobenzenes can be prolonged dramatically by ortho-fluorine substitution, resulting in half-lives of up to two years at room temperature [19]. These highly thermally stable (Z)-ortho-fluoroazobenzenes can be re-isomerized almost instantaneously in an electrocatalytic fashion [20]. Furthermore, (Z)-azobenzenes

An overview of recent advances in duplex DNA recognition by small molecules

• Sayantan Bhaduri,
• Nihar Ranjan and
• Dev P. Arya

Beilstein J. Org. Chem. 2018, 14, 1051–1086, doi:10.3762/bjoc.14.93

Fluorocyclisation via I(I)/I(III) catalysis: a concise route to fluorinated oxazolines

• Felix Scheidt,
• Christian Thiehoff,
• Gülay Yilmaz,
• Stephanie Meyer,
• Constantin G. Daniliuc,
• Gerald Kehr and
• Ryan Gilmour

Beilstein J. Org. Chem. 2018, 14, 1021–1027, doi:10.3762/bjoc.14.88

• -ray crystallographic analysis of a representative example. Given the importance of fluorine in drug discovery, its ability to modulate conformation, and the prevalence of the 2-oxazoline scaffold in Nature, this strategy provides a rapid entry into an important bioisostere class. Keywords: catalysis

• ]. Since hydrogen and hydroxy groups are often substituted by fluorine in molecular editing processes [12], this transformation would provide facile access to a bioisostere of the parent scaffold (Figure 1, right). In recent years, I(I)/I(III) catalysis has emerged as a powerful and expansive platform for

• the structure of oxazoline 2c bearing a p-NO2 group (Figure 4 and Table 2) [39]. The molecular structure reveals the expected gauche arrangement with a dihedral angle FCCO ≈ −73.4° due to σC–C→σC–F* and σC–H→σC–O* interactions. This observation is in agreement with the fluorine gauche effect

On the design principles of peptide–drug conjugates for targeted drug delivery to the malignant tumor site

• Eirinaios I. Vrettos,
• Gábor Mező and
• Andreas G. Tzakos

Beilstein J. Org. Chem. 2018, 14, 930–954, doi:10.3762/bjoc.14.80

• fluorine. It is sold under the brand name Gemzar by Eli Lilly and Company and has been FDA approved for the treatment of various cancers including breast, ovarian, non-small cell lung and pancreatic cancer. The main drawbacks for its use are the high and non-selective toxicity to normal cells, the

Local energy decomposition analysis of hydrogen-bonded dimers within a domain-based pair natural orbital coupled cluster study

• Ahmet Altun,
• Frank Neese and
• Giovanni Bistoni

Beilstein J. Org. Chem. 2018, 14, 919–929, doi:10.3762/bjoc.14.79

• used for the geometry optimizations. All valence electrons were included in the correlation treatment (only the core 1s orbitals of oxygen and fluorine atoms were frozen). Single point DLPNO-CCSD(T) energies and LED calculations employed the Foster–Boys scheme [52] for the localization of the occupied

Recent advances in synthetic approaches for medicinal chemistry of C-nucleosides

• Kartik Temburnikar and
• Katherine L. Seley-Radtke

Beilstein J. Org. Chem. 2018, 14, 772–785, doi:10.3762/bjoc.14.65

• proved to be the most promising compound. The fluorine on 29 was replaced with a methoxy group after re-installing the isopropylidene protecting group. The cyano group was then converted to an amide and the methoxy converted to a hydroxy group. Removal of the protecting groups on the sugar gave 25, which

Cobalt-catalyzed directed C–H alkenylation of pivalophenone N–H imine with alkenyl phosphates

• Wengang Xu and
• Naohiko Yoshikai

Beilstein J. Org. Chem. 2018, 14, 709–715, doi:10.3762/bjoc.14.60

• previously reported cobalt-catalyzed ortho C–H functionalization reactions [22][23][28][29], this regioselectivity may be ascribed to the role of the oxygen or fluorine atom as a secondary directing group to have an electrostatic interaction with the cobalt center during the C–H activation. For compound 3ja

• , an increased acidity of the ortho position of the fluorine atom could have also contributed to the observed regioselectivity [31]. Curiously, the reaction of 2-naphthylimine resulted in the preferential alkenylation of the more hindered 1-position rather than the 3-position, with a regioselectivity

Copper-catalyzed asymmetric methylation of fluoroalkylated pyruvates with dimethylzinc

• Kohsuke Aikawa,
• Kohei Yabuuchi,
• Kota Torii and
• Koichi Mikami

Beilstein J. Org. Chem. 2018, 14, 576–582, doi:10.3762/bjoc.14.44

• copper. Keywords: asymmetric methylation; chiral phosphine ligand; copper catalyst; dimethylzinc; trifluoropyruvate; Introduction The introduction of fluorine atoms into organic compounds plays an important role in the discovery of lead candidates with unique biological and physicochemical properties

Synthesis and stability of strongly acidic benzamide derivatives

• Frederik Diness,
• Niels J. Bjerrum and
• Mikael Begtrup

Beilstein J. Org. Chem. 2018, 14, 523–530, doi:10.3762/bjoc.14.38

• fluorine) may be generated in good yields and further functionalized through nucleophilic aromatic substitution or cross-coupling reactions. It was found that the products were stable in dilute aqueous solutions, but they slowly hydrolyzed in concentrated solutions or in the presence of other strong acids

Addition of dithi(ol)anylium tetrafluoroborates to α,β-unsaturated ketones

• Yu-Chieh Huang,
• An Nguyen,
• Simone Gräßle,
• Sylvia Vanderheiden,
• Nicole Jung and
• Stefan Bräse

Beilstein J. Org. Chem. 2018, 14, 515–522, doi:10.3762/bjoc.14.37

• dithiolane and dithiane protecting groups which are irreplaceable intermediates for the introduction of, e.g., fluorine via gem-difluorination [1][2]. They also allow the formation of valuable building blocks that can be used for diverse transformations in organic chemistry (e.g., Umpolung) [3]. Ketene 1,3

The selective electrochemical fluorination of S-alkyl benzothioate and its derivatives

• Shunsuke Kuribayashi,
• Tomoyuki Kurioka,
• Shinsuke Inagi,
• Ho-Jung Lu,
• Biing-Jiun Uang and
• Toshio Fuchigami

Beilstein J. Org. Chem. 2018, 14, 389–396, doi:10.3762/bjoc.14.27

• of S-alkyl benzothioate and its derivatives in various aprotic solvents using Et3N·nHF (n = 3–5) and Et4NF·nHF (n = 3–5) as supporting electrolyte and a fluorine source successfully provided the corresponding α-fluorinated products in moderate yields. Dichloromethane containing Et4NF·4HF was found to

• be the most suitable combination as electrolytic solvent and supporting salt as well as fluorine source for the anodic fluorination. The electrochemical fluorination of cyclic benzothioates such as benzothiophenone was also achieved. Keywords: anodic cyclization; diastereoselective fluorination

• ; electrosynthesis; fluorobenzothiophenone; selective fluorination; Introduction Due to the interesting properties of fluorine atoms and carbon–fluorine bonds, organofluorine compounds are widely used in various fields like pharmaceutical chemistry, agrochemistry, and materials sciences [1][2]. Therefore, the