Regioselective decarboxylative addition of malonic acid and its mono(thio)esters to 4-trifluoromethylpyrimidin-2(1H)-ones

• Sergii V. Melnykov,
• Andrii S. Pataman,
• Yurii V. Dmytriv,
• Svitlana V. Shishkina,
• Mykhailo V. Vovk and
• Volodymyr A. Sukach

Beilstein J. Org. Chem. 2017, 13, 2617–2625, doi:10.3762/bjoc.13.259

• modern drug discovery and development area [9][10]. As a result of intensive research efforts over the last decades, efficient fluorination and fluoroalkylation methods have emerged to prepare previously challenging molecules decorated with fluorine atoms or fluorinated groups which make them practically

Palladium-catalyzed Heck-type reaction of secondary trifluoromethylated alkyl bromides

• Tao Fan,
• Wei-Dong Meng and
• Xingang Zhang

Beilstein J. Org. Chem. 2017, 13, 2610–2616, doi:10.3762/bjoc.13.258

• past decade, investigations mainly focused on direct fluorination or fluoroalkylation of aromatics [1][2][3][4][5]. Fluoroalkylated alkenes are a kind of important fluorinated structural motifs and have wide applications in medicinal chemistry and advanced functional materials [6][7][8][9]. However

Synthesis of 1,3-cis-disubstituted sterically encumbered imidazolidinone organocatalysts

• Jan Wallbaum and
• Daniel B. Werz

Beilstein J. Org. Chem. 2017, 13, 2577–2583, doi:10.3762/bjoc.13.254

• accessible from amino acids, are widely used in these kinds of reactions [13][14][15][16][17][18]. More recent examples demonstrate the applicability in various reactions like diastereoselective α-fluorination [19], total syntheses [20][21], cross-dehydrogenative couplings [22], selectivity-reversed Friedel

Hydrolysis, polarity, and conformational impact of C-terminal partially fluorinated ethyl esters in peptide models

• Vladimir Kubyshkin and
• Nediljko Budisa

Beilstein J. Org. Chem. 2017, 13, 2442–2457, doi:10.3762/bjoc.13.241

• nucleus. Fluorination of molecular scaffolds can also selectively influence a molecule’s polarity, conformational preferences and chemical reactivity, properties that can be exploited for various chemical applications. A powerful route for incorporating fluorine atoms in biomolecules is last-stage

• fluorination of peptide scaffolds. One of these methods involves esterification of the C-terminus of peptides using a diazomethane species. Here, we provide an investigation of the physicochemical consequences of peptide esterification with partially fluorinated ethyl groups. Derivatives of N-acetylproline are

• used to model the effects of fluorination on the lipophilicity, hydrolytic stability and on conformational properties. The conformational impact of the 2,2-difluoromethyl ester on several neutral and charged oligopeptides was also investigated. Our results demonstrate that partially fluorinated esters

Fluorination of some highly functionalized cycloalkanes: chemoselectivity and substrate dependence

• Attila Márió Remete,
• Melinda Nonn,
• Santos Fustero,
• Matti Haukka,
• Ferenc Fülöp and
• Loránd Kiss

Beilstein J. Org. Chem. 2017, 13, 2364–2371, doi:10.3762/bjoc.13.233

• -amino ester stereo- and regioisomers, derived from unsaturated cyclic β-amino acids is described. The nucleophilic fluorinations involving hydroxy–fluorine exchange of some highly functionalized alicyclic diol derivatives have been carried out in view of selective fluorination, investigating substrate

• controlled efficient fluorination procedures. This high interest is clearly demonstrated by the number of various published papers on the field, and related recent comprehensive reviews [3][4][5][6][7][8][9][10][11][12]. The nucleophilic fluorination with commercially available organic fluorinating agents

• fluorination based on hydroxy–fluorine interconversion seems to be an eloquent, simple and efficient procedure for the creation of a certain fluorinated organic molecule, regio- and stereoselectivity, stereocontrol and substrate influence remain a challenge in the case of highly functionalized frameworks

Homologated amino acids with three vicinal fluorines positioned along the backbone: development of a stereoselective synthesis

• Raju Cheerlavancha,
• Ahmed Ahmed,
• Yun Cheuk Leung,
• Aggie Lawer,
• Qing-Quan Liu,
• Marina Cagnes,
• Hee-Chan Jang,
• Xiang-Guo Hu and
• Luke Hunter

Beilstein J. Org. Chem. 2017, 13, 2316–2325, doi:10.3762/bjoc.13.228

• describe the synthesis of δ-amino acids that contain three vicinal C–F bonds positioned along the backbone. The ultimately successful synthetic approach emerged through the investigation of several methods based on both electrophilic and nucleophilic fluorination chemistry. We show that different

• the repeating (CHF)n motif within the target molecule via an iterative synthetic approach (Scheme 1, boxed). We reasoned that an aldehyde such as 7 could undergo electrophilic fluorination, mediated by a chiral organocatalyst [18][19][20], to generate the fluorinated aldehyde 8 as a single

• stereoisomer. Then, if the carbon chain of 8 could be extended by one atom to give the homologated aldehyde 9, fluorination could be repeated and the cycle could continue until the desired number of fluorine atoms was installed. This hypothetical approach had several attractions, including (i) the flexibility

One-pot multistep mechanochemical synthesis of fluorinated pyrazolones

• Joseph L. Howard,
• William Nicholson,
• Yerbol Sagatov and
• Duncan L. Browne

Beilstein J. Org. Chem. 2017, 13, 1950–1956, doi:10.3762/bjoc.13.189

• has culminated in the development of a two-step, one-jar protocol for heterocycle formation and subsequent fluorination that has been successfully applied across a range of substrates, resulting in 12 difluorinated pyrazolones in moderate to excellent yields. Keywords: fluorination; heterocycles

• designed a 2-step reaction related to our recent work on liquid assisted grinding effects of the fluorination of 1,3-dicarbonyl compounds, in which the dicarbonyl will initially form a pyrazolone in the first reaction prior to undergoing difluorination in the second step (Scheme 1) [17]. Notably this

• the hydrazine is slow, meaning that the nucleophilicity is greatly retarded compared to lower acid loadings. Nonetheless, considering that the subsequent fluorination step should proceed optimally under basic conditions [17], the lowest amount of acid which also provided a good yield was thus chosen

Mechanochemical synthesis of small organic molecules

• Tapas Kumar Achar,
• Anima Bose and
• Prasenjit Mal

Beilstein J. Org. Chem. 2017, 13, 1907–1931, doi:10.3762/bjoc.13.186

• poor selectivity in mono- or polybrominations (Scheme 26). They have also explored halogenations of 1,3-dicarbonyl compounds to obtain dihalo derivatives in excellent yield [100]. In 2016, Browne and co-workers reported selective mechanochemical fluorination of 1,3-dicarbonyl compounds using

• reaction of electron-rich arenes [88][98]. Mechanochemical aryl halogenation reaction using trihaloisocyanuric acids [100]. Mechanochemical fluorination reaction by LAG method [102]. Mechanochemical Ugi reaction [116]. Mechanochemical Passerine reaction [116]. Mechanochemical synthesis of α-aminonitriles

Chiral phase-transfer catalysis in the asymmetric α-heterofunctionalization of prochiral nucleophiles

• Johannes Schörgenhumer,
• Maximilian Tiffner and
• Mario Waser

Beilstein J. Org. Chem. 2017, 13, 1753–1769, doi:10.3762/bjoc.13.170

• most important field of application of this catalytic principle. Based on several highly spectacular recent reports, we thus wish to discuss some of the most important achievements in this field within the context of this review. Keywords: amination; chlorination; fluorination; hydroxylation

• , enantiospecific nucleophilic displacement reactions [66][67]. α-Fluorinations The stereoselective electrophilic α-fluorination of carbonyl compounds became a thoroughly investigated field over the course of the last 15 years [68][69][70][71][72]. A variety of different catalytic approaches, either relying on the

• nucleophiles dates back to 2002, when Kim and Park described the first use of cinchona alkaloid-based quaternary ammonium salts A (i.e., derivative A1) for the enantioselective α-fluorination of β-ketoesters 1 by using N-fluorobenzenesulfonimide (NFSI, 2) as the fluoride-transfer reagent [73] (Scheme 2). By

Strategies toward protecting group-free glycosylation through selective activation of the anomeric center

• A. Michael Downey and
• Michal Hocek

Beilstein J. Org. Chem. 2017, 13, 1239–1279, doi:10.3762/bjoc.13.123

• from β-D-glucose pentaacetate, α-fluoro-D-glucose can be obtained with the key fluorination effected by using Olah’s reagent. The appeal of this procedure is obvious. It is an operationally simple and stereo- and regioselective method to obtain tri- and oligosaccharides containing a sucrose moiety

Molecular-level architectural design using benzothiadiazole-based polymers for photovoltaic applications

• Vinila N. Viswanathan,
• Arun D. Rao,
• Upendra K. Pandey,
• Arul Varman Kesavan and
• Praveen C. Ramamurthy

Beilstein J. Org. Chem. 2017, 13, 863–873, doi:10.3762/bjoc.13.87

• analogue P2, the LUMO energy decreased by 0.10 eV compared to P1 (indicating an increased electron affinity upon fluorination) and the corresponding HOMO level stabilized by 0.24 eV. Hence, both molecular energy levels could be tailored by the introduction of fluorine. In the case of P3, the HOMO level

• on the optoelectronics and photovoltaic performances has been demonstrated. It was observed that the incorporation of fluorine, a strong electron-withdrawing group, resulted in deeper HOMO energy levels for the polymer P2 as compared to polymer P1. The fluorination also enhances the intramolecular

• interaction between the polymer chains, which is reflected in the higher hole mobility of P2 over P1. Though the photovoltaic parameter values are very low for these polymers, it was observed that fluorination could increase the overall device performance by ≈110%. The effect of increased planarity along the

Synthesis of ribavirin 2’-Me-C-nucleoside analogues

• Fanny Cosson,
• Aline Faroux,
• Jean-Pierre Baltaze,
• Jonathan Farjon,
• Régis Guillot,
• Jacques Uziel and
• Nadège Lubin-Germain

Beilstein J. Org. Chem. 2017, 13, 755–761, doi:10.3762/bjoc.13.74

• decrease in the order: H5’b-H4’ > CH3 > H1’. The selective excitation of H1’ in 13a led to nOes with decreasing intensities in the order: H5’b-H4’ > CH3 > H3’, whereas for 13b the order was CH3 > H5’b-H4’. This second series of nOes confirms that CH3 is closer to H1’ in 13b than in 13a. The fluorination of

• fluorinated analogue 3 required a more complicated pathway. This included the selective protection of the 3’,5’ positions, the stereoselective methylation and the fluorination of the 2’ position. The synthesized compounds are currently investigated for their antiviral activities. Experimental Experimental

• . Structural study of isomeric compounds 13. Synthesis of 5-(2’-C-methyl-β-D-ribofuranosyl)-1,2,3-triazole-4-carboxamide (2). Synthesis of the 2’-keto derivatives 12a/12b. Fluorination of ethyl 1-benzyl-4-(2’-C-methyl-3’,5’-O-(tetraisopropyldisiloxane-1,3-diyl)-β-D-ribofuranosyl)-1,2,3-triazole-5-carboxylate

Fluorinated cyclohexanes: Synthesis of amine building blocks of the all-cis 2,3,5,6-tetrafluorocyclohexylamine motif

• Tetiana Bykova,
• Nawaf Al-Maharik,
• Alexandra M. Z. Slawin and
• David O'Hagan

Beilstein J. Org. Chem. 2017, 13, 728–733, doi:10.3762/bjoc.13.72

• then applied to diastereoisomers 8b and 8c as illustrated in Scheme 3. Fluorination of the isomer mixture 8b/8c with Et3N·3HF at 140 °C gave 9b and the racemic 9c as an inseparable mixture. Triflation of this product mixture generated 10b and 10c, isomeric products which could now be separated by

• chromatography. Finally fluorination of 10b and 10c in separate reactions with Et3N·3HF at 120 °C furnished nitrile 11b (51% yield) and 11c (31% yield) respectively. The structure and stereochemistry of both products were unambiguously confirmed by X-ray structure analysis (Scheme 3). Reduction of 11b with

Synthesis of 1-indanones with a broad range of biological activity

• Marika Turek,
• Dorota Szczęsna,
• Marek Koprowski and
• Piotr Bałczewski

Beilstein J. Org. Chem. 2017, 13, 451–494, doi:10.3762/bjoc.13.48

• derivatives 123 via the Nazarov cyclization followed by electrophilic fluorination, has been described in 2007 by Ma et al. [65]. This reaction was catalyzed by Cu(II) triflate and proceeded in the presence of N-fluorobenzenesulfonimide (NFSI) 122 as a fluorinating reagent (Scheme 39). Scientists are

Organofluorine chemistry: Difluoromethylene motifs spaced 1,3 to each other imparts facial polarity to a cyclohexane ring

• Mathew J. Jones,
• Ricardo Callejo,
• Alexandra M. Z. Slawin,
• Michael Bühl and
• David O'Hagan

Beilstein J. Org. Chem. 2016, 12, 2823–2827, doi:10.3762/bjoc.12.281

• also rendered fluorine containing compounds important in the development of organic materials such as liquid crystals [8][9]. Strategic fluorination can add polarity to a molecule, however, such compounds do not generally increase in their hydrophilic capacity, thus selective fluorination leads to

• polar-hydrophobic properties [10]. Although selective mono-fluorination and CF3 incorporation have had wide currency, the difluoromethylene (CF2) motif has received relatively less attention despite possessing unique properties [11][12][13][14]. For example CH2F2 shows the highest molecular dipole (1.97

• byproducts. The reaction of ketones 5a–c with 1,2-ethanedithiol in the presence of catalytic BF3·OEt2 afforded the corresponding bis-dithianes 6a–c in moderate to good yields [26] (Scheme 2). The reaction of diketone 5c also afforded the monoderivatised ketone 9 as a minor product. Direct fluorination of

Comparing blends and blocks: Synthesis of partially fluorinated diblock polythiophene copolymers to investigate the thermal stability of optical and morphological properties

• Pierre Boufflet,
• Sebastian Wood,
• Jessica Wade,
• Zhuping Fei,
• Ji-Seon Kim and
• Martin Heeney

Beilstein J. Org. Chem. 2016, 12, 2150–2163, doi:10.3762/bjoc.12.205

• blends. Here we explore the impact of backbone fluorination in block copolymers of poly(3-octyl-4-fluorothiophene)s and poly(3-octylthiophene) (F-P3OT-b-P3OT). Two block co-polymers with varying block lengths were prepared via sequential monomer addition under Kumada catalyst transfer polymerisation

• , suggesting that such materials may be interesting for enhanced thermal stability of organic photovoltaic active layers based on similar systems. Keywords: conjugated block-copolymer synthesis; fluorination; microphase stabilization; polythiophene; temperature-dependent Raman spectroscopy; Introduction With

• fluorination which increases backbone rigidity [41][42]. As an initial exploration, this contribution presents the synthesis and purification of two block copolymers of poly(3-octylthiophene) (P3OT) and poly(3-fluoro-4-octylthiophene) (F-P3OT) with different relative block lengths. The thermal behavior of the

Synthesis and characterization of fluorinated azadipyrromethene complexes as acceptors for organic photovoltaics

• Forrest S. Etheridge,
• Roshan J. Fernando,
• Sandra Pejić,
• Matthias Zeller and
• Geneviève Sauvé

Beilstein J. Org. Chem. 2016, 12, 1925–1938, doi:10.3762/bjoc.12.182

• Homoleptic zinc(II) complexes of di(phenylacetylene)azadipyrromethene (e.g., Zn(WS3)2) are potential non-fullerene electron acceptors for organic photovoltaics. To tune their properties, fluorination of Zn(WS3)2 at various positions was investigated. Three fluorinated azadipyrromethene-based ligands were

• chelated with zinc(II) and BF2+ and the optical and electrochemical properties were studied. Fluorination had little effect on the optical properties of both the zinc(II) and BF2+ complexes, with λmax in solution around 755 nm and 785 nm, and high molar absorptivities of 100 × 103 M−1cm−1 and 50 × 103 M

• −1cm−1, respectively. Fluorination of Zn(WS3)2 raised the oxidation potentials by 0.04 V to 0.10 V, and the reduction potentials by 0.01 V to 0.10 V, depending on the position and type of substitution. The largest change was observed for fluorine substitution at the proximal phenyl groups and CF3

Synthesis and in vitro cytotoxicity of acetylated 3-fluoro, 4-fluoro and 3,4-difluoro analogs of D-glucosamine and D-galactosamine

• Štěpán Horník,
• Lucie Červenková Šťastná,
• Petra Cuřínová,
• Jan Sýkora,
• Kateřina Káňová,
• Roman Hrstka,
• Ivana Císařová,
• Martin Dračínský and
• Jindřich Karban

Beilstein J. Org. Chem. 2016, 12, 750–759, doi:10.3762/bjoc.12.75

• 75 °C (conditions used for fluorination of 11), or in dichloromethane at rt was attempted. Disappointingly, only unreacted 15 was recovered. A very slow formation of several unidentified fluorine-containing compounds (19F NMR) was observed on prolonged reaction times. Oxidative debenzylation of 19

• analysis. Since fluorination of 12 with DAST failed to introduce fluorine at C-4β due to formation of orthoester 25, the reaction of 1,6:2,3-dianhydro-β-D-talopyranose 14 with DAST was utilized to give 1,6:2,3-dianhydro-4-deoxy-4-fluoro-β-D-talopyranose (30) with retention of the configuration at C-4 [39

• reported in [20]. Our synthesis of 5 is more practical (55% from 10 in 3 steps) than the earlier preparations which were reported troublesome owing to low yields (28% and 10%, respectively) of the key fluorination step [18][20]. For the remaining fluoro derivatives of 1,6-anhydro-2-azidohexopyranoses

A practical way to synthesize chiral fluoro-containing polyhydro-2H-chromenes from monoterpenoids

• Oksana S. Mikhalchenko,
• Dina V. Korchagina,
• Konstantin P. Volcho and
• Nariman F. Salakhutdinov

Beilstein J. Org. Chem. 2016, 12, 648–653, doi:10.3762/bjoc.12.64

• may undergo stereoselective trap by H2O to form alcohol epimers 2; these may then undergo a stereospecific SN2 reaction to form fluoride epimers 8; c) the fluorination and/or hydroxylation of cation 10, forming fluoride epimers 8 and alcohol epimers 2, respectively, may be reversible. This has several

• effects: firstly, reversible hydroxylation means that alcohol epimers 2 may convert to fluoride epimers 8 via cation 10 (pathway (a)); secondly, reversible fluorination and/or hydroxylation means that the diastereoselectivity of formation and/or 2 may be governed by product stability and not inherent

(Thio)urea-mediated synthesis of functionalized six-membered rings with multiple chiral centers

• Giorgos Koutoulogenis,
• Nikolaos Kaplaneris and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2016, 12, 462–495, doi:10.3762/bjoc.12.48

• of intermediates have been proposed to be the reactive intermediates in many reactions such as aldol, Michael, Mannich, and α-functionalization (α-chlorination, α-amination, α-fluorination) reactions. Proline-type organocatalysts are considered priviliged, because their corresponding enamines exist

Diastereoselective synthesis of new O-alkylated and C-branched inositols and their corresponding fluoro analogues

• Charlotte Collet,
• Françoise Chrétien,
• Yves Chapleur and
• Sandrine Lamandé-Langle

Beilstein J. Org. Chem. 2016, 12, 353–361, doi:10.3762/bjoc.12.39

• /or acetate migration. By reducing the reaction time to 15 minutes the byproducts formation could be lowered to 10% and myo-2 was obtained in 45% isolated yield. It is worthy to note that 41% of the starting material was recovered. At this stage, the fluorination was tested using DAST [48] on myo-20

• fluorination. The utilization of isopropenyl acetate as solvent in the presence of p-TSA at 80 °C for 2 h [52] gave the corresponding acetylated compounds myo-23 and scyllo-23 in good to excellent yields. The access to fluorinated compounds by nucleophilic substitution was investigated starting from these

• fully acetylated inositols. The fluorination reactions using potassium fluoride, 18-crown-6 in acetonitrile at 70 °C [53], TBAF in acetonitrile at 60 °C for 2 h [54] or KHF2 and 18-crown-6 in acetonitrile for 2 h at 60 °C [55] were performed. However, 19F NMR analyses of the reaction mixtures did not

Synthesis and nucleophilic aromatic substitution of 3-fluoro-5-nitro-1-(pentafluorosulfanyl)benzene

• Javier Ajenjo,
• Martin Greenhall,
• Camillo Zarantonello and
• Petr Beier

Beilstein J. Org. Chem. 2016, 12, 192–197, doi:10.3762/bjoc.12.21

• Abstract 3-Fluoro-5-nitro-1-(pentafluorosulfanyl)benzene was prepared by three different ways: as a byproduct of direct fluorination of 1,2-bis(3-nitrophenyl)disulfane, by direct fluorination of 4-nitro-1-(pentafluorosulfanyl)benzene, and by fluorodenitration of 3,5-dinitro-1-(pentafluorosulfanyl)benzene

• nitrogen nucleophiles provided 3-fluoro-5-nitro-1-(pentafluorosulfanyl)benzenes substituted in position four. Keywords: direct fluorination; fluorine; nucleophilic aromatic substitution; pentafluorosulfanyl group; vicarious nucleophilic substitution; Introduction Organic compounds with a

• fluorination of nitro-substituted diaryl disulfides leading to 3- or 4-nitro-1-(pentafluorosulfanyl)benzenes [7][8][9][10]. This reaction is conducted in tens of kilogram scale in industry. The second method is known as Umemoto’s synthesis and starts with aromatic thiols or diaryl disulfides which are

Copper-catalyzed aminooxygenation of styrenes with N-fluorobenzenesulfonimide and N-hydroxyphthalimide derivatives

• Yan Li,
• Xue Zhou,
• Guangfan Zheng and
• Qian Zhang

Beilstein J. Org. Chem. 2015, 11, 2721–2726, doi:10.3762/bjoc.11.293

• -tetramethylpiperidine-N-oxyl (TEMPO) [36]. NFSI is a very interesting reagent. Besides classic electrophilic fluorination reagent [37], it has been used not only as fluoride-atom transfer reagent [38][39][40] but also as nucleophilic/radical amination reagent [41]. We are highly interested in the multiple reaction

Carbon–carbon bond cleavage for Cu-mediated aromatic trifluoromethylations and pentafluoroethylations

• Tsuyuka Sugiishi,
• Hideki Amii,
• Kohsuke Aikawa and
• Koichi Mikami

Beilstein J. Org. Chem. 2015, 11, 2661–2670, doi:10.3762/bjoc.11.286

• , the research activity on selective fluorination and trifluoromethylation has reached a mature state. The progress in fluoroalkylation of organic compounds could be accelerated by the use of fluoroalkylating reagents, which are inexpensive and easy to handle. Perfluoroalkyl carboxylic acid derivatives

Versatile synthesis and biological evaluation of novel 3’-fluorinated purine nucleosides

• Hang Ren,
• Haoyun An,
• Paul J. Hatala,
• William C. Stevens Jr,
• Jingchao Tao and
• Baicheng He

Beilstein J. Org. Chem. 2015, 11, 2509–2520, doi:10.3762/bjoc.11.272

• direct glycosylation for the synthesis of 3’-fluorine modified guanosine derivatives is highly advantageous compared to the previously reported methods utilizing orthogonal protecting groups, selective deprotection, and fluorination of the starting guanosine [34]. Biological evaluation Newly synthesized