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

• ) complex 104 was obtained through the reaction of 102 with glycine (103) and Ni(NO3)2. The subsequent alkylation of complex 104 with fluorine-containing benzyl chlorides 105a–d followed by hydrolysis with HCl afforded enantiomerically enriched (<90% ee) (S)-fluorinated phenylalanine derivatives 53a, 81

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

Cascade trifluoromethylthiolation and cyclization of N-[(3-aryl)propioloyl]indoles

• Ming-Xi Bi,
• Shuai Liu,
• Yangen Huang,
• Xiu-Hua Xu and
• Feng-Ling Qing

Beilstein J. Org. Chem. 2020, 16, 657–662, doi:10.3762/bjoc.16.62

• converted to the mono(trifluoromethylthiolated) products in moderate yields. Further studies on applying radical cascade reactions to the construction of fluorine-containing heterocyclic scaffolds are in progress in our laboratory. Representative examples of biologically active pyrrolo[1,2-a]indol-3-one

Synthesis of 4-(2-fluorophenyl)-7-methoxycoumarin: experimental and computational evidence for intramolecular and intermolecular C–F···H–C bonds

• Vuyisa Mzozoyana,
• Fanie R. van Heerden and
• Craig Grimmer

Beilstein J. Org. Chem. 2020, 16, 190–199, doi:10.3762/bjoc.16.22

• atom in the 9α position of the structure [19]. Since then, the fluorine-containing drugs have come onto the market and they are amongst the best-selling pharmaceutical drugs, including Lipitor®, Prevacid®, Advair Discus® and Lexapro® [20][21][22]. The incorporation of fluorine may improve the activity

• aromatic triazole foldmers [37]. In their study, using crystallographic and DFT data, they concluded that their folded conformers are held by C–F···H–C hydrogen bonds. To further these studies, we have synthesized a fluorine-containing phenylcoumarin in order to study the fluorine-hydrogen bond. The

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

• , agricultural, and materials industries. The incorporation of fluorine-containing groups into organic molecules can improve their chemical and physical properties, which attracts continuous interest in organic synthesis. Among various reported methods, transition-metal-catalyzed fluorination/fluoroalkylation

• in the Earth’s crust is relatively abundant (13th most abundant element), scientists have identified only 21 kinds of fluorine-containing natural molecules [8][9]. Therefore, it is highly desirable to introduce a fluorine-containing substituent into a molecule artificially. However, traditional

Fluorine-containing substituents: metabolism of the α,α-difluoroethyl thioether motif

• Andrea Rodil,
• Alexandra M. Z. Slawin,
• Nawaf Al-Maharik,
• Ren Tomita and
• David O’Hagan

Beilstein J. Org. Chem. 2019, 15, 1441–1447, doi:10.3762/bjoc.15.144

Mechanochemical amorphization of chitin: impact of apparatus material on performance and contamination

• Thomas Di Nardo and
• Audrey Moores

Beilstein J. Org. Chem. 2019, 15, 1217–1225, doi:10.3762/bjoc.15.119

• . Contamination by fluorine containing species is harder to establish by ICP–OES, so in order to measure potential release when milling in PTFE, we turned to XPS (Figure S1, Supporting Information File 1). When milling in a PTFE jar with ZrO2, fluorine was found in the high concentration of 6.9%. This very high

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

Synthesis of fluoro-functionalized diaryl-λ³-iodonium salts and their cytotoxicity against human lymphoma U937 cells

• Prajwalita Das,
• Etsuko Tokunaga,
• Hidehiko Akiyama,
• Hiroki Doi,
• Norimichi Saito and
• Norio Shibata

Beilstein J. Org. Chem. 2018, 14, 364–372, doi:10.3762/bjoc.14.24

• , Toyoake, 470-1192, Japan Pharmaceutical Division, Ube Industries, Ltd. Seavans North Bldg., 1-2-1 Shibaura, Minato-ku, Tokyo 105-8449, Japan Institute of Advanced Fluorine-Containing Materials, Zhejiang Normal University, 688 Yingbin Avenue, 321004 Jinhua, China 10.3762/bjoc.14.24 Abstract Conscious of

• the potential bioactivity of fluorine, an investigation was conducted using various fluorine-containing diaryliodonium salts in order to study and compare their biological activity against human lymphoma U937 cells. Most of the compounds tested are well-known reagents for fluoro-functionalized

• research programs focused on the development of novel reagents for fluoro-functionalization [12][13][16][17][18][19][20][21][22][23], as well as the design and synthesis of biologically active fluorine-containing compounds [24][25][26][27][28], we noted that a series of fluoro-functionalization reagents

Gram-scale preparation of negative-type liquid crystals with a CF₂CF₂-carbocycle unit via an improved short-step synthetic protocol

• Tatsuya Kumon,
• Shohei Hashishita,
• Takumi Kida,
• Shigeyuki Yamada,
• Takashi Ishihara and
• Tsutomu Konno

Beilstein J. Org. Chem. 2018, 14, 148–154, doi:10.3762/bjoc.14.10

• ; tetrafluorinated cyclohexadiene; tetrafluorinated cyclohexane; Introduction Fluorine-containing organic compounds have attracted much attention in various areas, such as the medicinal, agrochemical, and materials science fields [1][2][3], due to the unique characteristics of the fluorine atom [4][5][6]. It is

• well known that fluorine atoms incorporated into organic substances very often lead to intriguing physical as well as chemical properties. Therefore, considerable attention has been devoted to the development of efficient synthetic protocols for fluorine-containing organic compounds. Owing to the

• these compounds. Therefore, for practical use of fluorine-containing LC molecules, the development of more efficient synthetic protocols is highly necessary. Herein, an improved short-step synthetic protocol for obtaining promising LC molecules containing the CF2CF2 fragment is demonstrated, where the

Ring-size-selective construction of fluorine-containing carbocycles via intramolecular iodoarylation of 1,1-difluoro-1-alkenes

• Takeshi Fujita,
• Ryo Kinoshita,
• Tsuyoshi Takanohashi,
• Naoto Suzuki and
• Junji Ichikawa

Beilstein J. Org. Chem. 2017, 13, 2682–2689, doi:10.3762/bjoc.13.266

• substituents [3][4][5]. Despite the limitation, the cationic cyclization of difluoroalkenes possesses high potential for the synthesis of fluorine-containing cyclic compounds. Thus, the development of this type of cyclization is highly desirable to further expand the utility of difluoroalkenes in organic

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

• useful [11][12][13][14]. A building-block approach remains an alternative strategy to the synthesis of fluorine-containing compounds. This complementary method takes advantage of specific reagents featuring original fluorinated motives and/or functional groups which affords more complex derivatives via

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

• experiments are remarkably sensitive [4]. Fluorine-containing groups can be incorporated into biopolymers by various approaches, including those that utilize biosynthesis [5][6][7], enzymatic conversion [8], chemical synthesis [9][10], and ligation reactions [11]. Depending on the research target, 19F NMR

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

• amide O-atom. Increasing the amount of Deoxofluor to 4 equiv resulted in the exclusive formation of the fluorine-containing oxazoline derivative (±)-3. Note that the addition of DBU did not have a significant effect on this reaction. When isolated hydroxyoxazoline (±)-2 is subjected to the fluorination

Comparative profiling of well-defined copper reagents and precursors for the trifluoromethylation of aryl iodides

• Peter T. Kaplan,
• Jessica A. Lloyd,
• Mason T. Chin and
• David A. Vicic

Beilstein J. Org. Chem. 2017, 13, 2297–2303, doi:10.3762/bjoc.13.225

• as the major fluorine-containing product. Because our group has developed the NHC-based copper reagents for trifluoromethylation reactions [10][11], we were interested in comparing the effects of electronics and sterics of the aryl halides using the NHC-based systems A1 and A2 with the phen system B2

Synthesis and application of trifluoroethoxy-substituted phthalocyanines and subphthalocyanines

• Satoru Mori and
• Norio Shibata

Beilstein J. Org. Chem. 2017, 13, 2273–2296, doi:10.3762/bjoc.13.224

• is small [21][22]. As a result, compounds into which fluorine has been introduced may show beneficial changes in their properties. In addition, among the chemical bonds formed by carbon, fluorine bonds have the highest binding energy [23], such that fluorine-containing compounds often show resistance

• an important key element in the fields of medical and agricultural chemistry [25][26][27][28][29][30][31]. As described above, fluorine is considered an essential element for next-generation science technology, and many researchers have studied methods for the synthesis of fluorine-containing

• compounds. By introducing a fluorine atom, phthalocyanines are also expected to become novel functional materials that reflect the specific properties of the fluorine atom. Fluorine-containing phthalocyanines have been found to behave differently from non-fluorine phthalocyanines due to the specific

Preparation of imidazo[1,2-a]-N-heterocyclic derivatives with gem-difluorinated side chains

• Layal Hariss,
• Kamal Bou Hadir,
• Mirvat El-Masri,
• Thierry Roisnel,
• René Grée and
• Ali Hachem

Beilstein J. Org. Chem. 2017, 13, 2115–2121, doi:10.3762/bjoc.13.208

• with gem-fluorinated side chains starting from easily accessible propargylic fluorides. Although the yields are only moderate to fair, this short (1–2 steps) method offers significant flexibility to prepare focused libraries of molecules with this core structure. Such new fluorine-containing

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

• -promoted α-methylenation of compounds 118 followed by cyclization of the resulting enones 119 allowed to obtain a series of 2-alkyl-1-indanones 120 in very good yields (Scheme 38). A stereoselective, catalytic, tandem transformation of α,β-unsaturated arylketones 121 to fluorine-containing 1-indanone

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

Synthesis, dynamic NMR characterization and XRD studies of novel N,N’-substituted piperazines for bioorthogonal labeling

• Constantin Mamat,
• Marc Pretze,
• Matthew Gott and
• Martin Köckerling

Beilstein J. Org. Chem. 2016, 12, 2478–2489, doi:10.3762/bjoc.12.242

• - and γ-detector of the HPLC device. Preparation of the nitro derivatives 4a and 5a and the fluorine-containing compounds 4b and 5b. Reagents and conditions: a) 1a, Et3N, CHCl3, 0 °C, 2 h, 0 °C then 2 h, rt; b) 1b, acetonitrile, 1 M HCl, rt, 4 h; c) 4-tosylbutyne, Et3N, THF, 60 °C, 3 d; d) 3-azidopropyl

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

• 41 from 19. 1-O-Deacetylation of monofluorinated hexosamines. Reagents and conditions: (a) BnNH2, THF, 62%; (b) C5H10NH, THF, 74%; (c) C5H10NH, THF, 60%; (d) silica gel, MeOH, 30 days, 40%. Acetolysis of the fluorine-containing intermediates and hydrogenation. IC50 mean values (μM) of selected

Asymmetric α-amination of 3-substituted oxindoles using chiral bifunctional phosphine catalysts

• Qiao-Wen Jin,
• Zhuo Chai,
• You-Ming Huang,
• Gang Zou and
• Gang Zhao

Beilstein J. Org. Chem. 2016, 12, 725–731, doi:10.3762/bjoc.12.72

• and 3s, which contain a fluorine atom, were obtained in good yield with good to execellent ee (Table 3, entries 6 and 14–16). Enantiomerically enriched fluorine-containing 2-oxoindoles are of great significance in drug discovery and development [45]. Unfortunately, there was no ee observed when the 3

Selectively fluorinated cyclohexane building blocks: Derivatives of carbonylated all-cis-3-phenyl-1,2,4,5-tetrafluorocyclohexane

• Mohammed Salah Ayoup,
• David B. Cordes,
• Alexandra M. Z. Slawin and
• David O'Hagan

Beilstein J. Org. Chem. 2015, 11, 2671–2676, doi:10.3762/bjoc.11.287

• derivatisation and facilitate the incorporation of the facially polarised all-cis-1,2,4,5-tetrafluorocyclohexane motif into more advanced molecular scaffolds. Keywords: cyclohexane carbonylation; fluorine containing building blocks: organofluorine chemistry; Introduction Selectively fluorinated building blocks

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

• contributed to the advancement of human life and the global demand for organofluorine compounds will continue to increase. Therefore, the introduction of fluorine-containing functional groups into organic molecules is recognized as a general strategy for the design of drugs and functional materials. In fact

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

• it imparts improve the bioavailability of fluorine-containing drugs. Relative to the unfluorinated derivative, fluorinated drugs have demonstrated favorable pharmacological, physicochemical, pharmacokinetic, pharmacodynamic and safety profiles for a number of compounds [21][22][23]. Several