SnCl₄-catalyzed solvent-free acetolysis of 2,7-anhydrosialic acid derivatives

• Kesatebrhan Haile Asressu and
• Cheng-Chung Wang

Beilstein J. Org. Chem. 2019, 15, 2990–2999, doi:10.3762/bjoc.15.295

• destabilizing electron-withdrawing carboxy group flanking atom C-2 and the lack of a participating auxiliary in position C-3 of 5. Glycal 24 is widely used for α-sialylation by utilizing neighboring group participation and site-selective fluorination at C-3 [12][13][14][41]. Moreover, it is the main precursor

Synthesis of a dihalogenated pyridinyl silicon rhodamine for mitochondrial imaging by a halogen dance rearrangement

• Jessica Matthias,
• Thines Kanagasundaram,
• Klaus Kopka and
• Carsten S. Kramer

Beilstein J. Org. Chem. 2019, 15, 2333–2343, doi:10.3762/bjoc.15.226

• restricted rotation of the xanthene pyridine bond. The 2-chloropyridinyl moiety in 15 is not only attractive because of its option for convenient fluorination, but also since its intrinsic targeting ability to acidic cellular compartments (such as the lysosomal-selective fluorophore 13). We assumed that our

• intrinsic mitochondria targeting ability, the radiolabelled analogue can find application in multimodal (PET/OI) imaging of mitochondria for diagnostic and therapeutic use in, e.g., cancer patients. (Radio)fluorination of dye 15 is the subject of ongoing research and will be presented elsewhere. (a

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

• . Keywords: catalysis; C-RF bond; fluorination; fluoroalkylation; transition metals; Introduction Compared with other halogens (Cl, Br, I), fluorine (F) has completely different physical and chemical properties, such as a unique electronic structure, strongest electronegativity, and small atomic radius

• fluorination methods to these building blocks, such as Friedel–Crafts-type electrophilic halogenation [10][11], Sandmeyer-type reactions of diazonium salts [12], and halogenations of preformed organometallic reagents [13], commonly involve multiple steps, harsh reaction conditions, and the use of

Selective benzylic C–H monooxygenation mediated by iodine oxides

• Kelsey B. LaMartina,
• Haley K. Kuck,
• Linda S. Oglesbee,
• Asma Al-Odaini and
• Nicholas C. Boaz

Beilstein J. Org. Chem. 2019, 15, 602–609, doi:10.3762/bjoc.15.55

• Ag/AgNO3 [52]. N-Hydroxysuccinimide (2f) and N-hydroxynapthylimide (2g) were both able to catalyze the oxidation of n-butylbenzene, albeit in slightly lower yield than NHPI. N,N’-dihydroxypyromellitimide (catalyst 2h), which was used as a successful catalyst in the C–H fluorination of benzylic

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

• clinical trials for type 2 diabetes mellitus. Xu et al. also presented the similar ring-opening/trifluoromethylation of cyclopropanols for the synthesis of various β-trifluoromethyl ketones [103]. In this year, Loh et al. [104] and Zhu et al. [105] proposed a oxidative ring-opening and fluorination of

• cyclopropanols 91 with Selectfluor to construct β-fluorinated ketones 114 (Scheme 25). In Loh’s work, the Fe(III)- or Ag(I)-catalyzed oxidative ring-opening and fluorination of cyclopropanols 91 via radical rearrangement is disclosed. Notably, this reaction proceeds at room temperature and tolerates a diverse

• array of cyclopropanols. In Zhu’s work, the fluorination of 91a was notable because the seven-membered cyclic product 114a and five-membered cyclic product 114b were formed. Lectka’s group also presented a new approach to β-fluorinated ketones 114 via photocatalyzed ring-opening and fluorination of

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

• -dependent manner the ability to induce the RNase H cleavage of the complementary RNA strand [35]. In continuation of our work we became interested in the fluorination of [4.3.0]bicyclo-DNA [36]. Consequently, the 6’-position of the [4.3.0]bicyclo-DNA was substituted with a difluoromethylene group, and the

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

• 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

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 optimum degree of fluorination of the alkoxide ligands for tungsten alkylidyne complexes [53][54]. It was found that the tungsten alkylidyne complex [MesC≡W{OC(CF3)Me2}3] (Figure 1, WF3) showed excellent catalytic performance not only in the metathesis of internal but also, for the first time with

• fluoroalkoxide ligands [55][56][57]. The difference in the optimum degree of fluorination for molybdenum and tungsten is rationalized by the increased intrinsic electrophilicity of tungsten compared to molybdenum [56]. Based on these insights into the structure–activity relationship of alkyne metathesis

• the ACM are summarized in Table 3. The depicted reactions selectively afforded the unsymmetrical alkynes, corroborating that the bimetallic tungsten complex W2F3 is able to introduce a trimethylsilyl protecting group to alkynes. Conclusion Previously, we have reported the optimum level of fluorination

Cobalt bis(acetylacetonate)–tert-butyl hydroperoxide–triethylsilane: a general reagent combination for the Markovnikov-selective hydrofunctionalization of alkenes by hydrogen atom transfer

• Xiaoshen Ma and
• Seth B. Herzon

Beilstein J. Org. Chem. 2018, 14, 2259–2265, doi:10.3762/bjoc.14.201

• reduction conditions, alkene 3a was transformed to isobutyl p-methoxybenzoate (4a) in 86% yield (entry 1, Table 1). Inspired by the methods of Boger [12] and Hiroya [13], a number of fluorination reagents were examined to achieve hydrofluorination. Although no product was observed using SelectFluor

Applications of organocatalysed visible-light photoredox reactions for medicinal chemistry

• Michael K. Bogdos,
• Emmanuel Pinard and
• John A. Murphy

Beilstein J. Org. Chem. 2018, 14, 2035–2064, doi:10.3762/bjoc.14.179

• either be guided, e.g., selective fluorination of a molecule or can also follow an unselective approach, e.g., fluorination in various positions, but in either case the goal is exploration of SAR directly on a lead structure and easy diversification. In addition, LSF can explore the addition of small

• chemistry is still quite sparse in the literature. Late-stage fluorination protocols are also rare and would be exhaustively used by the pharmaceutical industry. In addition, as has been pointed out in this review

Synthesis of 9-arylalkynyl- and 9-aryl-substituted benzo[b]quinolizinium derivatives by Palladium-mediated cross-coupling reactions

• Siva Sankar Murthy Bandaru,
• Darinka Dzubiel,
• Heiko Ihmels,
• Mohebodin Karbasiyoun,
• Mohamed M. A. Mahmoud and
• Carola Schulzke

Beilstein J. Org. Chem. 2018, 14, 1871–1884, doi:10.3762/bjoc.14.161

• . Nevertheless, this approach appears to be a useful, complementary method to the usual fluorination with KHF2. And it may be suggested that this simple procedure might be used as a general straightforward method for the generation of the synthetically highly useful aryltrifluoroborates. Absorption and emission

Recent advances in hypervalent iodine(III)-catalyzed functionalization of alkenes

• Xiang Li,
• Pinhong Chen and
• Guosheng Liu

Beilstein J. Org. Chem. 2018, 14, 1813–1825, doi:10.3762/bjoc.14.154

• protocol acted as an asymmetric gateway to the useful vicinal diamines. Aminofluorination of alkenes (Difluoroiodo)arenes (Ar-IF2), which can be prepared from HF with iodosoarenes, are hypervalent iodine compounds suitable for the fluorination of alkenes [59]. Based on Nevado’s stoichiometric

• high yields [61]. Recently, Jacobsen and co-workers reported the stereoselective synthesis of syn-β-fluoroaziridine building blocks via a chiral aryl iodide-catalyzed fluorination of allylic amines (Scheme 11) [62]. On the basis of their previous work, the C2-symmetric aryl iodide 31 as a catalyst was

• diastereoselective catalytic fluorination was developed by the same group (Scheme 14, bottom) [65] using the lactate-based resorcinol derivative 44 as the catalyst. By this route chiral 4-fluoroisochromanones 46 could be accomplished in high enantio- and diastereoselectivity. The same I(III) intermediate 47 was

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

• oxylation of ketones reported by Masson et al. α-Fluorination of β-keto esters. Alkynylation of β-ketoesters and amides catalyzed by phase-transfer catalyst. Alkynylation of β-ketoesters and dearomative alkynylation of phenols. Acknowledgements The authors highly acknowledge the financial assistance

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

• ; cyclisation; fluorination; gauche effect; hypervalent iodine; oxazolines; Introduction Marine and terrestrial natural product bioprospecting has established a broad spectrum of structurally complex, bioactive metabolites containing the venerable 2-oxazoline unit [1][2]. This diversity is exemplified by the

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

• [15][16]. The products of these reactions are diversely substituted (ketene) dithiolanes or dithianes which allow a wide range of transformations like oxidation [17], fluorination [18] and cyclative reaction with [19][20] and without conservation [21][22] of the dithioacetal functionality. Besides

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

• Chemical Technology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8502, Japan Department of Chemistry, National Tsing Hua University, 101, Sec 2, Kuang Fu Rd., Hsinchu 300, Taiwan, R.O.C 10.3762/bjoc.14.27 Abstract We herein report that the regioselective anodic fluorination

• 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

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

• actively working in this direction for decades [12][13][16][17][18][19][20][21][22][23]. Our primary goal has been to develop fluorinating and fluoro-functionalized reagents for fluorination [18][19], trifluoromethylation [13][18][19], trifluoromethylthiolation [12][21] and pentafluoroarylation [22][23

Conformational preferences of α-fluoroketones may influence their reactivity

• Graham Pattison

Beilstein J. Org. Chem. 2017, 13, 2915–2921, doi:10.3762/bjoc.13.284

• performed previously to quantify the effects that different α-halogen atoms have on carbonyl reactivity. This paper aims to examine some of the effects that α-halogenation can impart on carbonyl reactivity with a particular emphasis on the effects of α-fluorination. As the most electronegative element

Halogen-containing thiazole orange analogues – new fluorogenic DNA stains

• Aleksey A. Vasilev,
• Meglena I. Kandinska,
• Stanimir S. Stoyanov,
• Stanislava B. Yordanova,
• David Sucunza,
• Juan J. Vaquero,
• Obis D. Castaño,
• Stanislav Baluschev and
• Silvia E. Angelova

Beilstein J. Org. Chem. 2017, 13, 2902–2914, doi:10.3762/bjoc.13.283

• chromophores have been studied by Armitage and co-workers [42][43]. According to these studies the fluorination of the symmetrical [42] and unsymmetrical [43] cyanine dyes results in reduced aggregation and significantly improved the photostability and photophysical properties of the dyes. The authors [43

The synthesis of the 2,3-difluorobutan-1,4-diol diastereomers

• Robert Szpera,
• Nadia Kovalenko,
• Kalaiselvi Natarajan,
• Nina Paillard and
• Bruno Linclau

Beilstein J. Org. Chem. 2017, 13, 2883–2887, doi:10.3762/bjoc.13.280

• confirmed the presence of a primary fluoride. Hence, non-acidic epoxide opening conditions were investigated to circumvent the rearrangement (Scheme 4). Both the use of Bu4NH2F3 [18] and of the TBAF/KHF2 reagent combination [22] were successful (56% and 64%, respectively). While subsequent fluorination

Position-dependent impact of hexafluoroleucine and trifluoroisoleucine on protease digestion

• Susanne Huhmann,
• Anne-Katrin Stegemann,
• Kristin Folmert,
• Damian Klemczak,
• Johann Moschner,
• Michelle Kube and
• Beate Koksch

Beilstein J. Org. Chem. 2017, 13, 2869–2882, doi:10.3762/bjoc.13.279

• , and the aspartate protease pepsin. Results and Discussion Peptide design and structure To elucidate the impact of fluorination on proteolytic stability we previously designed the peptide FA (Figure 1b) that comprises the substrate specificities of α-chymotrypsin and pepsin [39][40]. Consequently, the

• hydrophobic than their hydrocarbon analogues [44][45]. Furthermore, fluorine substitution has been shown to polarize neighboring C–H bonds (here the γ-hydrogens) that could affect noncovalent interactions [9][11]. Since the amino acids used here (Figure 1a) differ in their degree of fluorination, spatial

• ’ substituted peptides, along with the control peptide FA, are almost or completely digested, P2’-HfLeuFA is still present to about 76%. In this case fluorination leads to protection against proteolysis by pepsin. Hfleu is obviously not well accommodated in this position. As already observed for position P1

Nucleophilic dearomatization of 4-aza-6-nitrobenzofuroxan by CH acids in the synthesis of pharmacology-oriented compounds

• Alexey M. Starosotnikov,
• Dmitry V. Shkaev,
• Maxim A. Bastrakov,
• Ivan V. Fedyanin,
• Svyatoslav A. Shevelev and
• Igor L. Dalinger

Beilstein J. Org. Chem. 2017, 13, 2854–2861, doi:10.3762/bjoc.13.277

• the singlet at 2.34 ppm belongs to the methyl group. This is consistent with known data on fluorinated diketones: stability of the enol tautomer increases with the degree of fluorination [29][30]. Apparently this could explain the difference in ratios of tautomers in addition products of structurally

The use of 4,4,4-trifluorothreonine to stabilize extended peptide structures and mimic β-strands

• Yaochun Xu,
• Isabelle Correia,
• Tap Ha-Duong,
• Nadjib Kihal,
• Jean-Louis Soulier,
• Julia Kaffy,
• Benoît Crousse,
• Olivier Lequin and
• Sandrine Ongeri

Beilstein J. Org. Chem. 2017, 13, 2842–2853, doi:10.3762/bjoc.13.276

• attracting increasing interest as around 100 peptides are on the pharmaceutical market [2]. Peptide fluorination has appeared as a general and effective strategy to enhance the stability against enzymatic, chemical and thermal denaturation while generally retaining the original structure and biological

Recent progress in the racemic and enantioselective synthesis of monofluoroalkene-based dipeptide isosteres

• Myriam Drouin and
• Jean-François Paquin

Beilstein J. Org. Chem. 2017, 13, 2637–2658, doi:10.3762/bjoc.13.262

• ]-Gly isosteres with control of the stereochemistry at the side chain will be discussed in this section. In particular, olefination reaction, defluorinative reduction of 3,3-difluoropropene derivatives and electrophilic fluorination of alkenylstannanes are presented. Pannecoucke’s group described the

• final saponification gave the monofluoroalkene-based dipeptide isostere 61. Finally, Fürstner’s group developed the silver-mediated fluorination of functionalized alkenylstannanes to access monofluoroalkenes [42]. Hydrostannation of the N-protected ynamines 62 followed by electrophilic fluorination with

• Selectfluor gave the corresponding (Z)-monofluoroalkenes 64 in good yields (Table 2). The reported results showed that the methodology was suitable to replace an amide bond and could be used in late-stage fluorination to access monofluoroalkene-based dipeptide isosteres. Xaa-ψ[CF=CH]-Xaa The preparation of