Recent advances in transition metal-catalyzed Csp²-monofluoro-, difluoro-, perfluoromethylation and trifluoromethylthiolation

• Grégory Landelle,
• Armen Panossian,
• Sergiy Pazenok,
• Jean-Pierre Vors and
• Frédéric R. Leroux

Beilstein J. Org. Chem. 2013, 9, 2476–2536, doi:10.3762/bjoc.9.287

• , 69263 Lyon, Cedex 09, France 10.3762/bjoc.9.287 Abstract In the last few years, transition metal-mediated reactions have joined the toolbox of chemists working in the field of fluorination for Life-Science oriented research. The successful execution of transition metal-catalyzed carbon–fluorine bond

• molecules. Recent years have witnessed exciting developments in mild catalytic fluorination techniques. In contrast to carbon–carbon, carbon–oxygen and carbon–nitrogen bond formations, catalytic carbon–fluorine bond formation remained an unsolved challenge, mainly due to the high electronegativity of

• fluorine, its hydration and thus reduced nucleophilicity [21]. The importance of this developing research field is reflected by the various review articles which have been published dealing with transition metal mediated or catalyzed fluorination [22][23][24], difluoromethylation [24], and

Structure of 1,5-benzodiazepinones in the solid state and in solution: Effect of the fluorination in the six-membered ring

• Marta Pérez-Torralba,
• Rosa M. Claramunt,
• M. Ángeles García,
• Concepción López,
• M. Carmen Torralba,
• M. Rosario Torres,
• Ibon Alkorta and
• José Elguero

Beilstein J. Org. Chem. 2013, 9, 2156–2167, doi:10.3762/bjoc.9.253

Synthesis of enantiomerically pure (2S,3S)-5,5,5-trifluoroisoleucine and (2R,3S)-5,5,5-trifluoro-allo-isoleucine

• Holger Erdbrink,
• Elisabeth K. Nyakatura,
• Susanne Huhmann,
• Ulla I. M. Gerling,
• Dieter Lentz,
• Beate Koksch and
• Constantin Czekelius

Beilstein J. Org. Chem. 2013, 9, 2009–2014, doi:10.3762/bjoc.9.236

• fluorinated amino acids to be less hydrophobic than their surface area would suggest. α-Helix propensity of L-5-F3Ile In general, fluorination of amino acids leads to a dramatic decrease in helix propensity [8][9][13]. As the extreme of this effect, we previously reported the complete loss of helix propensity

• the K-4’-F3Ile spectrum demonstrates a complete loss of helicity in the corresponding peptide (Figure 2). The drastic decrease in helix propensity upon fluorination has been previously attributed to a possible burial of fluorocarbon side chains in the unfolded state of the model peptide [8]. The

• increased in comparison to (2S,3S)-4,4,4-trifluoroisoleucine. Thus, fluorinating isoleucine’s δ-position rescues α-helix propensity, while the fluorination of isoleucine’s β-branched methyl group abolishes it. It remains to be elucidated as to what extent helix propensity affects protein stability at buried

Efficient regio- and stereoselective access to novel fluorinated β-aminocyclohexanecarboxylates

• Loránd Kiss,
• Melinda Nonn,
• Reijo Sillanpää,
• Santos Fustero and
• Ferenc Fülöp

Beilstein J. Org. Chem. 2013, 9, 1164–1169, doi:10.3762/bjoc.9.130

• –fluorine or oxo–fluorine exchange. Keywords: amino acids; epoxidation; fluorination; hydroxylation; stereoselective reaction; Introduction Fluorine chemistry is an expanding area of research that has generated increasing interest in pharmaceutical and medicinal chemistry in recent years because of its

• follows two different strategies. One is based on regio- and stereoselective hydroxylation via iodooxazine formation, followed by fluorination, while the other includes stereoselective epoxidation and regioselective oxirane opening, followed by hydroxy–fluorine exchange. In the former protocol, amino

Synthesis of SF₅-containing benzisoxazoles, quinolines, and quinazolines by the Davis reaction of nitro-(pentafluorosulfanyl)benzenes

• Petr Beier and
• Tereza Pastýříková

Beilstein J. Org. Chem. 2013, 9, 411–416, doi:10.3762/bjoc.9.43

• of SF5 organics is their limited availability. In SF5-aromatics, para- and meta-nitro-(pentafluorosulfanyl)benzenes (3 and 4) (Figure 1) are available by the direct fluorination of the corresponding bis(nitrophenyl)disulfides [18][19][20], and several other SF5-benzenes are available through

Total synthesis and biological evaluation of fluorinated cryptophycins

• Christine Weiß,
• Tobias Bogner,
• Benedikt Sammet and
• Norbert Sewald

Beilstein J. Org. Chem. 2012, 8, 2060–2066, doi:10.3762/bjoc.8.231

• [10][11]. Fluorinated drugs are gaining increasing importance, and currently about 20% of all pharmaceuticals on the world market contain fluorine substituents [12][13]. Fluorination is supposed to enhance bioavailability and receptor selectivity. The van der Waals-radius of a fluorine substituent

Recyclable fluorous cinchona alkaloid ester as a chiral promoter for asymmetric fluorination of β-ketoesters

• Wen-Bin Yi,
• Xin Huang,
• Zijuan Zhang,
• Dian-Rong Zhu,
• Chun Cai and
• Wei Zhang

Beilstein J. Org. Chem. 2012, 8, 1233–1240, doi:10.3762/bjoc.8.138

• , Boston, MA 02125, USA 10.3762/bjoc.8.138 Abstract A fluorous cinchona alkaloid ester has been developed as a chiral promoter for the asymmetric fluorination of β-ketoesters. It has comparable reactivity and selectivity to the nonfluorous versions of cinchona alkaloids and can be easily recovered from

• the reaction mixture by simple fluorous solid-phase extraction (F-SPE) and used for the next round of reaction without further purification. Keywords: asymmetric fluorination; β-ketoester; fluorous cinchona ester; organocatalysis; recyclable chiral promoter; Introduction Fluorinated organic

• organofluorine chemistry plays an important role in the life sciences [3][4]. A fluorine atom has been introduced to the α-position of some biologically interesting β-ketoesters, such as erythromycin and sesquiterpenic drimane (Figure 1) [5][6]. The achiral fluorination of β-ketoesters can be achieved by

Highly selective synthesis of (E)-alkenyl-(pentafluorosulfanyl)benzenes through Horner–Wadsworth–Emmons reaction

• George Iakobson and
• Petr Beier

Beilstein J. Org. Chem. 2012, 8, 1185–1190, doi:10.3762/bjoc.8.131

• aromatic meta- and para-nitro-(pentafluorosufanyl)benzenes (1 and 2) are made by direct fluorination of the corresponding bis(nitrophenyl)disulfides [10][11][12]. A recent report also described a two step synthesis of SF5-benzenes from diaryl disulfides avoiding the use of elemental fluorine [13]. While

Discovery of practical production processes for arylsulfur pentafluorides and their higher homologues, bis- and tris(sulfur pentafluorides): Beginning of a new era of “super-trifluoromethyl” arene chemistry and its industry

• Teruo Umemoto,
• Lloyd M. Garrick and
• Norimichi Saito

Beilstein J. Org. Chem. 2012, 8, 461–471, doi:10.3762/bjoc.8.53

• stepwise fluorination of diphenyl disulfide with expensive silver difluorides (AgF2) in a fluorocarbon solvent [3]. However, the yield was only 9%. Since then, many substituted phenylsulfur pentafluorides have been prepared by this method, but still with very low yields [3][20][31][32]. In 2000, a new

Synthesis of fluorinated maltose derivatives for monitoring protein interaction by ¹⁹F NMR

• Michaela Braitsch,
• Hanspeter Kählig,
• Georg Kontaxis,
• Michael Fischer,
• Toshinari Kawada,
• Robert Konrat and
• Walther Schmid

Beilstein J. Org. Chem. 2012, 8, 448–455, doi:10.3762/bjoc.8.51

• studies of protein–ligand interaction interfaces. Keywords: fluorination; 19F NMR; maltose-binding protein (MBP); maltose derivatives; protein interaction; Introduction In recent years, we have witnessed significant improvements in NMR spectroscopy, especially as a powerful tool for studying protein

• anomeric acetyl group of compound 2 with hydrazine acetate [29] yielding derivative 7, followed by nucleophilic fluorination with DAST [30][31] generating the diasteriomeric mixture 8. The α-anomer was isolated by HPLC and subsequent Zemplén saponification of the remaining acetate protecting groups yielded

• regioselective reductive ring opening of benzylidene acetals in the maltose derivative 11 was performed with a complex of BH3/Bu2BOTf at −70 °C [32][33]. Fluorination with DAST [34][35] was performed in a sealed tube for 1 h at 80 °C under microwave conditions. The deprotection of the benzyl group was achieved

Valence isomerization of cyclohepta-1,3,5-triene and its heteroelement analogues

• Helen Jansen,
• J. Chris Slootweg and
• Koop Lammertsma

Beilstein J. Org. Chem. 2011, 7, 1713–1721, doi:10.3762/bjoc.7.201

• -aromatic tropylium cation [46], which has a NICS(1) value of −8.2 ppm. Adding electronegative substituents enhances the effect, and fully aromatic systems are obtained after complete fluorination of the heteropines (Figure 1) [50]. In contrast, the flattened transition structures for ring inversion of

Development of the titanium–TADDOLate-catalyzed asymmetric fluorination of β-ketoesters

• Lukas Hintermann,
• Mauro Perseghini and
• Antonio Togni

Beilstein J. Org. Chem. 2011, 7, 1421–1435, doi:10.3762/bjoc.7.166

• Lewis acids catalyze the α-fluorination of β-ketoesters by electrophilic N–F-fluorinating reagents. Asymmetric catalysis with TADDOLato–titanium(IV) dichloride (TADDOL = α,α,α',α'-tetraaryl-(1,3-dioxolane-4,5-diyl)-dimethanol) Lewis acids produces enantiomerically enriched α-fluorinated β-ketoesters in

• TADDOL ligand structure on the catalytic activity and enantioselectivity were investigated. The absolute configuration of several fluorination products was assigned through correlation. Evidence for ionization of the catalyst complex by chloride dissociation, followed by generation of titanium β

• -ketoenolates as key reaction intermediates, was obtained. Based on the experimental findings, a general mechanistic sketch and a steric model of induction are proposed. Keywords: Asymmetric catalysis; fluorination; fluoroorganic compounds; TADDOL; titanium; Introduction Fluoroorganic compounds have peculiar

Combination of gold catalysis and Selectfluor for the synthesis of fluorinated nitrogen heterocycles

• Antoine Simonneau,
• Pierre Garcia,
• Jean-Philippe Goddard,
• Virginie Mouriès-Mansuy,
• Max Malacria and
• Louis Fensterbank

Beilstein J. Org. Chem. 2011, 7, 1379–1386, doi:10.3762/bjoc.7.162

• the elucidation of the mechanism and Selectfluor was suggested to play the double role of promoting the oxidation of gold(I) to a gold(III) active species and also the electrophilic fluorination of the enamine intermediates. Keywords: cycloisomerization reactions; fluorinated pyrrolidines; gold

• explained either by direct fluorination of the enamine resulting from the gold-promoted alkyne hydroamination or by oxidation of the intermediate vinyl gold(I) complex by Selectfluor into a gold(III) fluoride species followed by a reductive elimination. Moreover, the formation of C(sp2)–F bonds, either by

• chemists. Recently also, the literature has featured valuable access routes to pyrrolidine promoted by catalytic systems [18][19][20][21][22][23][24][25][26]. Results and Discussion Studies on the scope and limitation of the cyclization–fluorination sequence were carried out with Selectfluor as a source of

Continuous gas/liquid–liquid/liquid flow synthesis of 4-fluoropyrazole derivatives by selective direct fluorination

• Jessica R. Breen,
• Graham Sandford,
• Dmitrii S. Yufit,
• Judith A. K. Howard,
• Jonathan Fray and
• Bhairavi Patel

Beilstein J. Org. Chem. 2011, 7, 1048–1054, doi:10.3762/bjoc.7.120

• : continuous flow reactions; fluorine; fluoropyrazole; gas-liquid flow reactor; selective direct fluorination; Introduction Organic systems which bear fluorine atoms are used in an ever widening range of applications in the life sciences. Many commercially significant pharmaceutical and agrochemical products

• fluorination methodology, we have been exploring the use of elemental fluorine, a previously underused reagent in organic chemistry, for the synthesis of fluoroorganic systems [8][9][10]. Methodologies for the preparation of, for example, a range of fluorinated aliphatic [11], carbonyl [12][13][14], aromatic

• [15] and heterocyclic [16][17] systems have been established and scaled-up by our industrial collaborators for use in the synthesis of commercially important pharmaceutical intermediates [18]. As part of our studies, aimed at further control of the direct fluorination procedures for larger scale

Aromatic and heterocyclic perfluoroalkyl sulfides. Methods of preparation

• Vladimir N. Boiko

Beilstein J. Org. Chem. 2010, 6, 880–921, doi:10.3762/bjoc.6.88

• NO2, CF3 or COCl in the aromatic ring of trichlorothioanisole does not influence the fluorination and the reaction is not hindered by bulky ortho-substituents e.g., phthalic acid imide [53] or N-substituted anilines [54]. Other reactive substituents, for example 3-SCCl3 or 4-COCl are also fluorinated

• reaction of anhydrous hydrogen fluoride with aryl α,α,β-trichloroisobutyl sulfide at 20 °C leads only to substitution of the α-chlorine atoms, whilst at a higher temperature and pressure a more complete fluorination with rearrangement is observed [67] (Scheme 4). Hydrogen fluoride/fluoride complexes such

Shelf-stable electrophilic trifluoromethylating reagents: A brief historical perspective

• Norio Shibata,
• Andrej Matsnev and
• Dominique Cahard

Beilstein J. Org. Chem. 2010, 6, No. 65, doi:10.3762/bjoc.6.65

• (or selenides) with m-chloroperbenzoic acid followed by cyclization of the corresponding sulfoxides (or selenoxides) either with triflic anhydride or by direct fluorination with 10% F2/N2 in the presence of one equivalent of triflic acid or HBF4 (Scheme 2). The tellurophenium salt 7 was synthesized in

Synthesis and crystallographic analysis of meso-2,3-difluoro-1,4-butanediol and meso-1,4-dibenzyloxy-2,3-difluorobutane

• Bruno Linclau,
• Leo Leung,
• Jean Nonnenmacher and
• Graham Tizzard

Beilstein J. Org. Chem. 2010, 6, No. 62, doi:10.3762/bjoc.6.62

• ; epoxide opening; gauche effect; organofluorine; vicinal difluoride; Introduction Selective fluorination of bioactive compounds is a widely employed strategy for the modification of their properties [1]. Fluorine atoms can be introduced to modulate the pKa of adjacent acidic and basic functional groups as

• 1,3-C–F bonds are destabilised. As an application, liquid crystals have been prepared containing a vicinal difluoride motif [14][17][18]. Efficient stereodefined synthesis of vicinal difluoride moieties is not straightforward. Direct methods include fluorination of alkenes with F2 [19], XeF2 [20], or

Prins fluorination cyclisations: Preparation of 4-fluoro-pyran and -piperidine heterocycles

• Guillaume G. Launay,
• Alexandra M. Z. Slawin and
• David O'Hagan

Beilstein J. Org. Chem. 2010, 6, No. 41, doi:10.3762/bjoc.6.41

• -piperidines were investigated. The products were obtained in good yields, but only with moderate diastereoselectivity. These Prins fluorination reactions can be accelerated under microwave conditions. The study extends the Prins fluorination methodology for the generation of the C–F bond in heterocycles

• limited range of fluorination reagents and methodologies available to synthetic organic chemistry, and novel methods for introducing fluorine into organic molecules continue to be valuable [4]. In this paper we focus on extending the scope of the Prins fluorination reaction as a synthetic methodology. The

• noted separately by Jaber et al. [12] and subsequently by Kataoka et al. [13]. For example, homoallylic alcohol 1 was converted to pyran 2 with a high diastereoselectivity (Scheme 1) [12]. Most recently, oxa-, aza- and thia-Prins fluorination cyclisations have been carried out using ionic liquid

Preparation, structures and preliminary host–guest studies of fluorinated syn-bis-quinoxaline molecular tweezers

• Markus Etzkorn,
• Jacob C. Timmerman,
• Matthew D. Brooker,
• Xin Yu and
• Michael Gerken

Beilstein J. Org. Chem. 2010, 6, No. 39, doi:10.3762/bjoc.6.39

• modifications in the pincer sidewalls (degree of fluorination). Although only the larger cyclooctadiene-derived scaffolds 16a–d could function as molecular tweezers, we also synthesized the fluorinated cyclohexadiene-derived compounds 15b–d with their smaller π-π–distances. A Diels–Alder reaction of

• between 312–316 nm with a poorly resolved vibrational structure. The spectra of the cyclohexadiene-derived scaffolds 15 and the cyclooctadiene-derived frameworks 16 are very similar. Within each series we could not observe a gradual blue-shift for the electronic transitions as the degree of fluorination

• –c, depicting the inversion of the electrostatic potential in the pincer subunits upon increasing the degree of fluorination. NMR titration experiments with electron-rich arenes (1,4-dimethoxybenzene, 1,3,5-trimethoxybenzene, N,N-dimethylaniline, N,N,N′,N′-tetramethyl-p-phenylenediamine) were carried

The C–F bond as a conformational tool in organic and biological chemistry

• Luke Hunter

Beilstein J. Org. Chem. 2010, 6, No. 38, doi:10.3762/bjoc.6.38

• properties of functional molecules to be optimised through selective fluorination chemistry. This concept has been demonstrated in diverse areas including medicine, catalysis, materials science and biotechnology. It is hoped that the examples highlighted in this review have persuaded the reader of the great

Ring-alkyl connecting group effect on mesogenic properties of p-carborane derivatives and their hydrocarbon analogues

• Aleksandra Jankowiak,
• Piotr Kaszynski,
• William R. Tilford,
• Kiminori Ohta,
• Adam Januszko,
• Takashi Nagamine and
• Yasuyuki Endo

Beilstein J. Org. Chem. 2009, 5, No. 83, doi:10.3762/bjoc.5.83

• fluorination [18][19] on mesophase stability, and also the effectiveness of shielding of a lateral substituent [8][16][20] and chirality transfer phenomena [17]. Results of these studies are important for the design of new materials and optimizing of their properties for applications. During our investigation

Three step synthesis of single diastereoisomers of the vicinal trifluoro motif

• Vincent A. Brunet,
• Alexandra M. Z. Slawin and
• David O'Hagan

Beilstein J. Org. Chem. 2009, 5, No. 61, doi:10.3762/bjoc.5.61

• diastereoisomeric series of this motif. The route is a significant improvement on an earlier six step strategy. Keywords: C–F bond; organo–fluorine chemistry; stereospecific fluorination; vicinal trifluoro motif; Introduction Selective fluorination is an important strategy for the design of performance molecules

• manner. Conversion of the free hydroxyl group to fluorine would generate α-fluoro-epoxides B. Epoxide ring opening with an HF source could then provide difluoroalcohols C. Insertion of the third fluorine would reasonably be achieved by fluorination of the free hydroxyl group of C to generate D. Such a

• and relative stereochemistry of the crystalline threo-isomer (2R,3S,4S)-7a was confirmed by X-ray structure analysis as shown in Figure 2. With a strategy to access both stereoisomeric series of the allylic alcohol epoxides A in place, the fluorination reactions were then explored. The fluorination of

Synthesis of phosphonate and phostone analogues of ribose-1-phosphates

• Pitak Nasomjai,
• David O'Hagan and
• Alexandra M. Z. Slawin

Beilstein J. Org. Chem. 2009, 5, No. 37, doi:10.3762/bjoc.5.37

• are the same involving installation of the dimethyl phosphonate moiety on a 2,3-O-isopropylidene ribofuranoside via a Wadsworth-Emmons reaction [4]. Route A (Scheme 2) started with acetonide protection of D-ribonic-γ-lactone (12) to generate 2,3-isopropylidene 14 [5]. Fluorination of the free 5

Efficient 1,4-addition of α-substituted fluoro(phenylsulfonyl)methane derivatives to α,β-unsaturated compounds

• G. K. Surya Prakash,
• Xiaoming Zhao,
• Sujith Chacko,
• Fang Wang,
• Habiba Vaghoo and
• George A. Olah

Beilstein J. Org. Chem. 2008, 4, No. 17, doi:10.3762/bjoc.4.17

• active methylene derivatives has attracted considerable attention particularly in the field of medicinal chemistry [5][6]. One of the major interests in our group has focused on developing new fluorination reagents or fluorinated building blocks for preparation of fluorine-substituted compounds [7][8][9

DBFOX- Ph/metal complexes: Evaluation as catalysts for enantioselective fluorination of 3-(2-arylacetyl)-2-thiazolidinones

• Takehisa Ishimaru,
• Norio Shibata,
• Dhande Sudhakar Reddy,
• Takao Horikawa,
• Shuichi Nakamura and
• Takeshi Toru

Beilstein J. Org. Chem. 2008, 4, No. 16, doi:10.3762/bjoc.4.16

• enantioselective fluorination of 3-(2-arylacetyl)-2-thiazolidinones 1 with N-fluorobenzenesulfonimide (NFSI) by DBFOX-Ph/metal complexes under a variety of conditions. After optimization of the metal salts, solvents and additives, we found that the fluoro-2-thiazolidinones 2 were obtained in good to high yields

• with moderate to good enantioselectivities (up to 78% ee) when the reaction was carried out in the presence of DBFOX-Ph (11 mol%), Ni(ClO4)2·6H2O (10 mol%) and 2,6-lutidine (0 or 1.0 equiv) in CH2Cl2. Keywords: fluorination; enantioselective; nickel; Lewis acid; catalyst; Background Enantioselective

• electrophilic fluorination represents an important and straightforward strategy for C-F bond formation at a carbon stereocenter, providing easy access to chiral fluoro-organic compounds [1][2]. Due to the significance of chiral fluoro-organic compounds, such as fluorinated quinolones [3][4] and liquid crystals