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

Trifluoromethyl ethers – synthesis and properties of an unusual substituent

• Frédéric R. Leroux,
• Baptiste Manteau,
• Jean-Pierre Vors and
• Sergiy Pazenok

Beilstein J. Org. Chem. 2008, 4, No. 13, doi:10.3762/bjoc.4.13

• , essentially trichloromethylanisole is obtained [20]. The fluorination of the trichloromethyl ether succeeds then easily as shown above. The chlorination/fluorination sequence described above can be simplified by producing the trichloromethyl aryl ethers without isolation and through in situ conversion into

• developed an approach based on the readily accessible, although highly toxic aryl chlorothionoformates 1. They can be cleanly converted by chlorination into trichloromethyl aryl ethers [17]. This step is then followed by fluorination using antimony trifluoride and a catalytic amount of antimony

• desulfurization-fluorination has been disclosed by Hiyama [24][25][26][27]. When dithiocarbonates (2, xanthogenates) are exposed to a huge excess of hydrogen fluoride-pyridine and 1,3-dibromo-5,5-dimethylhydantoin, trifluoromethyl ethers form in moderate to excellent yields (Scheme 5 and Table 5). What makes this

Themed series in organo- fluorine chemistry

• David O'Hagan

Beilstein J. Org. Chem. 2008, 4, No. 11, doi:10.3762/bjoc.4.11

• practiced particularly when tuning the properties of molecules for specialist functions. Of particular prominence is the role fluorine substitution finds in pharmaceutical development [1], and selective fluorination has made a major contribution to the bioactivity of a wide range of agrochemical products [2

• ]. Organo-fluorine compounds have also found a significant role in soft materials chemistry such as liquid crystals, photoresist polymers and self assembling monolayers [3]. Allied to this breadth of activity is a steady development in the number and range of fluorination reagents and methodologies. DAST

Single and double stereoselective fluorination of (E)-allylsilanes

• Marcin Sawicki,
• Angela Kwok,
• Matthew Tredwell and
• Véronique Gouverneur

Beilstein J. Org. Chem. 2007, 3, No. 34, doi:10.1186/1860-5397-3-34

• Marcin Sawicki Angela Kwok Matthew Tredwell Veronique Gouverneur University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, UK 10.1186/1860-5397-3-34 Abstract Acyclic allylic monofluorides were prepared by electrophilic fluorination of branched (E)-allylsilanes with

• Selectfluor. These reactions proceeded with efficient transfer of chirality from the silylated to the fluorinated stereocentre. Upon double fluorination, an unsymmetrical ethyl syn-2,5-difluoroalk-3-enoic ester was prepared, the silyl group acting as an anti stereodirecting group for the two C-F bond forming

• events. Findings Asymmetric C-F bond formation continues to challenge chemists, inspiring the development of increasingly effective protocols for stereocontrolled fluorination. [1][2][3][4][5][6][7][8][9][10][11] Studies from our laboratory illustrated that allylsilanes undergo electrophilic

Contemporary organosilicon chemistry

• Steve Marsden

Beilstein J. Org. Chem. 2007, 3, No. 4, doi:10.1186/1860-5397-3-4

• fluorination, cyclopropane chemistry and the development of silicon-containing drug candidates should be available shortly. Be sure to check back to keep abreast of the latest developments as the Series grows. Steve Marsden Guest Editor

The vicinal difluoro motif: The synthesis and conformation of erythro- and threo- diastereoisomers of 1,2-difluorodiphenylethanes, 2,3-difluorosuccinic acids and their derivatives

• David O'Hagan,
• Henry S. Rzepa,
• Martin Schüler and
• Alexandra M. Z. Slawin

Beilstein J. Org. Chem. 2006, 2, No. 19, doi:10.1186/1860-5397-2-19

• . Early synthetic methods to vicinal difluoro compounds have involved direct fluorination of alkenes with for eg. elemental fluorine (F2) [4] or XeF2 [5]. Such methods however are either difficult to carry out in a standard laboratory environment or they suffer from very poor stereoselectivity. The direct

• (bromo/iodo)fluorination of alkenes followed by halide substitution with silver fluoride [15]. The reaction has been applied to a variety of alkenes some of which (eg 6-9) are illustrated in Scheme 3. We were interested in accessing diastereomerically pure samples of erythro- and threo- 2,3

• -difluorosuccinic acids 19. The preparation of stereoisomers of 2,3-difluorosuccinic acids, has involved conversions of tartaric acids (esters) [6][7], as described above in Scheme 1. Other approaches have involved the direct fluorination of fumaric acid [16] and the catalytic hydrogenation of 2,3-difluoromaleic

Stereoselective α-fluoroamide and α-fluoro- γ-lactone synthesis by an asymmetric zwitterionic aza-Claisen rearrangement

• Kenny Tenza,
• Julian S. Northen,
• David O'Hagan and
• Alexandra M. Z. Slawin

Beilstein J. Org. Chem. 2005, 1, No. 13, doi:10.1186/1860-5397-1-13

• Background Asymmetric introduction of fluorine α-to a carbonyl has become popular recently, largely because the direct fluorination of enolates by asymmetric electrophilic fluorinating reagents has improved, and as a result such compounds are becoming attractive synthons. We have sought an alternative but

• are finding increasing utility in pharmaceutical, fine chemicals and materials research. The zwitterionic aza-Claisen rearrangement proved to be an effective and competitive complement to asymmetric electrophilic fluorination strategies and provides access to versatile synthetic intermediates with

• -actives of pharmaceutical interest.[15] It is well known too that selective fluorination can improve pharmacokinetics and the fluorine substituent can often modify bio-activity in an advantageous manner.[16] For example in the structural series relevant to this study the α-fluorinated-γ-lactone 5 is a key