C–H bond halogenation catalyzed or mediated by copper: an overview

• Wenyan Hao and
• Yunyun Liu

Beilstein J. Org. Chem. 2015, 11, 2132–2144, doi:10.3762/bjoc.11.230

• of many fluorinated chemicals. Accordingly, C–H fluorination reactions also become an issue of broad concern as such a transformation offers a straightforward route for rapid synthesis of diversity-enriched fluorinated products. On the basis of the Pd-catalyzed oxidative C–H fluorination of

• functionalized 8-methylquinolinyl substrates reported by Sanford et al. [43], Daugulis and co-worker [44] established in 2013 a copper-catalyzed arene C–H o-fluorination of N-(quinolin-8-yl)benzamides 14. The mono- and/or difluorination took place in the presence of CuI, N-methylmorpholine N-oxide (NMO) and

• promoted the 1,5-H abstraction and atom transfer process in the form of SET via free radical 71. In 2012, Lectka and co-workers [69] reported an interesting C–H fluorination method for alkynes 72 via a Cu-catalyzed aliphatic C(sp3)–H functionalization. Monofluorinated products 73 were obtained by employing

Lewis acid-promoted hydrofluorination of alkynyl sulfides to generate α-fluorovinyl thioethers

• Davide Bello and
• David O'Hagan

Beilstein J. Org. Chem. 2015, 11, 1902–1909, doi:10.3762/bjoc.11.205

• . When 70% HF·Py was employed, up to 70% conversion was achieved, but with over-fluorination to generate only the difluoromethylene thioether 4a (not isolated). In view of the lack of control with HF·Py attention turned to triethylamine trihydrogen fluoride (3HF·Et3N). This proved unsuccessful presumably

Chemoselective O-acylation of hydroxyamino acids and amino alcohols under acidic reaction conditions: History, scope and applications

• Tor E. Kristensen

Beilstein J. Org. Chem. 2015, 11, 446–468, doi:10.3762/bjoc.11.51

• eventually open up for just such a possibility. Trifluoroacetic acid (CF3CO2H) has been known since 1922 [21], but its widespread application was only made possible sometime later, much due to the development of electrochemical fluorination processes (Simons process) for production of organofluorine

Synthesis and biological evaluation of a novel MUC1 glycopeptide conjugate vaccine candidate comprising a 4’-deoxy-4’-fluoro-Thomsen–Friedenreich epitope

• Manuel Johannes,
• Maximilian Reindl,
• Bastian Gerlitzki,
• Edgar Schmitt and
• Anja Hoffmann-Röder

Beilstein J. Org. Chem. 2015, 11, 155–161, doi:10.3762/bjoc.11.15

• [48] in excellent 85% yield over three steps. Acid-catalyzed 4,6-benzylidene deprotection and 6-O-tritylation then afforded alcohol 5 (83% over two steps), which was further converted into an intermediate triflate for subsequent nucleophilic fluorination with TBAF to provide the 4-fluorothioglycoside

• enzymatic stability upon fluorination, glycosyl amino acid 11 was incorporated at position 6 of a full 20mer MUC1 tandem repeat domain by SPPS following a previously published procedure [44] (Scheme 2 and Supporting Information File 1). Thus, by using HBTU/HOBt/DIPEA in DMF for the coupling of the standard

Highly selective electrochemical fluorination of dithioacetal derivatives bearing electron-withdrawing substituents at the position α to the sulfur atom using poly(HF) salts

• Bin Yin,
• Shinsuke Inagi and
• Toshio Fuchigami

Beilstein J. Org. Chem. 2015, 11, 85–91, doi:10.3762/bjoc.11.12

• Bin Yin Shinsuke Inagi Toshio Fuchigami Department of Electronic Chemistry, Tokyo Institute of Technology, Nagatsuta, Midori-ku, Yokohama 226-8502, Japan 10.3762/bjoc.11.12 Abstract Anodic fluorination of dithioacetals bearing electron-withdrawing ester, acetyl, amide, and nitrile groups at their

• α-positions was comparatively studied using various supporting poly(HF) salts like Et3N·nHF (n = 3–5) and Et4NF·nHF (n = 3–5). In the former two cases, the corresponding α-fluorination products or fluorodesulfurization products were obtained selectively depending on supporting poly(HF) salts used

• . In sharp contrast, in the latter two cases, fluorination product selectivity was strongly affected by the electron-withdrawing ability of α-substituents: A dithioacetal bearing a relatively weak electron-withdrawing amide group provided a fluorodesulfurization product selectively while a dithioacetal

The Shono-type electroorganic oxidation of unfunctionalised amides. Carbon–carbon bond formation via electrogenerated N-acyliminium ions

• Alan M. Jones and
• Craig E. Banks

Beilstein J. Org. Chem. 2014, 10, 3056–3072, doi:10.3762/bjoc.10.323

• fluorodesulfurization occurred (Scheme 7). Direct Shono-type fluorination of an α-carbon to an amide has also been reported [37]. Technical advances in the Shono electroxidation reaction The “cation-pool” method for the generation of N-acyliminium ions [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] has

Recent advances in the electrochemical construction of heterocycles

• Robert Francke

Beilstein J. Org. Chem. 2014, 10, 2858–2873, doi:10.3762/bjoc.10.303

• (ArSSAr)+ species can either be generated prior to addition of 31 or in presence of the substrates. The use of tetrafluoroborate salts is associated with low yields due to fluorination of intermediate 34 and therefore has to be avoided. In contrast, good results are obtained when the reaction is carried

Supercritical carbon dioxide: a solvent like no other

• Jocelyn Peach and
• Julian Eastoe

Beilstein J. Org. Chem. 2014, 10, 1878–1895, doi:10.3762/bjoc.10.196

• microemulsion stability and the effects of fluorination have also been investigated, with studies showing that longer surfactant tails lead to increased stability in microemulsions. This is possibly due to increased interfacial activity and the changing of the terminal group from -CF3 to -CF2H reduces ease of

• di-CF1 having the minimum level of fluorination, Table 1, compounds 2–5), and a HC control analogue (di-C5SS, Table 1, compound 6) containing no fluorine. The study also looked at the effects of replacing a terminal fluorine atom with hydrogen (n-CF3 to n-CF2H), hereby introducing a dipole moment at

Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules

• Thilo Focken and
• Stephen Hanessian

Beilstein J. Org. Chem. 2014, 10, 1848–1877, doi:10.3762/bjoc.10.195

• -monofluoroalkylphosphonic acids were synthesized by diastereoselective fluorination of phosphonamides bearing (−)-ephedrine as chiral auxiliary, originally introduced by Sting and Steglich for the synthesis of aminoalkylphosphonic acids [7] (Scheme 16). Thus, condensation of the phosphonic acid dichloride obtained from

• 134a,b with ephedrine yielded a separable mixture of diastereomeric phosphonamides, trans-135a,b and cis-136a,b. The fluorination with N-fluorobenzenesulfonimide (NFSI) of either trans-135a or cis-136a was found to be strongly dependant on the base used to generate the phosphonamidate anion. The best

• diastereomeric ratio of 3.8:1 (58% de) in favor of trans-S-137a was observed with NaHMDS as base in the reaction of trans-135a. The cis-isomer 136a gave a similar result with NaHMDS, whereas the fluorination of m-(phenyl)benzyl phosphonamides 135b and 136b proved to be less selective. Although the

Syntheses of fluorooxindole and 2-fluoro-2-arylacetic acid derivatives from diethyl 2-fluoromalonate ester

• Antal Harsanyi,
• Graham Sandford,
• Dmitri S. Yufit and
• Judith A.K. Howard

Beilstein J. Org. Chem. 2014, 10, 1213–1219, doi:10.3762/bjoc.10.119

• processes. Keywords: fluorinated building blocks; fluoroarylacetic acid; fluoromalonate; fluorooxindole; organo-fluorine; selective fluorination; Introduction Since 1954, when Fried and Sabo observed that the incorporation of a fluorine atom into a corticosteroid derivative led to valuable enhanced

• –fluorine bonds are ‘man-made’. Syntheses rely either on the construction of carbon–fluorine bonds using a fluorinating agent (‘late-stage’ fluorination) or the application of polyfunctional fluorine-containing small molecule building blocks (‘early stage’ fluorination) which may be employed in further

• transformations involving all the reactions and techniques available to synthetic organic chemists [10][11][12][13]. Of course, the success of an ‘early stage’ fluorination approach depends on the availability of a range of appropriately functionalised, fluorinated building blocks and the establishment of

A novel family of (1-aminoalkyl)(trifluoromethyl)- and -(difluoromethyl)phosphinic acids – analogues of α-amino acids

• Natalia V. Pavlenko,
• Tatiana I. Oos,
• Yurii L. Yagupolskii,
• Igor I. Gerus,
• Uwe Doeller and
• Lothar Willms

Beilstein J. Org. Chem. 2014, 10, 722–731, doi:10.3762/bjoc.10.66

• . Incorporation of fluorine or fluorinated moieties can be used for the alteration of physiological properties of many biologically significant substances. The changes of their biological properties caused by this fluorination are influenced by complex factors, however. The similarity of the diameters of fluorine

Aminofluorination of 2-alkynylanilines: a Au-catalyzed entry to fluorinated indoles

• Antonio Arcadi,
• Emanuela Pietropaolo,
• Antonello Alvino and
• Véronique Michelet

Beilstein J. Org. Chem. 2014, 10, 449–458, doi:10.3762/bjoc.10.42

• Paris, UMR 8247, Ecole Nationale Supérieure de Chimie de Paris, Chimie ParisTech, 11 rue P. et M. Curie, F-75231 Paris Cedex 05, France 10.3762/bjoc.10.42 Abstract The scope and limitations of gold-catalyzed tandem cycloisomerization/fluorination reactions of unprotected 2-alkynylanilines to have

• access to 3,3-difluoro-2-aryl-3H-indoles and 3-fluoro-2-arylindoles are described. An unprecedented aminoauration/oxidation/fluorination cascade reaction of 2-alkynylanilines bearing a linear alkyl group on the terminal triple bond is reported. Keywords: 2-alkynylanilines; fluorination; gold catalysis

• moiety of respective indoles was accomplished through a variety of methods [14]. 4-Fluoroindole derivatives have been prepared through nucleophilic attack on intermediate 4-indolediazonium salts [15]. The regioselective fluorination of the benzene ring of indole to give the important neurochemicals 4

Organocatalytic asymmetric fluorination of α-chloroaldehydes involving kinetic resolution

• Kazutaka Shibatomi,
• Takuya Okimi,
• Yoshiyuki Abe,
• Akira Narayama,
• Nami Nakamura and
• Seiji Iwasa

Beilstein J. Org. Chem. 2014, 10, 323–331, doi:10.3762/bjoc.10.30

• enantioselective α-fluorination of racemic α-chloroaldehydes with a chiral organocatalyst yielded the corresponding α-chloro-α-fluoroaldehydes with high enantioselectivity. It was also revealed that kinetic resolution of the starting aldehydes was involved in this asymmetric fluorination. This paper describes the

• determination of the absolute stereochemistry of a resulting α-chloro-α-fluoroaldehyde. Some information about the substrate scope and a possible reaction mechanism are also described which shed more light on the nature of this asymmetric fluorination reaction. Keywords: α-branched aldehyde; asymmetric

• catalysis; chlorination; fluorination; organocatalyst; organo-fluorine; Introduction Fluorinated organic molecules are of considerable interest in pharmaceutical and agricultural chemistry owing to the unique properties of the fluorine atom [1][2]. These compounds, especially with one or more fluorinated

The difluoromethylene (CF₂) group in aliphatic chains: Synthesis and conformational preference of palmitic acids and nonadecane containing CF₂ groups

• Yi Wang,
• Ricardo Callejo,
• Alexandra M. Z. Slawin and
• David O’Hagan

Beilstein J. Org. Chem. 2014, 10, 18–25, doi:10.3762/bjoc.10.4

• in the extended anti-zig-zag chain and suggests a design modification for long chain aliphatics which can introduce conformational stability. Keywords: difluoromethylene; fatty acids; fluorination; organic fluorine chemistry; organo-fluorine; palmitic acid; Introduction The selective replacement of

• palmitic acid 6a is illustrated in Scheme 1. At the outset aldehyde 8 was condensed with the acetylide of 1-octyne to afford propargylic alcohol 9, an alcohol which was readily oxidized to ketone 10. Treatment with DAST afforded difluoromethyleneacetylene 11 in good yield. The fluorination of propargylic

• then oxidation, to ketone 18, generated the second fluorination substrate of the synthesis. DAST treatment gave pentadecabenzene 19, which was again oxidised by RuO3 to the corresponding palmitic acid 6b. Palmitic acid 6c was prepared again relying on the methodology developed by Grée et al. [14][15

Modulating NHC catalysis with fluorine

• Yannick P. Rey and
• Ryan Gilmour

Beilstein J. Org. Chem. 2013, 9, 2812–2820, doi:10.3762/bjoc.9.316

• , Münster, Germany 10.3762/bjoc.9.316 Abstract Fluorination often confers a range of advantages in modulating the conformation and reactivity of small molecule organocatalysts. By strategically introducing fluorine substituents, as part of a β-fluoroamine motif, in a triazolium pre-catalyst, it was

• charge at nitrogen generates the requisite X–Cα–Cβ–Fδ− system (X = N+), thus providing a facile approach to controlling rotation around this bond (ΦXCCF ≈ 60°). In this study, the influence of fluorination on catalyst behaviour is extended to the study of triazolium salts such as 2, which can be

• substitution is evaluated in the NHC-catalysed, enantioselective Steglich rearrangement of oxazolyl carbonates 3 to C-carboxyazlactones 4 [29], recently reported by Smith and co-workers [30][31][32][33][34][35][36]. Fluorination sites were selected based on their proximity to the ring junction nitrogen of the

Flow microreactor synthesis in organo-fluorine chemistry

• Hideki Amii,
• Aiichiro Nagaki and
• Jun-ichi Yoshida

Beilstein J. Org. Chem. 2013, 9, 2793–2802, doi:10.3762/bjoc.9.314

• synthesis and reactions of fluorine-containing molecules by the use of flow microreactor systems to overcome long-standing problems in fluorine chemistry. Keywords: defluorination; fluorine; fluorination; flow microreactor; organo-fluorine; perfluoroalkylation; Review Fluorine is a key element in the

• microreactor technology to overcome long-standing problems in synthetic organofluorine chemistry are showcased. Reactions using hazardous fluorinating reagents Direct fluorination employing elemental fluorine (F2) is one of the most straightforward methods to make fluorine-containing molecules with high atom

• economy. However, handling F2 needs special care and there are a lot of practical difficulties associated with direct fluorination. Elemental fluorine is a poisonous pale yellow gas at room temperature (bp −188 °C). Reactions of organic substances with elemental fluorine are typically strongly exothermic

The renaissance of organic radical chemistry – deja vu all over again

• Corey R. J. Stephenson,
• Armido Studer and
• Dennis P. Curran

Beilstein J. Org. Chem. 2013, 9, 2778–2780, doi:10.3762/bjoc.9.312

• ][14][15][16], e) radical trifluoromethylation [17] and radical fluorination [18][19][20], f) natural product synthesis [21], g) new main group radical chemistry involving elements like boron [22], phosphorous [23] and selenium [24], tellurium [25], among others, h) synthesis or functionalization of

Stereoselectively fluorinated N-heterocycles: a brief survey

• Xiang-Guo Hu and
• Luke Hunter

Beilstein J. Org. Chem. 2013, 9, 2696–2708, doi:10.3762/bjoc.9.306

• possibilities in the future of drug development. To date, the introduction of fluorine into medicinal entities [1][2] has mostly taken the form of aryl fluorination [3][4] or trifluoromethylation [5][6], and fascinating developments in synthetic methodology of this type are continuing to occur [7][8][9

• ]. However, with the advent of stereoselective fluorination methods [10][11] it seems clear that the subset of stereoselectively fluorinated N-heterocycles [12] offers particularly rich possibilities. We therefore felt that it would be worthwhile to examine in a brief review some of the unique features of

• clear that medicinal chemistry is not the only field that stands to benefit from a deeper understanding of these fascinating molecules: for example, attractive prospects are also clear in the field of organocatalysis [13]. 2. Fluorination can influence N-heterocycles’ stability and reactivity If a

Multigramme synthesis and asymmetric dihydroxylation of a 4-fluorobut-2E-enoate

• James A. B. Laurenson,
• John A. Parkinson,
• Jonathan M. Percy,
• Giuseppe Rinaudo and
• Ricard Roig

Beilstein J. Org. Chem. 2013, 9, 2660–2668, doi:10.3762/bjoc.9.301

• multigramme scale using a free radical procedure. A phase transfer catalysed fluorination transformed these species to the 4-fluorobut-2E-enoates reproducibly and at scale (48–53%, ca. 300 mmol). Asymmetric dihydroxylation reactions were then used to transform the butenoate, ultimately into all four

• d-chloroform/diisopropyl tartrate showed distinct baseline separated signals for different enantiomers. Keywords: asymmetric; dihydroxylation; ee determination; fluorination; fluorosugars; organo-fluorine; Introduction Selective fluorination can be used to make subtle but decisive modifications of

• ][9][10]. The synthesis of fluorinated analogues of sugars can be approached in two strategically different ways. The most common, and often most efficient approach, identifies a sugar precursor, isolates the locus for fluorination (usually an hydroxy group) by protecting all the other functional

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