(Thio)urea-mediated synthesis of functionalized six-membered rings with multiple chiral centers

• Giorgos Koutoulogenis,
• Nikolaos Kaplaneris and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2016, 12, 462–495, doi:10.3762/bjoc.12.48

• of intermediates have been proposed to be the reactive intermediates in many reactions such as aldol, Michael, Mannich, and α-functionalization (α-chlorination, α-amination, α-fluorination) reactions. Proline-type organocatalysts are considered priviliged, because their corresponding enamines exist

Diastereoselective synthesis of new O-alkylated and C-branched inositols and their corresponding fluoro analogues

• Charlotte Collet,
• Françoise Chrétien,
• Yves Chapleur and
• Sandrine Lamandé-Langle

Beilstein J. Org. Chem. 2016, 12, 353–361, doi:10.3762/bjoc.12.39

• /or acetate migration. By reducing the reaction time to 15 minutes the byproducts formation could be lowered to 10% and myo-2 was obtained in 45% isolated yield. It is worthy to note that 41% of the starting material was recovered. At this stage, the fluorination was tested using DAST [48] on myo-20

• fluorination. The utilization of isopropenyl acetate as solvent in the presence of p-TSA at 80 °C for 2 h [52] gave the corresponding acetylated compounds myo-23 and scyllo-23 in good to excellent yields. The access to fluorinated compounds by nucleophilic substitution was investigated starting from these

• fully acetylated inositols. The fluorination reactions using potassium fluoride, 18-crown-6 in acetonitrile at 70 °C [53], TBAF in acetonitrile at 60 °C for 2 h [54] or KHF2 and 18-crown-6 in acetonitrile for 2 h at 60 °C [55] were performed. However, 19F NMR analyses of the reaction mixtures did not

Synthesis and nucleophilic aromatic substitution of 3-fluoro-5-nitro-1-(pentafluorosulfanyl)benzene

• Javier Ajenjo,
• Martin Greenhall,
• Camillo Zarantonello and
• Petr Beier

Beilstein J. Org. Chem. 2016, 12, 192–197, doi:10.3762/bjoc.12.21

• Abstract 3-Fluoro-5-nitro-1-(pentafluorosulfanyl)benzene was prepared by three different ways: as a byproduct of direct fluorination of 1,2-bis(3-nitrophenyl)disulfane, by direct fluorination of 4-nitro-1-(pentafluorosulfanyl)benzene, and by fluorodenitration of 3,5-dinitro-1-(pentafluorosulfanyl)benzene

• nitrogen nucleophiles provided 3-fluoro-5-nitro-1-(pentafluorosulfanyl)benzenes substituted in position four. Keywords: direct fluorination; fluorine; nucleophilic aromatic substitution; pentafluorosulfanyl group; vicarious nucleophilic substitution; Introduction Organic compounds with a

• fluorination of nitro-substituted diaryl disulfides leading to 3- or 4-nitro-1-(pentafluorosulfanyl)benzenes [7][8][9][10]. This reaction is conducted in tens of kilogram scale in industry. The second method is known as Umemoto’s synthesis and starts with aromatic thiols or diaryl disulfides which are

Copper-catalyzed aminooxygenation of styrenes with N-fluorobenzenesulfonimide and N-hydroxyphthalimide derivatives

• Yan Li,
• Xue Zhou,
• Guangfan Zheng and
• Qian Zhang

Beilstein J. Org. Chem. 2015, 11, 2721–2726, doi:10.3762/bjoc.11.293

• -tetramethylpiperidine-N-oxyl (TEMPO) [36]. NFSI is a very interesting reagent. Besides classic electrophilic fluorination reagent [37], it has been used not only as fluoride-atom transfer reagent [38][39][40] but also as nucleophilic/radical amination reagent [41]. We are highly interested in the multiple reaction

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

• , the research activity on selective fluorination and trifluoromethylation has reached a mature state. The progress in fluoroalkylation of organic compounds could be accelerated by the use of fluoroalkylating reagents, which are inexpensive and easy to handle. Perfluoroalkyl carboxylic acid derivatives

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

• direct glycosylation for the synthesis of 3’-fluorine modified guanosine derivatives is highly advantageous compared to the previously reported methods utilizing orthogonal protecting groups, selective deprotection, and fluorination of the starting guanosine [34]. Biological evaluation Newly synthesized

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