Biochemistry of fluoroprolines: the prospect of making fluorine a bioelement

• Vladimir Kubyshkin,
• Rebecca Davis and
• Nediljko Budisa

Beilstein J. Org. Chem. 2021, 17, 439–460, doi:10.3762/bjoc.17.40

• properties. These factors may translate into an altered structure and stability of a protein containing a fluorinated fragment. What consequences fluorination would have regarding the fitness and survival of the organism relying on fluorine-containing proteins remains an open question. In this context, the

Synthesis of trifluoromethyl ketones by nucleophilic trifluoromethylation of esters under a fluoroform/KHMDS/triglyme system

• Yamato Fujihira,
• Yumeng Liang,
• Makoto Ono,
• Kazuki Hirano,
• Takumi Kagawa and
• Norio Shibata

Beilstein J. Org. Chem. 2021, 17, 431–438, doi:10.3762/bjoc.17.39

• , Nagoya 466-5888, Japan Tosoh Finechem Corporation, 4988, Kaiseicho, Shunan, 746-0006, Japan Institute of Advanced Fluorine-Containing Materials, Zhejiang Normal University, 688 Yingbin Avenue, 321004 Jinhua, China 10.3762/bjoc.17.39 Abstract A straightforward method that enables the formation of

• examined [46]. Trifluoromethyl ketones (TFMKs) are valuable fluorine-containing synthetic targets of bioactive compounds [55][56] that behave as mimics of the tetrahedral transition-state intermediate of enzymatic hydrolysis of esters and amides by stabilizing their hydrates (Figure 1a) [57]. In fact, the

Diels–Alder reaction of β-fluoro-β-nitrostyrenes with cyclic dienes

• Savva A. Ponomarev,
• Roman V. Larkovich,
• Alexander S. Aldoshin,
• Andrey A. Tabolin,
• Sema L. Ioffe,
• Jonathan Groß,
• Till Opatz and
• Valentine G. Nenajdenko

Beilstein J. Org. Chem. 2021, 17, 283–292, doi:10.3762/bjoc.17.27

• powerful tool for assembling a variety of fluorinated carbo- and heterocycles using either the diene [24][25][26][27][28][29][30] or the dienophile component [31][32][33][34][35][36][37][38][39] as fluorine-containing building blocks. The application of [4 + 2] cycloadditions for the preparation of

• fluorinated bicyclic compounds has attracted much attention [40][41][42][43][44][45][46][47]. In this regard, the development of new protocols to relevant monofluorinated bicyclic molecules involving novel versatile fluorine-containing building blocks is of key importance. Fluoroalkenes are recognized to be

• one of the most widely used fluorine-containing building blocks [48][49]. Recently, we have developed an efficient stereoselective synthesis of β-fluoro-β-nitrostyrenes 1 based on the radical nitration of 2-bromo-2-fluorostyrenes [50]. This process takes place with simultaneous elimination of bromine

The preparation and properties of 1,1-difluorocyclopropane derivatives

• Kymbat S. Adekenova,
• Peter B. Wyatt and
• Sergazy M. Adekenov

Beilstein J. Org. Chem. 2021, 17, 245–272, doi:10.3762/bjoc.17.25

• the gem-dihalomethylene fragment. Thus, they are of interest not only for the direct application as biologically active substances and functional materials but also as precursors to other fluorine-containing compounds [1][2]. Fluorine forms stable bonds to carbon and due to its high electronegativity

• difluorocyclopropane and its derivatives can be distinguished: carbene and non-carbene methods of cyclopropanation along with functional group transformations of existing cyclopropanes. The most popular route to prepare fluorocyclopropanes is to generate fluorine-containing carbenes (or carbenoids), which then react

• with multiple bonds, resulting in cyclopropanation. One of the important properties of fluorine-containing carbenes and carbenoids is their electrophilicity, which is a result of the high electronegativity of fluorine. Also, fluorine has an +M effect which tends to reduce the reactivity of the carbenes

Exploring the possibility of using fluorine-involved non-conjugated electron-withdrawing groups for thermally activated delayed fluorescence emitters by TD-DFT calculation

• Dongyang Chen and
• Eli Zysman-Colman

Beilstein J. Org. Chem. 2021, 17, 210–223, doi:10.3762/bjoc.17.21

• thermally activated delayed fluorescence (TADF) emitters. In the present study, we investigate computationally the potential of other fluorine-containing acceptors, trifluoromethoxy (OCF3), trifluoromethylthio (SCF3), and pentafluorosulfanyl (SF5), within two families of donor–acceptor TADF emitters. Time

• within TADF emitter design (Figure 1) [25][26][27]. In the present study, we report on the impact of incorporating other fluorine-containing electron-withdrawing groups beyond trifluoromethyl (CF3), including trifluoromethoxy (OCF3), trifluoromethylthio (SCF3), and pentafluorosulfanyl (SF5) groups, and

• , and 2CzBP of −1.70 eV, −1.63 eV, and −1.67 eV, respectively, are much deeper those of the fluorine-containing emitters in Figure 3, which is a reflection of the greater conjugation length present in compounds with an extended π-accepting framework. The corresponding ΔEg of 2CzBN (4.19 eV), 2CzTRZ

Facile preparation and conversion of 4,4,4-trifluorobut-2-yn-1-ones to aromatic and heteroaromatic compounds

• Takashi Yamazaki,
• Yoh Nakajima,
• Minato Iida and
• Tomoko Kawasaki-Takasuka

Beilstein J. Org. Chem. 2021, 17, 132–138, doi:10.3762/bjoc.17.14

• ; salicylate derivatives; Introduction It is well known that the incorporation of a fluorine atom or a fluorine-containing group into organic compounds sometimes affects their original biological activities [1][2][3], and thus the development of methods for the construction of such molecules with this atom or

Benzothiazolium salts as reagents for the deoxygenative perfluoroalkylthiolation of alcohols

• Armin Ariamajd,
• Nils J. Gerwien,
• Benjamin Schwabe,
• Stefan Dix and
• Matthew N. Hopkinson

Beilstein J. Org. Chem. 2021, 17, 83–88, doi:10.3762/bjoc.17.8

• directly from readily available alcohols. Keywords: alcohols; benzothiazolium salts; deoxygenative reactions; fluorine; perfluoroalkylthiolation; thioethers; Introduction The incorporation of fluorine-containing groups into organic molecules to modulate their biological or physical properties is nowadays

Deoxyfluorination of acyl fluorides to trifluoromethyl compounds by FLUOLEAD^®/Olah’s reagent under solvent-free conditions

• Yumeng Liang,
• Akihito Taya,
• Zhengyu Zhao,
• Norimichi Saito and
• Norio Shibata

Beilstein J. Org. Chem. 2020, 16, 3052–3058, doi:10.3762/bjoc.16.254

• -5888, Japan Pharmaceutical Division, Ube Industries, Ltd., Seavans North Bldg, 1-2-1 Shibaura, Minato-ku, Tokyo 105-8449, Japan Institute of Advanced Fluorine-Containing Materials, Zhejiang Normal University, 688 Yingbin Avenue, 321004 Jinhua, China 10.3762/bjoc.16.254 Abstract A new protocol enabling

• fluorine-containing functional groups into organic molecules has become a common strategy in pharmaceutical and agrochemical industries [1][2][3][4][5]. Among various fluorine-containing functional groups, the trifluoromethyl (CF3) group has received countless attention in the design of novel drugs [6][7

Synthesis of purines and adenines containing the hexafluoroisopropyl group

• Viacheslav Petrov,
• Rebecca J. Dooley,
• Alexander A. Marchione,
• Elizabeth L. Diaz,
• Brittany S. Clem and
• William Marshall

Beilstein J. Org. Chem. 2020, 16, 2739–2748, doi:10.3762/bjoc.16.224

• investigational therapeutic agents, including antitumorals and antivirals […]” [8]. Interestingly, most fluorine-containing benzimidazoles contain the fluorinated substituent either on the aromatic ring or on a side chain connected to the aromatic ring; examples of benzimidazoles containing a fluoroalkyl group

Asymmetric Mannich reactions of (S)-N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimines with yne nucleophiles

• Ziyi Li,
• Li Wang,
• Yunqi Huang,
• Haibo Mei,
• Hiroyuki Konno,
• Hiroki Moriwaki,
• Vadim A. Soloshonok and
• Jianlin Han

Beilstein J. Org. Chem. 2020, 16, 2671–2678, doi:10.3762/bjoc.16.217

• -nucleophile; CF3-aldimine; fluorinated propargylamine; Introduction In recent years, substitution of hydrogen by fluorine atoms or fluorine-containing groups usually provides unexpected biological and physicochemical properties, which thus has become an established approach for the development of

Synthesis of novel fluorinated building blocks via halofluorination and related reactions

• Attila Márió Remete,
• Tamás T. Novák,
• Melinda Nonn,
• Matti Haukka,
• Ferenc Fülöp and
• Loránd Kiss

Beilstein J. Org. Chem. 2020, 16, 2562–2575, doi:10.3762/bjoc.16.208

• Deoxo-Fluor®. The fluorine-containing products thus obtained were subjected to elimination reactions, yielding various fluorine-containing small-molecular entities. Keywords: fluorine; fluoroselenation; functionalization; halofluorination; stereocontrol; Introduction The effects of fluorine on

• discovering new reagents and conditions for the introduction of fluorine and fluorine-containing groups into a certain organic molecule [11][12][13][14][15][16][17][18], several known methods have been studied and improved over the past decade. One such long-known method is halofluorination. During this

• uncovered, too. The oxidation of (rac)-31 under basic conditions delivered the conjugated diene (rac)-34, possibly through a deselenation/E1cB elimination sequence similar to the one shown in Scheme 22. Conclusion In conclusion, novel fluorine-containing, functionalized small-molecular scaffolds have been

Conformational preferences of fluorine-containing agrochemicals and their implications for lipophilicity prediction

• Daniela Rodrigues Silva,
• Joyce K. Daré and
• Matheus P. Freitas

Beilstein J. Org. Chem. 2020, 16, 2469–2476, doi:10.3762/bjoc.16.200

• fluorine-containing agrochemicals. Accordingly, this study aims to determine the most likely conformers of some fluorine-containing agrochemicals and to correlate their molecular dipole moments with the respective n-octanol/water partition coefficients (log P), in order to investigate the dependence of the

• helps in explaining the expressive amount of fluorine-containing agrochemical candidates (around 30%) as well as pharmaceuticals (around 20%) [5][6]. In this sense, the chemistry of fluorine-containing compounds has been extensively investigated in order to better understand the effects of fluorination

• substituents originated from the rotation of fluorine-containing C–C bonds should affect the polarity and, therefore, the physicochemical and biological properties of organofluorine compounds. However, there is a lack of studies that explain how these well-known conformational effects directly alter

Chan–Evans–Lam N1-(het)arylation and N1-alkеnylation of 4-fluoroalkylpyrimidin-2(1H)-ones

• Viktor M. Tkachuk,
• Oleh O. Lukianov,
• Mykhailo V. Vovk,
• Isabelle Gillaizeau and
• Volodymyr A. Sukach

Beilstein J. Org. Chem. 2020, 16, 2304–2313, doi:10.3762/bjoc.16.191

• conditions. There are a few thorough studies on this reaction with pyrimidine and purine nucleoside bases and their derivatives which are most closely related to fluorine-containing substrates 1 [40][41][42]. However, considering the high sensitivity and capricious nature of CEL reaction, we wish to report

Regioselective cobalt(II)-catalyzed [2 + 3] cycloaddition reaction of fluoroalkylated alkynes with 2-formylphenylboronic acids: easy access to 2-fluoroalkylated indenols

• Tatsuya Kumon,
• Miroku Shimada,
• Jianyan Wu,
• Shigeyuki Yamada and
• Tsutomu Konno

Beilstein J. Org. Chem. 2020, 16, 2193–2200, doi:10.3762/bjoc.16.184

• -fluoroalkylated indenols, together with a very small amount of 3-fluoroalkylated indanones as side products. Keywords: [2 + 3] cycloaddition; cobalt catalyst; fluorine-containing; indenols; regioselective; Introduction 2,3-Disubstituted indenol derivatives are important compounds possessing high potential due

• . Despite their effective advantages, on the other hand, the reports on cycloaddition reactions with fluorine-containing alkynes for the construction of fluoroalkylated indene derivatives are rare [21][26]. Recently, our group has reported the first practical synthesis of fluoroalkylated indenol derivatives

Photosensitized direct C–H fluorination and trifluoromethylation in organic synthesis

• Shahboz Yakubov and
• Joshua P. Barham

Beilstein J. Org. Chem. 2020, 16, 2151–2192, doi:10.3762/bjoc.16.183

Reactions of 3-aryl-1-(trifluoromethyl)prop-2-yn-1-iminium salts with 1,3-dienes and styrenes

• Thomas Schneider,
• Michael Keim,
• Bianca Seitz and
• Gerhard Maas

Beilstein J. Org. Chem. 2020, 16, 2064–2072, doi:10.3762/bjoc.16.173

• reaction of propyn-1-iminium salt 1a with styrene in acetonitrile was considered first and was monitored by 19F NMR spectroscopy. Whereas no reaction appeared to occur at room temperature, a slow transformation into two fluorine-containing products was observed at 70 °C, which after neutralization and work

• signals. Assuming that some of the signals represented products that would easily undergo further thermal reactions, the solution was additionally heated at 70 °C for 40 hours. The resulting reaction mixture still contained several products, of which only the major fluorine-containing component (δF

Selective preparation of tetrasubstituted fluoroalkenes by fluorine-directed oxetane ring-opening reactions

• Clément Q. Fontenelle,
• Thibault Thierry,
• Romain Laporte,
• Emmanuel Pfund and
• Thierry Lequeux

Beilstein J. Org. Chem. 2020, 16, 1936–1946, doi:10.3762/bjoc.16.160

• took place away from the bulky alkyl chain, resulting in the observed E-selectivity. These outcomes were opposite to those obtained with the fluorinated substrate series, consistent with steric hindrance governing the non-fluorine containing oxetane reactions but electronics influencing and reversing

Polarity effects in 4-fluoro- and 4-(trifluoromethyl)prolines

• Vladimir Kubyshkin

Beilstein J. Org. Chem. 2020, 16, 1837–1852, doi:10.3762/bjoc.16.151

• Vladimir Kubyshkin University of Manitoba, Dysart Rd. 144, Winnipeg, R3T 2N2, Canada 10.3762/bjoc.16.151 Abstract Fluorine-containing analogues of proline are valuable tools in engineering and NMR spectroscopic studies of peptides and proteins. Their use relies on the fundamental understanding of

• identify structural breaks in a sequence. This fact contributes to the reputation of proline as a polar residue [3][4][5]. There is a rich portfolio of fluorine-containing proline analogues that have been developed to date (Figure 1B): fluorinated [6][7][8][9][10][11][12], trifluoromethylated [13][14][15

• ][16][17][18][19][20][21][22][23], chimeric [16][19][24][25][26][27][28][29], conformationally restricted [30][31][32][33] having variations in the ring size [34][35][36][37][38][39], non-α [40][41][42][43][44], and other analogues [45][46][47][48]. The fluorine-containing functional groups are usually

Pauson–Khand reaction of fluorinated compounds

• Jorge Escorihuela,
• Daniel M. Sedgwick,
• Alberto Llobat,
• Mercedes Medio-Simón,
• Pablo Barrio and
• Santos Fustero

Beilstein J. Org. Chem. 2020, 16, 1662–1682, doi:10.3762/bjoc.16.138

• the PKR of enynes containing a fluoride moiety. Keywords: alkene; alkyne; enyne; fluorine; Pauson–Khand; Introduction The prevalence of fluorine-containing molecules in drug-discovery programs is nowadays unquestionable [1][2][3]. The presence of fluorine atoms or fluorine-containing units at

• use, fluorine-containing molecules have also found key applications in the field of medical diagnosis. Two of the most powerful imaging techniques used nowadays, positron-emission tomography (PET) and magnetic resonance imaging (MRI), are routinely carried out using fluorine-containing organic

• that will be discussed in this review belongs to the fluorinated building blocks category. More specifically, the participation of fluorine-containing olefins and alkynes in the Pauson–Khand cyclization, with a special focus on the intramolecular version using fluorinated enynes, which will be

Fluorohydration of alkynes via I(I)/I(III) catalysis

• Jessica Neufeld,
• Constantin G. Daniliuc and
• Ryan Gilmour

Beilstein J. Org. Chem. 2020, 16, 1627–1635, doi:10.3762/bjoc.16.135

• C(sp3)–C(sp3) bond-forming reactions [16][17], and closely resembles one of the very few biological blueprints for the preparation of fluorine-containing materials [18][19][20][21]. However, in translating the fluoroacetate-like building blocks to a laboratory paradigm, the intrinsic toxicity of

An overview on disulfide-catalyzed and -cocatalyzed photoreactions

• Yeersen Patehebieke

Beilstein J. Org. Chem. 2020, 16, 1418–1435, doi:10.3762/bjoc.16.118

• fluorine-containing groups can effectively change the physical and chemical properties and biological activities of organic molecules [21][22]. The addition reaction using disulfide as the visible-light catalyst is an effective and atom-economic method for introducing fluorine-containing groups. In 2016

• . In 1996, Burton and co-workers reported the stereoselective synthesis of cis-1,2-difluorotriethylsilyethylene and its conversion to a variety of cis-1,2-difluoroethylene synthons, which are important building blocks in the preparation of fluorine-containing pharmaceuticals, polymers, and bioactive

Photocatalytic trifluoromethoxylation of arenes and heteroarenes in continuous-flow

• Alexander V. Nyuchev,
• Ting Wan,
• Borja Cendón,
• Carlo Sambiagio,
• Job J. C. Struijs,
• Michelle Ho,
• Moisés Gulías,
• Ying Wang and
• Timothy Noël

Beilstein J. Org. Chem. 2020, 16, 1305–1312, doi:10.3762/bjoc.16.111

• catalysis; trifluoromethoxylation; Introduction The number of fluorine-containing compounds and their influence in medicine and agrochemistry are increasing every year [1][2]. The introduction in a drug (or a bioactive compound in general) of single fluorine atoms, or multiple fluorine-containing

Copper-based fluorinated reagents for the synthesis of CF₂R-containing molecules (R ≠ F)

• Louise Ruyet and
• Tatiana Besset

Beilstein J. Org. Chem. 2020, 16, 1051–1065, doi:10.3762/bjoc.16.92

• of fluorine-containing molecules in the pharmaceutical and agrochemical industries. In a world eager to eco-friendlier tools, the need for innovative methods has been growing. To address these two challenges, copper-based reagents were developed to introduce CF2H, CF2RF, CF2CH3, CF2PO(OEt)2 and

Fluorinated phenylalanines: synthesis and pharmaceutical applications

• Laila F. Awad and
• Mohammed Salah Ayoup

Beilstein J. Org. Chem. 2020, 16, 1022–1050, doi:10.3762/bjoc.16.91

• ) complex 104 was obtained through the reaction of 102 with glycine (103) and Ni(NO3)2. The subsequent alkylation of complex 104 with fluorine-containing benzyl chlorides 105a–d followed by hydrolysis with HCl afforded enantiomerically enriched (<90% ee) (S)-fluorinated phenylalanine derivatives 53a, 81

Recent advances in Cu-catalyzed C(sp³)–Si and C(sp³)–B bond formation

• Balaram S. Takale,
• Ruchita R. Thakore,
• Elham Etemadi-Davan and
• Bruce H. Lipshutz

Beilstein J. Org. Chem. 2020, 16, 691–737, doi:10.3762/bjoc.16.67