Development of fluorinated benzils and bisbenzils as room-temperature phosphorescent molecules

• Shigeyuki Yamada,
• Takuya Higashida,
• Yizhou Wang,
• Masato Morita,
• Takuya Hosokai,
• Kaveendra Maduwantha,
• Kaveenga Rasika Koswattage and
• Tsutomu Konno

Beilstein J. Org. Chem. 2020, 16, 1154–1162, doi:10.3762/bjoc.16.102

• effects of structural modification (i.e., the benzil structure with a tolane vs bisbenzil moiety) and incorporation of fluorine atoms on the phosphorescence, the ratio between the peak intensities at ≈395 and ≈560 nm (I560/I395) was quantitatively calculated, and the results are summarized in Table 1. The

• , although the PL intensity of nonfluorinated 3c increases by approximately three times. Judging from these comprehensive observations, the benzil structure promotes ISC from S1 to T1, causing increment phosphorescence, unlike the corresponding bisbenzil scaffold. Moreover, fluorine substituents on the

• corresponding bis-oxidized bisbenzil derivatives. Based on theoretical calculations, the selective formation of the fluorinated analogues stemmed from the slight modulation of the charge distribution at the alkyne moiety of the reactant induced by the electron-withdrawing fluorine atoms. Evaluation of the

Synthesis of esters of diaminotruxillic bis-amino acids by Pd-mediated photocycloaddition of analogs of the Kaede protein chromophore

• Esteban P. Urriolabeitia,
• Pablo Sánchez,
• Alexandra Pop,
• Cristian Silvestru,
• Eduardo Laga,
• Ana I. Jiménez and
• Carlos Cativiela

Beilstein J. Org. Chem. 2020, 16, 1111–1123, doi:10.3762/bjoc.16.98

• -palladated ring on the other side of the plane, shows that the compound obtained is the epsilon (ε) isomer, according to the classification of Stoermer [61][62]. The non-bonding intramolecular distance between the ortho-fluorine F1 and the cyclobutane proton H4 is d(F1...H4) = 2.286(3) Å, which is much

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

• molecules using copper-based fluorinated reagents will be given. Keywords: copper; difluoromethylation; fluorinated reagents; fluorine chemistry; synthetic methodologies; Introduction In a society in which fluorinated molecules are playing a pivotal role in pharmaceutical and agrochemical industries as

• fluorine atom or a fluorinated moiety of unique properties [15]. Despite the tremendous advances made in that field, key synthetic challenges remain to synthesize fluorinated scaffolds. Among the different developed strategies to ravel synthetic issues, the use of inexpensive and readily available copper

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

• pharmaceutical applications with a focus on published synthetic methods that introduce fluorine into the phenyl, the β-carbon or the α-carbon of ᴅ-or ʟ-phenylalanines. Keywords: α-fluorophenylalanine; β- and β,β-difluorophenylalanine; fluorinated phenylalanines; PET; pharmaceuticals application; Introduction

• Major efforts have been focused on the synthesis of fluorinated organic molecules particularly for drug development. The replacement of hydrogen by fluorine has been used in the development to improve the biophysical and chemical properties of bioactives. Such tuning in properties arises from the small

• size of fluorine, the next in size to hydrogen. However, the high electronegativity of the fluorine leads to low polarizability and a strong covalent bond to carbon [1][2][3][4]. Therefore, the introduction of fluorine into phenylalanine (Phe) can modulate the acidity, basicity, hydrophobicity

Aryl-substituted acridanes as hosts for TADF-based OLEDs

• Naveen Masimukku,
• Dalius Gudeika,
• Oleksandr Bezvikonnyi,
• Ihor Syvorotka,
• Rasa Keruckiene,
• Dmytro Volyniuk and
• Juozas V. Grazulevicius

Beilstein J. Org. Chem. 2020, 16, 989–1000, doi:10.3762/bjoc.16.88

• , Figure 4b, and Table 2). The IPPES values were further used for constructing OLED structures. The highest IPPES of 5.62 eV was obtained for compound 6 which contains electron-accepting fluorine atoms. The other compounds (3–5) demonstrated similar IPPES values mainly attributed to removing an electron

Accelerating fragment-based library generation by coupling high-performance photoreactors with benchtop analysis

• Quentin Lefebvre,
• Christophe Salomé and
• Thomas C. Fessard

Beilstein J. Org. Chem. 2020, 16, 982–988, doi:10.3762/bjoc.16.87

• of complex amines: bicyclopentanamines, azetidines, spiroazetidines, spiropyrrolidines and spiropiperidines. Functional group tolerance was probed by using functionalized building blocks bearing esters, carbamates, alcohols, tertiary amines, ethers, sulfones and fluorine atoms (Scheme 2 and Scheme 3

Reaction of indoles with aromatic fluoromethyl ketones: an efficient synthesis of trifluoromethyl(indolyl)phenylmethanols using K₂CO₃/n-Bu₄PBr in water

• Thanigaimalai Pillaiyar,
• Masoud Sedaghati and
• Gregor Schnakenburg

Beilstein J. Org. Chem. 2020, 16, 778–790, doi:10.3762/bjoc.16.71

• into organic molecules can dramatically influence their physiochemical and biological properties in comparison with non-fluorinated analogs [18] (see compounds I and II in Figure 1). Many pharmaceuticals and agrochemicals developed in recent decades have either a fluorine atom or a trifluoromethyl

• group [19][20][21][22]. Given this, the development of a method for the incorporation of fluorine or trifluoromethyl group into organic molecules perhaps remains a current challenge in organic chemistry methodology. For example, trifluoromethyl-substituted (1H-indol-3-yl)methanol derivatives were

• trifluoroacetophenones did not significantly influence the yield of the reaction. The trifluoromethyl ketones having electron-rich heteroaromatics such as 2-(trifluoroacetyl)furan (2g) and 2-(trifluoroacetyl)thiophene (2h) gave the desired products 3g (97%) and 3h (98%) in excellent yields. Next, the role of fluorine in

Efficient synthesis of dipeptide analogues of α-fluorinated β-aminophosphonates

• Marcin Kaźmierczak and
• Henryk Koroniak

Beilstein J. Org. Chem. 2020, 16, 756–762, doi:10.3762/bjoc.16.69

• that was proposed based on NMR studies. Keywords: dipeptide analogues; fluorinated aminophosphonates; fluorine; nucleophilic fluorination; phosphorus; Introduction The chemistry of fluorinated aminophosphonates is constantly being developed, mainly due to their wide spectra of applications. What is

• -Chloro-N-tosylbenzene-1-sulfonimidoyl fluoride (SulfoxFluor, 3, Figure 1) may be an interesting alternative to 1 or 2. It is not commercially available yet, however, it can be obtained from inexpensive materials [24]. Very often small organic molecules containing a fluorine atom are transformed into

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

Synthesis of organic liquid crystals containing selectively fluorinated cyclopropanes

• Zeguo Fang,
• Nawaf Al-Maharik,
• Peer Kirsch,
• Matthias Bremer,
• Alexandra M. Z. Slawin and
• David O’Hagan

Beilstein J. Org. Chem. 2020, 16, 674–680, doi:10.3762/bjoc.16.65

• vertical alignment (VA) LCD technology, liquid crystals with negative dielectric anisotropy are required [3]. Fluorine, as the most electronegative atom, forms stable bonds to carbon and can thus induce polarity. It is also attractive as a design feature due to the low polarizability of the C–F bond

• which contain axial fluorine substituents (Figure 1, 1 and 2), however, due to the propensity for HF elimination from these molecules over time, these liquid crystals have not been adopted as commercial products [6][7]. 2,3-Difluoroaryl motifs such as 3 have proven to be a successful class of negative

• explore the cyclopropane motif containing fluorine atoms. Selectively fluorinated cyclopropanes have been widely used in pharmaceutical research [11], however, the introduction of fluorinated cyclopropanes into liquid crystal scaffolds has not received much attention. Haufe et al. [12], reported

Cascade trifluoromethylthiolation and cyclization of N-[(3-aryl)propioloyl]indoles

• Ming-Xi Bi,
• Shuai Liu,
• Yangen Huang,
• Xiu-Hua Xu and
• Feng-Ling Qing

Beilstein J. Org. Chem. 2020, 16, 657–662, doi:10.3762/bjoc.16.62

• and agrochemical industries [3][4][5]. Traditional methods to access these compounds mainly include halogen–fluorine exchange of halomethyl sulfides and trifluoromethylation of sulfur-containing compounds [6][7][8]. Over the last decade, tremendous efforts have been triggered to develop methods for

• converted to the mono(trifluoromethylthiolated) products in moderate yields. Further studies on applying radical cascade reactions to the construction of fluorine-containing heterocyclic scaffolds are in progress in our laboratory. Representative examples of biologically active pyrrolo[1,2-a]indol-3-one

Asymmetric synthesis of CF₂-functionalized aziridines by combined strong Brønsted acid catalysis

• Xing-Fa Tan,
• Fa-Guang Zhang and
• Jun-An Ma

Beilstein J. Org. Chem. 2020, 16, 638–644, doi:10.3762/bjoc.16.60

• ; difluoromethyl compounds; fluorinated diazo reagents; strong Brønsted acids; Introduction Chiral aziridines are prevalently found in natural products and artificially made bioactive molecules, thus receiving significant attention in the past decades [1][2][3][4][5][6]. Among them, the introduction of fluorine

• or fluoroalkyl groups into three-membered N-heterocycles has emerged as an attractive direction due to the unique fluorine effect in pharmaceuticals and biology [7][8][9][10][11]. In this context, it is not surprising that the syntheses of trifluoromethylaziridines have been pursued from versatile

Synthesis of 4-amino-5-fluoropyrimidines and 5-amino-4-fluoropyrazoles from a β-fluoroenolate salt

• Tobias Lucas,
• Jule-Philipp Dietz and
• Till Opatz

Beilstein J. Org. Chem. 2020, 16, 445–450, doi:10.3762/bjoc.16.41

• heterocycles; fluorine; pyrazoles; pyrimidines; Introduction Due to its extremely widespread application in virtually all areas of synthetic organic chemistry, fluorine is considered a “magic” element. It confers metabolic stability and other unique properties to organic molecules and a large fraction of

• modern pharmaceuticals [1][2][3][4][5][6] and agrochemicals [7] contain at least one fluorine atom [8][9][10][11][12][13][14][15]. One of the approaches for their synthesis is the use of small fluorinated building blocks which avoids the often cumbersome regioselective fluorination at a later synthetic

• emtricitabine [30] (ingredient of Truvada®) and capecitabine [31] (Xeloda®) (see Figure 1) [32][33]. While the introduction of fluorine into preexisting heterocycles can require difficult-to-handle, expensive and highly corrosive electrophilic fluorine species [16][34][35], the present approach employs a

Architecture and synthesis of P,N-heterocyclic phosphine ligands

• Wisdom A. Munzeiwa,
• Bernard Omondi and
• Vincent O. Nyamori

Beilstein J. Org. Chem. 2020, 16, 362–383, doi:10.3762/bjoc.16.35

• dibromomethane to furnish the desired ligand 19. The nature of the halide in the precursors also influences the reaction progress. Fluorine and chlorine usually require strong bases for the metal–halogen exchange, while relatively mild bases can be used for bromo and iodo derivatives. Structurally inflexible

• chiral acetal ligands have been reported by Lyle et al. where the fluorine–metal exchange was achieved by treatment with potassium tert-butoxide for a relatively long period (24 h) (Scheme 4) [65]. Acid-catalyzed condensation of compound 20 with enantiomerically pure C2-symmetric 1,2-tosylate analogs 21

Synthesis and circularly polarized luminescence properties of BINOL-derived bisbenzofuro[2,3-b:3’,2’-e]pyridines (BBZFPys)

• Ryo Takishima,
• Yuji Nishii,
• Tomoaki Hinoue,
• Yoshitane Imai and
• Masahiro Miura

Beilstein J. Org. Chem. 2020, 16, 325–336, doi:10.3762/bjoc.16.32

• using cesium carbonate as base in DMF at 40 °C [42], giving both the enantiomers of 2 in optically pure forms. The remaining fluorine substituents were subsequently replaced by a series of phenols including unsubstituted phenol, p-tert-butylphenol, and m-tert-butylphenol to produce the corresponding

Copper-promoted/copper-catalyzed trifluoromethylselenolation reactions

• Clément Ghiazza and
• Anis Tlili

Beilstein J. Org. Chem. 2020, 16, 305–316, doi:10.3762/bjoc.16.30

• advances have been made in the field of trifluoromethylselenolations of organic compounds where copper catalysis played a crucial role. Recent developments in this field are highlighted in this minireview. Keywords: copper catalysis; fluorine; homogenous catalysis; trifluoromethylselenolation

• ; Introduction In recent years, the incorporation of fluorine or fluorinated motifs into organic molecules has gained widespread interest. This is mainly due to the new properties associated with the introduction of these modifications. In particular, chalcogen trifluoromethyl motifs are of prime interest since

Recent developments in photoredox-catalyzed remote ortho and para C–H bond functionalizations

• Rafia Siddiqui and
• Rashid Ali

Beilstein J. Org. Chem. 2020, 16, 248–280, doi:10.3762/bjoc.16.26

• challenging task in synthetic organic chemistry. Although several methods are available for direct fluorine introduction in the literature, most of them suffer from poor yields and low selectivities [165][166][167]. In this context, Fukuzumi and co-workers reported the transformation of C–H bonds into C–F

• bonds in the presence of photoredox catalyst 8, with a similar mechanism as shown in Figure 22, and the photocatalytic mechanism was elucidated by nanosecond laser flash photolysis (Scheme 24) [168]. Fluorine-18 is an important radioisotope used in the radiopharmaceutical industry (e.g., for drug

• (5a). Monofluorination using QuCN-ClO4 (8). Fluorination with fluorine-18. Aerobic amination with acridinium catalyst 3a. Aerobic aminations with semiconductor photoredox catalyst 18. Perfluoroalkylation of arenes. Synthesis of benzonitriles in the presence of 3a. Acknowledgments We are grateful to

Synthesis of 4-(2-fluorophenyl)-7-methoxycoumarin: experimental and computational evidence for intramolecular and intermolecular C–F···H–C bonds

• Vuyisa Mzozoyana,
• Fanie R. van Heerden and
• Craig Grimmer

Beilstein J. Org. Chem. 2020, 16, 190–199, doi:10.3762/bjoc.16.22

• this F···H interaction. The single crystal X-ray structure and the DFT-optimized structure showed that the fluorinated phenyl ring favors the orientation with the fluorine atom closer to H5 than H3. The X-ray structure also showed the existence of the intermolecular C–F···H–C interaction. Keywords

• cross-coupling reaction [17], Negishi cross-coupling reaction [18] and Wittig reaction [17]. The concept of the incorporation of fluorine into organic molecules has gained much interest since Fried and Sabo reported the improvement of the therapeutic index of cortisol by the incorporation of a fluorine

• atom in the 9α position of the structure [19]. Since then, the fluorine-containing drugs have come onto the market and they are amongst the best-selling pharmaceutical drugs, including Lipitor®, Prevacid®, Advair Discus® and Lexapro® [20][21][22]. The incorporation of fluorine may improve the activity

Synthesis, liquid crystalline behaviour and structure–property relationships of 1,3-bis(5-substituted-1,3,4-oxadiazol-2-yl)benzenes

• Afef Mabrouki,
• Malek Fouzai,
• Armand Soldera,
• Abdelkader Kriaa and
• Ahmed Hedhli

Beilstein J. Org. Chem. 2020, 16, 149–158, doi:10.3762/bjoc.16.17

• moments were also investigated. Keywords: dipole moment; fluorine; liquid crystal; oxadiazole; Introduction Liquid-crystalline (LC) materials have been known for over a century [1]. It is clear that architecture and functionalization are essential aspects in molecular engineering of liquid crystals [2

• ]. The introduction of fluorine atoms in the molecular structure presents a successful strategy to control the liquid crystal proprieties. The element Fluorine presents the highest electronegativity, the lowest polarizability and a small radius. When bonded to carbon, it forms the strongest single bond

• in organic chemistry [3]. The C–F bond is highly polarized and this polarity inhibits the lone pair donation from fluorine, making this element a weak coordinator. These properties are the basis for the unique properties of perfluoroalkylated compounds such as high viscosity, high density, high

Halogen-bonding-induced diverse aggregation of 4,5-diiodo-1,2,3-triazolium salts with different anions

• Xingyu Xu,
• Shiqing Huang,
• Zengyu Zhang,
• Lei Cao and
• Xiaoyu Yan

Beilstein J. Org. Chem. 2020, 16, 78–87, doi:10.3762/bjoc.16.10

• have been omitted for clarity. Packing structure of 2-OAc. Hydrogen atoms and solvent molecules have been omitted for clarity. Packing structure of 2-TFA. Hydrogen atoms and disorder of fluorine atoms have been omitted for clarity. Side view (left) and top view (right). Packing structure of 2-I.1.5I2

Palladium-catalyzed synthesis and nucleotide pyrophosphatase inhibition of benzo[4,5]furo[3,2-b]indoles

• Hoang Huy Do,
• Saif Ullah,
• Alexander Villinger,
• Joanna Lecka,
• Jean Sévigny,
• Peter Ehlers,
• Jamshed Iqbal and
• Peter Langer

Beilstein J. Org. Chem. 2019, 15, 2830–2839, doi:10.3762/bjoc.15.276

• exhibited π–π T-shaped interactions connecting the indole and furan rings with Tyr340. However, π–alkyl linkage was observed between the benzofuran moiety of compound 5c and amino acid Lys295. The fluorine atom of the 4-fluorophenyl group was involved in the binding with the zinc ion and Ser377. Hydrogen

• -shaped and π–alkyl related bindings were noticed, connecting Ile235, Phe220, Ala546, Trp322 and Ile419. The fluorine atom was perceived interacting with Ile419. Docking studies of h-ENPP3 inhibitors The binding of ENPP3 was studied for selective inhibitor 5e. A dual affinity was observed for 5h and 6e

• docking of compound 6e revealed distinct bonding, due to the presence of a fluorine atom on the phenyl ring. The fluorine atom was attached to the side chains of Asn226 and Asp225. The aromatic ring of indole was coupled via π–alkyl line interactions with Leu239 (Figure 5d). The docking studies of

Chemical tuning of photoswitchable azobenzenes: a photopharmacological case study using nicotinic transmission

• Lorenzo Sansalone,
• Jun Zhao,
• Matthew T. Richers and
• Graham C. R. Ellis-Davies

Beilstein J. Org. Chem. 2019, 15, 2812–2821, doi:10.3762/bjoc.15.274

• groups to control a wide variety of biological process photoreversibly [8][9]. Furthermore, chemists have paid attention to spectral tuning of the AB chromophore [10][11]. Recently, an improved set of fluorine-substituted AB photochromes was developed by Hecht and co-workers [12][13]. ABs with two or

A combinatorial approach to improving the performance of azoarene photoswitches

• Joaquin Calbo,
• Aditya R. Thawani,
• Rosina S. L. Gibson,
• Andrew J. P. White and
• Matthew J. Fuchter

Beilstein J. Org. Chem. 2019, 15, 2753–2764, doi:10.3762/bjoc.15.266

• scaffold, the theoretical calculations at the PBE0-D3/6-31G** level indicate that an insertion of electron-poor fluorine atoms in the ortho-position of the aryl ring (4pzH-F1 and 4pzH-F2) leads to an increase in the half-life from ca. 1000 days in 4pzH to 2000 days in 4pzH-F1 and to 4000 days in 4pzH-F2

• noncovalent forces are also predicted in the twisted Z-isomers of the 4pzMe-X family, for which θ remains approximately constant. Furthermore, the atomic charge of fluorine is calculated to be ca. −0.30e, which allows for electrostatic interactions with positively charged C atoms (ca. +0.40e) of the pyrazole

• . Thus, a tilting of the pyrazole moiety away from orthogonality with respect to the plane generated by the aryl ring leads the n–π* excitation to be symmetry-allowed, with the corresponding increase in intensity. For example, the heteroring in fluorine-substituted 4pzH-F2 photoswitch is tilted with a θ

Fluorinated maleimide-substituted porphyrins and chlorins: synthesis and characterization

• Valentina A. Ol’shevskaya,
• Elena G. Kononova and
• Andrei V. Zaitsev

Beilstein J. Org. Chem. 2019, 15, 2704–2709, doi:10.3762/bjoc.15.263

• on 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin (1) as the starting compound. The presence of fluorine atoms on the four phenyl rings at the meso-positions of the porphyrin structure can make a strong influence on the hydrophobic interactions and lipophilicity, metabolic stability, thus modulating

• . Complexes 2a and 2b readily reacted with the excess of NaN3 in DMF/DMSO to afford porphyrins 3a and 3b in high yields via the selective substitution of fluorine atoms in the para-position of the pentafluorophenyl substituents with four azide functions. The subsequent reduction of para-tetraazidoporphyrinato

In search of visible-light photoresponsive peptide nucleic acids (PNAs) for reversible control of DNA hybridization

• Lei Zhang,
• Greta Linden and
• Olalla Vázquez

Beilstein J. Org. Chem. 2019, 15, 2500–2508, doi:10.3762/bjoc.15.243

• an improved TM difference between the trans- and cis-PNA15(oF4Azo)2 10 (up to ≈3.7 °C), which was the best for our system. Azobenzene (Azo)-containing PNAs behaved similarly to PNA(oF4Azo) (Table 2), which verified that the fluorine substitution did not affected the binding properties. The