Exploring the role of halogen bonding in iodonium ylides: insights into unexpected reactivity and reaction control

• Carlee A. Montgomery and
• Graham K. Murphy

Beilstein J. Org. Chem. 2023, 19, 1171–1190, doi:10.3762/bjoc.19.86

• resulting in two different ligand coupling outcomes. While most of their reactions expel an iodoarene to produce functionalized β-dicarbonyl motifs, ligand coupling with the arene motif is also possible, such as in the (radio)fluorination of iodonium ylides. Finally, intramolecular σ-hole bonding offers the

• elimination (e.g., with the β-dicarbonyl or arene) could occur (see Scheme 1). A prominent example of the coupling occurring between the Lewis base and the arene is in reactions with fluoride, which has been translated to enable the radiofluorination of non-activated arenes. While this fluorination reaction

• ]. Computational investigations were conducted to better understand these reactions, and it was determined that the changing alkyl motif (e.g., dimethyl, cyclopentyl, adamantyl) had minimal impact on the activation energy of the fluorination reactions. The reaction coordinate was calculated for Meldrum’s acid

Transition-metal-catalyzed C–H bond activation as a sustainable strategy for the synthesis of fluorinated molecules: an overview

• Louis Monsigny,
• Floriane Doche and
• Tatiana Besset

Beilstein J. Org. Chem. 2023, 19, 448–473, doi:10.3762/bjoc.19.35

• direct dehydrogenative 2,2,2-trifluoroethoxylation of (hetero)arenes, often using 2,2,2-trifluoroethanol as a readily available, inexpensive, and green fluorination source [159][160], is still underexplored. In 2004, Sanford and co-workers reported the dehydrogenative 2,2,2-trifluoroethoxylation of benzo

• directing group (namely NHPA and CONHPIP for 53 and 55, respectively), the groups of Chen [71] and Shi [192] independently reported the palladium-catalyzed selective 2,2,2-trifluoroethoxylation of aliphatic amines and amides at the γ and β positions, respectively, using trifluoroethanol as fluorination

Dipeptide analogues of fluorinated aminophosphonic acid sodium salts as moderate competitive inhibitors of cathepsin C

• Karolina Wątroba,
• Małgorzata Pawełczak and
• Marcin Kaźmierczak

Beilstein J. Org. Chem. 2023, 19, 434–439, doi:10.3762/bjoc.19.33

• the catalytic cysteine Cys234 [10]. Phosphonates, as well as their analogues phosphonic acids, can be modified in a number of ways, one of which is the introduction of a fluorine atom into their molecules by fluorination or alkylfluorination [11][12][13][14]. However, the reaction of β-aminoalcohols

Redox-active molecules as organocatalysts for selective oxidative transformations – an unperceived organocatalysis field

• Elena R. Lopat’eva,
• Igor B. Krylov,
• Dmitry A. Lapshin and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2022, 18, 1672–1695, doi:10.3762/bjoc.18.179

• -hydroxybenzimidazole core has several modification sites that allow one to control the properties of the catalyst over a wide range. The authors demonstrated the high efficiency of N-hydroxybenzimidazole catalysts in the benzylic CH-amination with diethyl azodicarboxylate and the CH-fluorination of aldehydes with

• of ethylbenzene and CH-fluorination of aldehydes catalyzed by N-hydroxybenzimidazoles, precursors of corresponding N-oxyl radicals. Mixed hetero-/homogeneous TiO2/N-hydroxyimide photocatalysis in the selective benzylic oxidation. Electrochemical benzylic iodination and benzylation of pyridine by

On drug discovery against infectious diseases and academic medicinal chemistry contributions

• Yves L. Janin

Beilstein J. Org. Chem. 2022, 18, 1355–1378, doi:10.3762/bjoc.18.141

• [288][289][290][291][292][293]. Moreover, the use/design of new chemical reactions may lead to hard-to-get and original analogues possibly better than the one reported. One example, depicted in Scheme 2, would be the fluorination, under superacid conditions [294], of the highly elaborated anticancer

Reductive opening of a cyclopropane ring in the Ni(II) coordination environment: a route to functionalized dehydroalanine and cysteine derivatives

• Oleg A. Levitskiy,
• Olga I. Aglamazova,
• Yuri K. Grishin and
• Tatiana V. Magdesieva

Beilstein J. Org. Chem. 2022, 18, 1166–1176, doi:10.3762/bjoc.18.121

• fluorination of arylcyclopropane derivatives was reported recently [46][47], difluorinated or oxyfluorinated products were obtained [47]. Notably, anodic fluorination of cyclopropane derivatives bearing arylthio groups gives rise to a variety of possible reaction paths yielding monofluorinated sulfoxides as

Introducing a new 7-ring fused diindenone-dithieno[3,2-b:2',3'-d]thiophene unit as a promising component for organic semiconductor materials

• Valentin H. K. Fell,
• Joseph Cameron,
• Alexander L. Kanibolotsky,
• Eman J. Hussien and
• Peter J. Skabara

Beilstein J. Org. Chem. 2022, 18, 944–955, doi:10.3762/bjoc.18.94

• example, ITIC (10), is shown in Figure 4. ITIC [17], in combination with polymer 11, achieved a power conversion efficiency (PCE) of 6.8%, which was the best value for NFA organic solar cells at the time of publication. Fluorination of ITIC, obtaining IT-4F (12), shown in Figure 5, reduced ELUMO. Combined

Cathodic generation of reactive (phenylthio)difluoromethyl species and its reactions: mechanistic aspects and synthetic applications

• Sadanobu Iwase,
• Shinsuke Inagi and
• Toshio Fuchigami

Beilstein J. Org. Chem. 2022, 18, 872–880, doi:10.3762/bjoc.18.88

• from an aspect of green chemistry [7][8][9][10]. In this context, we have developed various electrochemical methodologies for efficient selective fluorination [11][12] and molecular conversion of organofluorine compounds to date [13][14][15][16][17][18]. We have also achieved the gem-difluorination of

Multi-faceted reactivity of N-fluorobenzenesulfonimide (NFSI) under mechanochemical conditions: fluorination, fluorodemethylation, sulfonylation, and amidation reactions

• José G. Hernández,
• Karen J. Ardila-Fierro,
• Dajana Barišić and
• Hervé Geneste

Beilstein J. Org. Chem. 2022, 18, 182–189, doi:10.3762/bjoc.18.20

• solution, the mechanochemical reactions were accomplished in the absence of solvents, in short reaction times, and in yields comparable to or higher than their solvent-based counterparts. Keywords: amidation; ball mill; fluorination; in situ monitoring; mechanochemistry; NFSI; Raman monitoring

• reagent [9][10][11], and phenylsulfonyl group transfer reagent [12][13]. In the field of mechanochemistry, the usefulness of N-fluorobenzenesulfonimide has been exemplified in the asymmetric fluorination of β-keto esters (Scheme 1a) [14], and in diastereoselective fluorinations (Scheme 1b) [15], which

• functionalizations [22][23]. In particular, efficient fluorination protocols are long sought after in several areas of science, including medicinal chemistry [24]. Next to fluorination, in this work, we also have investigated NFSI as a source for mechanochemical sulfonylation of imidazoles and amidation reactions

Recent advances in the tandem annulation of 1,3-enynes to functionalized pyridine and pyrrole derivatives

• Yi Liu,
• Puying Luo,
• Yang Fu,
• Tianxin Hao,
• Xuan Liu,
• Qiuping Ding and
• Yiyuan Peng

Beilstein J. Org. Chem. 2021, 17, 2462–2476, doi:10.3762/bjoc.17.163

• functionalized pyridine and pyrrole derivatives from easily available 1,3-enynes. Therefore, the significant challenges will focus on the following aspects in the future: i) development of more functionalizations of pyridines and pyrroles (such as fluorination, trifluoromethylthiolation, olefination

Halides as versatile anions in asymmetric anion-binding organocatalysis

• Lukas Schifferer,
• Martin Stinglhamer,
• Kirandeep Kaur and
• Olga García Macheño

Beilstein J. Org. Chem. 2021, 17, 2270–2286, doi:10.3762/bjoc.17.145

• between the catalyst and the substrate, which exclusively stabilize the transition state that forms the major enantiomer. Furthermore, Gouverneur and co-workers established an enantioselective nucleophilic fluorination protocol using a chiral bis-urea catalyst 41 and CsF as an inorganic fluoride source

• catalyzed by chiral squaramide 37 by Jacobsen et al. Bis-urea-catalyzed enantioselective fluorination of a) β-bromosulfides and b) β-haloamines by Gouverneur et al. a) Bifunctional thiourea anion-binding – basic/nucleophilic catalysts. Selected applications in b) enantioselective α-alkylation of aldehydes

A study on selective transformation of norbornadiene into fluorinated cyclopentane-fused isoxazolines

• Zsanett Benke,
• Attila M. Remete and
• Loránd Kiss

Beilstein J. Org. Chem. 2021, 17, 2051–2066, doi:10.3762/bjoc.17.132

• ) late-stage fluorination, when the fluorine atom is incorporated in the final step of the synthetic protocol (e.g., deoxofluorinations) or ii) application of various commercial fluorine-containing scaffolds (e.g., fluorine-containing amines, fluorine-containing alkenes etc.) [49][50][51][52][53][54][55

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

• Renato L. Carvalho,
• Amanda S. de Miranda,
• Mateus P. Nunes,
• Roberto S. Gomes,
• Guilherme A. M. Jardim and
• Eufrânio N. da Silva Júnior

Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126

• physicochemical properties of a compound, thus affecting its pharmacodynamic and pharmacokinetic profile. Consequently, fluorination methods are particularly useful in the synthesis of bioactive substances, including marketed drugs (24 and 25) (Scheme 10A) [93]. In addition to oxygen insertion, vanadium use has

• also been reported for the direct C(sp3)–H fluorination. Chen and co-workers [94] described a fluorination method employing Selectfluor as fluorine source and the commercially available V2O3 to give fluorine-containing compounds under mild conditions and with moderate to good yields (Scheme 10B,C). The

• reaction showed to be chemoselective, maintaining good yields with compounds bearing varied functional groups, whereas low yields were observed for benzylic fluorination. Preliminary mechanistic studies suggested the C–H abstraction to be the rate-determining step and the high oxygen sensitivity of the

Development of N-F fluorinating agents and their fluorinations: Historical perspective

• Teruo Umemoto,
• Yuhao Yang and
• Gerald B. Hammond

Beilstein J. Org. Chem. 2021, 17, 1752–1813, doi:10.3762/bjoc.17.123

• and reactions of these reagents are described chronologically and the review also discusses the relative fluorination power of each reagent and their mechanisms chronicling developments from a historical perspective. Keywords: N-F fluorinating agent; fluorination; fluorodiazoniabicyclo[2.2.2]octane

• fluorination of pyridine or 2-fluoropyridine in anhydrous hydrogen fluoride [17][18] (Scheme 2). Not surprisingly, 1-1 did not become a popular reagent. In 1967, Banks et al. reported reactions of 1-1 with piperidine and triphenylphosphine, -arsine, and -stibine (Scheme 3, entries 1 and 2) [19]. The former

•  4) [23]. However, there were no reports on the fluorination capability of these N-F compounds. The purpose of this research was to establish if the presence of perfluoroacyl groups was sufficient to stabilize the Xe–N bond. Their experiment revealed that the intermediate F–Xe-N compounds were not

Sustainable manganese catalysis for late-stage C–H functionalization of bioactive structural motifs

• Jongwoo Son

Beilstein J. Org. Chem. 2021, 17, 1733–1751, doi:10.3762/bjoc.17.122

• active molecules and complex peptides, which are of great importance to medicinal chemists and are categorized according to the transformations involved. Review Manganese-catalyzed late-stage C–H fluorination The fluorination of organic molecules [13][14][15][16], a highly valuable synthetic

• late-stage fluorination (Csp3–F) is relatively challenging due to the omnipresent unactivated C–H bonds of the substrate molecules. In 2012, Groves et al. revealed a manganese porphyrin-catalyzed late-stage Csp3–H fluorination method (Scheme 1) [22]. In the authors’ approach, a direct late-stage

• process facilitated the fluorination of sclareolide (1) and complex steroid 3. Sclareolide (1) is a naturally available terpenoid with antifungal and anticancer activities [23]. Under the optimized reaction conditions, sclareolide (1) is fluorinated at the C2 and C3 positions in 42% (see 2a) and 16% yield

Chemical approaches to discover the full potential of peptide nucleic acids in biomedical applications

• Nikita Brodyagin,
• Martins Katkevics,
• Venubabu Kotikam,
• Christopher A. Ryan and
• Eriks Rozners

Beilstein J. Org. Chem. 2021, 17, 1641–1688, doi:10.3762/bjoc.17.116

• uracil with fluorine or trifluoromethyl improved PNA binding affinity for complementary DNA and RNA [127]. Moreover, fluorination increased the cellular uptake of PNAs [127]. Fluorinated uracil derivatives are also useful probes for studying different binding modes of PNA using 19F NMR [128]. PNA

Recent advances in the application of isoindigo derivatives in materials chemistry

• Andrei V. Bogdanov and
• Vladimir F. Mironov

Beilstein J. Org. Chem. 2021, 17, 1533–1564, doi:10.3762/bjoc.17.111

• = 1.08 cm2⋅V−1⋅s−1). For comparison, a similar device based on a nonfluorinated analog showed a value of μh = 2.71 cm2⋅V−1⋅s−1 [74]. Continuing the study of the effect of the substituent nature on the OFET efficiency, a number of polymers 47 with varying degree of fluorination of the monomer structural

• . Monothienylisoindigos bearing π-extended electron-donor backbones. Role of fluorination and the molecular weight on OSC efficiency on the base of the bithiopheneisoindigo series. Trithiopheneisoindigo polymers with variation in the substituent structure. Polymeric thienyl-linked bisisoindigos for OSCs. Isoindigo

• substituent as side-chain photon trap. Isoindigo derivatives for OFET technology with the best mobility. Monoisoindigos as low-molecular-weight semiconductors. Polymeric bithiopheneisoindigos for OFET creation. Fluorination as a tool to improve isoindigo-based OFET devices. Diversely DPP–isoindigo-conjugated

Synthesis of multiply fluorinated N-acetyl-D-glucosamine and D-galactosamine analogs via the corresponding deoxyfluorinated glucosazide and galactosazide phenyl thioglycosides

• Vojtěch Hamala,
• Lucie Červenková Šťastná,
• Martin Kurfiřt,
• Petra Cuřínová,
• Martin Dračínský and
• Jindřich Karban

Beilstein J. Org. Chem. 2021, 17, 1086–1095, doi:10.3762/bjoc.17.85

• Technology Prague, Technická 5, 16628 Praha 6, Czech Republic NMR Spectroscopy group, Institute of Organic Chemistry and Biochemistry of the CAS, Flemingovo náměstí 542/2, 16000 Praha, Czech Republic 10.3762/bjoc.17.85 Abstract Multiple fluorination of glycostructures has emerged as an attractive way of

• molecules [12]. The fluorination of sugars is also a promising strategy to improve unfavorable pharmacokinetic properties of natural carbohydrates such as low lipophilicity [13][14][15][16] and fast metabolic degradation [17][18][19]. Over the last few years, considerable effort has been expended on the

• biomedical applications due to their ability to inhibit the glycan and glycosaminoglycan biosynthesis [34][35][36][37]. The fluorine substituent has typically been introduced into these GlcNAc and GalNAc analogues using nucleophilic fluorination. The primary position (C6 hydroxy group) was fluorinated by

Beyond ribose and phosphate: Selected nucleic acid modifications for structure–function investigations and therapeutic applications

• Christopher Liczner,
• Kieran Duke,
• Gabrielle Juneau,
• Martin Egli and
• Christopher J. Wilds

Beilstein J. Org. Chem. 2021, 17, 908–931, doi:10.3762/bjoc.17.76

• natural antibiotic nucleocidin [203][205]. Damha reasoned that the incorporation of fluorine at both C2' and C4' could lead to a stable nucleoside due to the glycosidic bond stabilization brought about by 2'-fluorination [206] which turned out to be correct after successful isolation of both 2',4'-diF-rU

Manganese/bipyridine-catalyzed non-directed C(sp³)–H bromination using NBS and TMSN₃

• Kumar Sneh,
• Takeru Torigoe and
• Yoichiro Kuninobu

Beilstein J. Org. Chem. 2021, 17, 885–890, doi:10.3762/bjoc.17.74

• reported the manganese-porphyrin-catalyzed chlorination and bromination of C(sp3)−H bonds, respectively (Scheme 1d). Groves et al. also reported the manganese-salen-catalyzed fluorination of benzylic C(sp3)−H bonds [49]. Although these methods are efficient, they have a limited substrate scope

Metal-free visible-light-enabled vicinal trifluoromethyl dithiolation of unactivated alkenes

• Xiaojuan Li,
• Qiang Zhang,
• Weigang Zhang,
• Jinzhu Ma,
• Yi Wang and
• Yi Pan

Beilstein J. Org. Chem. 2021, 17, 551–557, doi:10.3762/bjoc.17.49

• ], fluorination [40], and selenylation [41] have been reported (Scheme 1a). However, the visible-light-induced trifluoromethylthio difunctionalization of alkenes remained underdeveloped. For instance, Magnier and co-workers have documented a practical intramolecular carbotrifluoromethylthiolation of acrylamides

Synthesis and physicochemical evaluation of fluorinated lipopeptide precursors of ligands for microbubble targeting

• Masayori Hagimori,
• Estefanía E. Mendoza-Ortega and
• Marie Pierre Krafft

Beilstein J. Org. Chem. 2021, 17, 511–518, doi:10.3762/bjoc.17.45

• incorporating the new F-lipopeptides were determined and compared to those of reference MBs of similar phospholipid composition. Results and Discussion Synthesis and characterization of the lipid–peptide conjugates Since the degree of fluorination of the hydrophobic chains of the lipid conditions the extent of

• , reflecting a progressive adsorption at the interface, then reached a plateau, and stabilized at the equilibrium surface pressure (πeq). The adsorption kinetics demonstrate that the F-lipopeptides formed stable monolayers at the interface. The πeq values increased with the degree of fluorination of the F

• , reflecting the insertion in the DPPC monolayer. The higher the degree of fluorination, the higher the amount inserted, with a maximal efficiency observed for lipopeptide 3 (C8F17). However, the behavior of the F-lipopeptide 2 with an odd number of carbon atoms (C7F15) is closer to that of 1 (C6F13) than to

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

• compared to proline (Figure 5) [19]. Although, the difference is small, it may have an impact on the overall features of the peptides and proteins that rely on polarity. 2.4 Proline puckering In addition to the general impact of fluorination, there are some properties specifically attributed to the proline

• folding, thereby stabilizing or destabilizing particular secondary structure folds. Fluorination creates a pucker bias due to orbital interactions of the carbon–fluorine bond within the molecule, known as the gauche-effect [50]. The parent proline structure has a negligible energetic difference between

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

• of fluorine(s) into organic molecules usually leads to significant changes in the chemical and physicochemical properties of the original compounds [5][6]. Hence, the fluorination and related fluoro-functionalization of drug candidates are powerful strategies in drug design to appropriately bias

• cost of target compounds [11][12][13][14][15]. Thus, the development of low-cost and straightforward chemical synthetic technologies, including fluorination and trifluoromethylation, are matters of considerable importance to pharmaceutical and agrochemical industries. Fluoroform (HCF3, HFC-23) is an

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

• ) were successful. Therefore, alternative methods such as intramolecular cyclizations, exchange fluorination, and transformation of functional groups in fluorinated rings have been developed in order to provide access to fluorinated cyclopropanes with electron-withdrawing substituents. 1.1