Visible-light-promoted radical cyclisation of unactivated alkenes in benzimidazoles: synthesis of difluoromethyl- and aryldifluoromethyl-substituted polycyclic imidazoles

• Yujun Pang,
• Jinglan Yan,
• Nawaf Al-Maharik,
• Qian Zhang,
• Zeguo Fang and
• Dong Li

Beilstein J. Org. Chem. 2025, 21, 234–241, doi:10.3762/bjoc.21.15

• benzimidazole ring also successfully underwent smooth cyclization, leading to the formation of products 3c and 3d. Furthermore, the methodology was compatible with 5,6-disubstituted N-alkenylbenzimidazoles, including those with -difluoro, -dichloro, -dibromo, and -dimethyl substitutions, resulting in the

Nickel-catalyzed cross-coupling of 2-fluorobenzofurans with arylboronic acids via aromatic C–F bond activation

• Takeshi Fujita,
• Haruna Yabuki,
• Ryutaro Morioka,
• Kohei Fuchibe and
• Junji Ichikawa

Beilstein J. Org. Chem. 2025, 21, 146–154, doi:10.3762/bjoc.21.8

• coupling between these components (Scheme 1b). Among aromatic fluorides, we have targeted 2-fluorobenzofurans 1 for C–F bond activation [19]. These compounds, which we prepared efficiently via 5-endo-trig cyclization of β,β-difluoro-o-hydroxystyrenes [20][21], possess a C–C double bond with an electron

Synthesis, characterization, and photophysical properties of novel 9‑phenyl-9-phosphafluorene oxide derivatives

• Shuxian Qiu,
• Duan Dong,
• Jiahui Li,
• Huiting Wen,
• Jinpeng Li,
• Yu Yang,
• Shengxian Zhai and
• Xingyuan Gao

Beilstein J. Org. Chem. 2024, 20, 3299–3305, doi:10.3762/bjoc.20.274

• % yield over 2 steps) [34]. Upon exposure to NaNO2/HCl, diamine 3 was transformed into a diazonium salt, which was captured by KI to deliver the diiodide 4. Treatment of 4 with n-BuLi, PhPCl2, and H2O2 sequentially gave 2,8-difluoro-5-phenylbenzo[b]phosphindole 5-oxide (5) in 68% yield. With compound 5 in

Synthesis of extended fluorinated tripeptides based on the tetrahydropyridazine scaffold

• Thierry Milcent,
• Pascal Retailleau,
• Benoit Crousse and
• Sandrine Ongeri

Beilstein J. Org. Chem. 2024, 20, 3174–3181, doi:10.3762/bjoc.20.262

• for peptide synthesis. Consequently, developing a simple and efficient methodology is still challenging. Our new strategy to synthesize these compounds is based on an aza-Barbier reaction on difluoro- or trifluoromethylated hydrazones. The thus obtained compounds will then be oxidized and cyclized in

• order to lead to the expected fluorinated tetrahydropyridazines (Figure 4). Results and Discussion First, the difluoro- and trifluoromethylated hydrazones 3a–f were synthesized by condensing the corresponding hydrazide with the fluorinated aldehyde hemiacetal 2a or 2b (Scheme 2). Benzyl and tert-butyl

• trifluoro/difluoromethylated tetrahydropyridazine acids. Synthetic strategy to obtain fluorinated tetrahydropyridazines from difluoro- or trifluoromethylated hydrazones. X-ray diffraction of compound 8f. Reported syntheses of tetrahydropyridazine ester derivatives. Synthesis of fluorinated hydrazones 3a–f

Hypervalent iodine-mediated intramolecular alkene halocyclisation

• Charu Bansal,
• Oliver Ruggles,
• Albert C. Rowett and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 3113–3133, doi:10.3762/bjoc.20.258

• fluorinated oxazolines 32 was also reported using an electrochemical approach in 2019 by Waldvogel and co-workers (Scheme 17) [40]. The authors used electrochemical oxidation to form p-tolyl-difluoro-λ3-iodane 10 on the anode using an undivided cell with platinium electrodes in a 1:1 solution of CH2Cl2 and

• alkene forms the oxazoline A, and SN2 substitution with the fluoride ion displaces iodotoluene to form the product. An electrochemical approach was also reported by Lennox and co-workers for the synthesis of chromanes 34 (Scheme 18) [42]. The authors reported using p-tolyl-difluoro-λ3-iodane 10, formed

gem-Difluorovinyl and trifluorovinyl Michael acceptors in the synthesis of α,β-unsaturated fluorinated and nonfluorinated amides

• Monika Bilska-Markowska,
• Marcin Kaźmierczak,
• Wojciech Jankowski and
• Marcin Hoffmann

Beilstein J. Org. Chem. 2024, 20, 2946–2953, doi:10.3762/bjoc.20.247

• -difluoroalkenes and trifluoroalkenes in reactions with Grignard reagents [13][31]. Although, similar compounds are reported to be unstable molecules that are prone to decomposition under reaction conditions [32][33]. The goal of this work was the formation of gem-difluoro- and trifluorovinyl Michael acceptors by

4,6-Diaryl-5,5-difluoro-1,3-dioxanes as chiral dopants for liquid crystal compositions

• Maurice Médebielle,
• Peer Kirsch,
• Jérémy Merad,
• Carolina von Essen,
• Clemens Kühn and
• Andreas Ruhl

Beilstein J. Org. Chem. 2024, 20, 2940–2945, doi:10.3762/bjoc.20.246

• Darmstadt, Germany Institute of Materials Science, Technical University of Darmstadt, Peter-Grünberg-Str. 2, D-64287 Darmstadt, Germany 10.3762/bjoc.20.246 Abstract Two racemic anti-4,6-diphenyl-5,5-difluoro-1,3-dioxanes were prepared and the corresponding enantiomers were evaluated as potential new chiral

• still remain elusive and are not well understood [29]. Recently we have become interested in the preparation of racemic [30] anti- and highly enantioenriched 2,2-difluoro-1,3-diols [30][31][32] through an acylative double catalytic kinetic resolution (DoCKR) process [33]. While the 1,3-diol motif is

• found in some natural products [34] with some fluorinated analogues [35][36], this motif is rarely found in LCs [37][38][39]. Based on these observations and literature data, we embarked in the synthesis and evaluation of enantiomerically pure acetals derived from anti-2,2-difluoro-1,3-diols as

Recent advances in transition-metal-free arylation reactions involving hypervalent iodine salts

• Ritu Mamgain,
• Kokila Sakthivel and
• Fateh V. Singh

Beilstein J. Org. Chem. 2024, 20, 2891–2920, doi:10.3762/bjoc.20.243

• decarboxylation of α,α-difluoro-β-keto acid esters 11 with the help of aryl(TMP)iodonium tosylates 12 in toluene at 100 °C to yield α,α-difluoroketones 13 in excellent yield (Scheme 4). The reaction proceeds via ligand exchange between the fluorinated carboxylate and the tosylate anion of the hypervalent iodine

Mechanochemical difluoromethylations of ketones

• Jinbo Ke,
• Pit van Bonn and
• Carsten Bolm

Beilstein J. Org. Chem. 2024, 20, 2799–2805, doi:10.3762/bjoc.20.235

• contain a unique structural motif with potential for further functionalizations into highly diverse secondary or tertiary difluoroalkyl ethers. Dolbier and co-workers investigated reactions of difluorocarbene generated from its precursor trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (TFDA) and

• as heteroconjugated alkenes with difluorocarbene to give 2,2-difluoro-2,3-dihydrofurans [50] remained unsuccessful (Scheme S2 in Supporting Information File 1). Two mechanisms have been proposed for the difluoromethylation of ketones, as illustrated in Scheme 4A. In both cases, the process begins

Synthesis and conformational analysis of pyran inter-halide analogues of ᴅ-talose

• Olivier Lessard,
• Mathilde Grosset-Magagne,
• Paul A. Johnson and
• Denis Giguère

Beilstein J. Org. Chem. 2024, 20, 2442–2454, doi:10.3762/bjoc.20.208

• halo-divergent strategy from known 1,6-anhydro-2,3-dideoxy-2,3-difluoro-β-ᴅ-mannopyranose. In solution and in the solid-state, all analogues adopt standard 4C1-like conformations despite 1,3-diaxial repulsion between the F2 and the C4 halogen. Moreover, the solid-state conformational analysis of

• 1,6-anhydro-2,3-dideoxy-2,3-difluoro-β-ᴅ-mannopyranose (5) readily accessible form levoglucosan (1, Scheme 1) [24]. Activation of the C4 hydroxy group as triflate and direct treatment with a nucleophilic halogen furnished intermediates 8–11. The latter compounds proved to be difficult to purify

Novel truxene-based dipyrromethanes (DPMs): synthesis, spectroscopic characterization and photophysical properties

• Shakeel Alvi and
• Rashid Ali

Beilstein J. Org. Chem. 2024, 20, 2163–2170, doi:10.3762/bjoc.20.186

• in addition to the stimulating photophysical properties and distinct architectures emerging from the self-assembly processes [42]. Noticeably, most extensively used DPMs belong to the 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY), owing to their high propensity toward chemical manipulations and

1,2-Difluoroethylene (HFO-1132): synthesis and chemistry

• Liubov V. Sokolenko,
• Taras M. Sokolenko and
• Yurii L. Yagupolskii

Beilstein J. Org. Chem. 2024, 20, 1955–1966, doi:10.3762/bjoc.20.171

• -difluoroethylene and the disappearance of vinyl protons resonances in the 1H NMR spectra [78]. Addition to the C=C bond Halogen addition: 1,2-Difluoroethylene was reported to react with chlorine [46][79] and bromine [51] under irradiation, yielding 1,2-difluoro-1,2-dihaloethanes in moderate to high yield (Scheme 9

• reacted with hexachlorocyclopentadiene at 200–220 °C within 3–4 days, forming 5,6-endo,endo-difluoro-1,2,3,4,7,7-hexachlorobicyclo[2.2.1]-2-heptene (Scheme 20) in 66% yield. At the same time, (E)-1,2-difluoroethylene, which formed the endo,exo-adduct, reacted much slower, and completion of the reaction

• required 2–3 weeks at the same temperature. In this case, sufficient E–Z isomerization of the starting olefin occurred during the reaction, and the major product was 5,6-endo,endo-difluoro-1,2,3,4,7,7-hexachlorobicyclo[2.2.1]-2-heptene, which was formed from (Z)-1,2-difluoroethylene (Scheme 20). Both

Oxidative fluorination with Selectfluor: A convenient procedure for preparing hypervalent iodine(V) fluorides

• Samuel M. G. Dearman,
• Xiang Li,
• Yang Li,
• Kuldip Singh and
• Alison M. Stuart

Beilstein J. Org. Chem. 2024, 20, 1785–1793, doi:10.3762/bjoc.20.157

• ) fluorides in good isolated yields (72–90%). Stability studies revealed that bicyclic difluoro(aryl)-λ5-iodane 6 was much more stable in acetonitrile-d3 than in chloroform-d1, presumably due to acetonitrile coordinating to the iodine(V) centre and stabilising it via halogen bonding. Keywords: fluorination

• ) fluorides by reacting iodine(III) precursors with commercially available Selectfluor. The method avoids large excesses of reagents and pure iodine(V) fluorides are isolated after a simple work-up. Results and Discussion Preparation of bicyclic difluoro(aryl)-λ5-iodanes Two different types of bicyclic

• difluoro(aryl)-λ5-iodanes were designed originally because of the stabilisation afforded from two five-membered rings (Figure 1). We started our investigation with bicyclic difluoro(aryl)-λ5-iodane 6, building on the hypervalent iodine core skeleton used in fluoroiodane 2, with an additional 5-membered

Hypervalent iodine-catalyzed amide and alkene coupling enabled by lithium salt activation

• Akanksha Chhikara,
• Fan Wu,
• Navdeep Kaur,
• Prabagar Baskaran,
• Alex M. Nguyen,
• Zhichang Yin,
• Anthony H. Pham and
• Wei Li

Beilstein J. Org. Chem. 2024, 20, 1405–1411, doi:10.3762/bjoc.20.122

• will then enable soft nucleophiles such as unadorned amides to readily participate in the ensuing olefin addition. In this regard, we wondered if the hypervalent iodine with difluoro ligands could undergo salt metathesis with lithium salts such as LiBF4 or LiPF6 to afford the more reactive cationic

• iodine catalyst with difluoro ligands. Interestingly, the use of different lithium salts also impacted the overall reaction rate, with the reaction using the less coordinating LiAsF6 salt proceeding faster than LiPF6 and LiBF4. This time study suggested that the hypervalent iodine precatalyst with the

Rhodium-catalyzed homo-coupling reaction of aryl Grignard reagents and its application for the synthesis of an integrin inhibitor

• Kazuyuki Sato,
• Satoki Teranishi,
• Atsushi Sakaue,
• Yukiko Karuo,
• Atsushi Tarui,
• Kentaro Kawai,
• Hiroyuki Takeda,
• Tatsuo Kinashi and
• Masaaki Omote

Beilstein J. Org. Chem. 2024, 20, 1341–1347, doi:10.3762/bjoc.20.118

• amount of 3,3''-difluoro-1,1':3',1''-terphenyl (6h) as side product, that might derive from an SNAr reaction of 3h with the Grignard reagent of 5h. Moreover, bromoxylenes 5m–o also gave the corresponding products 3m–o, respectively, although the position of substituents affected the yields. On the other

Synthesis and physical properties of tunable aryl alkyl ionic liquids based on 1-aryl-4,5-dimethylimidazolium cations

• Stefan Fritsch and
• Thomas Strassner

Beilstein J. Org. Chem. 2024, 20, 1278–1285, doi:10.3762/bjoc.20.110

• increasing viscosity of the TAAILs, which can be explained by the increase in molar mass and stronger van-der-Waals interactions. The only exceptions are the methoxy and 2,4-difluoro substituted TAAILs, demonstrating that the effects of the aryl substitution can have a stronger influence on the viscosity

Synthesis of 1,4-azaphosphinine nucleosides and evaluation as inhibitors of human cytidine deaminase and APOBEC3A

• Maksim V. Kvach,
• Stefan Harjes,
• Harikrishnan M. Kurup,
• Geoffrey B. Jameson,
• Elena Harjes and
• Vyacheslav V. Filichev

Beilstein J. Org. Chem. 2024, 20, 1088–1098, doi:10.3762/bjoc.20.96

• . Recently, a combination of the CDA inhibitor (4R)-2′-deoxy-2′,2′-difluoro-3,4,5,6-tetrahydrouridine (cedazuridine, Ib, Figure 1B) with the anticancer drug decitabine was approved as an oral pill (i.e., C-DEC or ASTX727) for the treatment of patients with intermediate or high-risk myelodysplastic syndrome

Synthesis of 2,2-difluoro-1,3-diketone and 2,2-difluoro-1,3-ketoester derivatives using fluorine gas

• Alexander S. Hampton,
• David R. W. Hodgson,
• Graham McDougald,
• Linhua Wang and
• Graham Sandford

Beilstein J. Org. Chem. 2024, 20, 460–469, doi:10.3762/bjoc.20.41

• Swing Road, Greensboro, North Carolina, NC 27409, USA 10.3762/bjoc.20.41 Abstract Solutions of 1,3-diketones and 1,3-ketoester derivatives react with fluorine to give the corresponding 2,2-difluoro-1,3-dicarbonyl derivatives in the presence of quinuclidine. Quinuclidine reacts with fluorine in situ to

• agents offers an alternative fluorination route, for example, the reactions of MeCN solutions of 1,3-diketones with electrophilic fluorinating agents such as Selectfluor eventually give the corresponding 2,2-difluoro-1,3-diketone derivatives [12]. Monofluorination of the 1,3-diketone substrates is rapid

• -diketones occurs rapidly because the substrates lie predominantly in their enol tautomeric forms. The resulting 2-difluoro-1,3-diketones, on the other hand, are formed in their keto-tautomeric forms. Thus, we found difluorination could only be achieved upon addition of water or a base to accelerate the

Mono or double Pd-catalyzed C–H bond functionalization for the annulative π-extension of 1,8-dibromonaphthalene: a one pot access to fluoranthene derivatives

• Nahed Ketata,
• Linhao Liu,
• Ridha Ben Salem and
• Henri Doucet

Beilstein J. Org. Chem. 2024, 20, 427–435, doi:10.3762/bjoc.20.37

• (8) has also been successfully prepared from 2-fluorobenzonitrile. The first arylation between 1,2,3-trifluorobenzene and 1,8-dibromonaphthalene also takes place ortho to one of the fluorine atoms to give compound 9 in 71% yield. The use of 1,2-difluoro-3-methylbenzene allowed us to obtain 7,8

• -difluoro-9-methylfluoranthene (10) with a yield of 45%. Four fluorobenzenes bearing chloro, methyl or methoxy substituents at two positions were then employed. In all cases, the desired fluoranthenes 11–14 bearing substituents at positions 7–10 were obtained in moderate yields. With 1,3-dichlorobenzene

Chiral phosphoric acid-catalyzed transfer hydrogenation of 3,3-difluoro-3H-indoles

• Yumei Wang,
• Guangzhu Wang,
• Yanping Zhu and
• Kaiwu Dong

Beilstein J. Org. Chem. 2024, 20, 205–211, doi:10.3762/bjoc.20.20

• synthesis of optically active difluoro-substituted indoline derivatives starting from the corresponding 3H-indoles by chiral phosphoric acid-catalyzed transfer hydrogenation was developed. Using Hantzsch ester as the hydrogen source under mild reaction conditions, the target products can be obtained with

• asymmetric reduction studies focused on alkyl or aryl-substituted 3H-indoles whereas the synthesis of chiral difluorinated indole derivatives could have potential applications in pharmaceutical chemistry. Herein, an organocatalyzed transfer hydrogenation of 3,3-difluoro-3H-indoles to obtain fluorinated 3H

• -indolines was developed (Scheme 1c). With this method, a variety of chiral 3,3-difluoroindolines were synthesized in high yield and enantioselectivity under mild reaction conditions. Results and Discussion We conducted a preliminary exploration of the reaction using 3,3-difluoro-2-(phenylethynyl)-3H-indole

Quinoxaline derivatives as attractive electron-transporting materials

• Zeeshan Abid,
• Liaqat Ali,
• Sughra Gulzar,
• Faiza Wahad,
• Raja Shahid Ashraf and
• Christian B. Nielsen

Beilstein J. Org. Chem. 2023, 19, 1694–1712, doi:10.3762/bjoc.19.124

• based on Qxs is of significant interest in the field of organic electronics. A compelling indication of this potential is the remarkable achievements made by a relatively simple polymer, poly[(thiophene)-alt-(6,7-difluoro-2-(2-hexyldecyloxy)quinoxaline)] (PTQ10). PTQ10 has demonstrated impressive power

• , wherein researchers substituted alkoxy chains to enhance solubility and difluoro groups to lower the highest occupied molecular orbital (HOMO) energy level. Qx-derived polymer acceptors have witnessed significant progress in recent years, driven by a contextual understanding of the major issues hindering

• ability of NFAs. Huang et al. synthesized noncovalently fused-ring electron acceptors (NFREAs), Qx20 and Qx21, featuring 6,7-difluoro-2,3-diphenylquinoxaline core. The fluorine atoms of the core formed multiple noncovalent bonds (N···H and S···F) thus improving backbone coplanarity. This approach enhanced

Morpholine-mediated defluorinative cycloaddition of gem-difluoroalkenes and organic azides

• Tzu-Yu Huang,
• Mario Djugovski,
• Sweta Adhikari,
• Destinee L. Manning and
• Sudeshna Roy

Beilstein J. Org. Chem. 2023, 19, 1545–1554, doi:10.3762/bjoc.19.111

• are available [2][3], only a couple of cycloaddition reactions has been reported [4]. For example, [3 + 2] dipolar cycloadditions to form saturated difluoroisoxazolidines [5][6] and difluoropyrrolidines [7] and [4 + 2] cycloaddition reactions with gem-difluoro-1,3-dienes [8]. The overall landscape of

• 19F NMR spectroscopy to monitor the consumption of the gem-difluoro starting material 1, which was completely consumed within 16 h (Figure 3). However, a 48 h time course gave a superior yield (Table 1, entry 13 vs entry 20). We hypothesize this might be due to the volatile nature of the gem

Simple synthesis of multi-halogenated alkenes from 2-bromo-2-chloro-1,1,1-trifluoroethane (halothane)

• Yukiko Karuo,
• Atsushi Tarui,
• Kazuyuki Sato,
• Kentaro Kawai and
• Masaaki Omote

Beilstein J. Org. Chem. 2022, 18, 1567–1574, doi:10.3762/bjoc.18.167

• afford 1,1-difluoro-2-haloethyl ethers, although their boiling points are below 6 °C, which often causes handling problems (Scheme 1A) [8]. 1,1-Difluoro-2-haloethyl ethers have been obtained by reacting HCFC-133a with alcohols in the presence of a small amount of water, but the reaction requires the use

Bioinspired tetraamino-bisthiourea chiral macrocycles in catalyzing decarboxylative Mannich reactions

• Hao Guo,
• Yu-Fei Ao,
• De-Xian Wang and
• Qi-Qiang Wang

Beilstein J. Org. Chem. 2022, 18, 486–496, doi:10.3762/bjoc.18.51

• 5-methyl (8i), 5-methoxy (8k), 6- or 7-fluoro (8l,m), 5,6-difluoro (8n), 5-, 6- or 7-chloro (8p–r), 5-, 6-, or 7-bromo (8t–v), and 7-trifluoromethyl (8w), all reactions completed within 36–48 h and afforded the products in good to excellent yields with 60–75% ee. In contrast, the reaction was

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

• two equivalents of NFSI afforded 4,4-difluoro-3,5-dimethoxy-2,5-cyclohexadienone (2c'') as the major product in 80% yield (Scheme 2a). Mechanistically, formation of 2c'' from 1,3,5-trimethoxybenzene (1c) requires a fluorodemethylation pathway to be operational under the ball-milling conditions, for