N-Glycosides of indigo, indirubin, and isoindigo: blue, red, and yellow sugars and their cancerostatic activity

• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 2840–2869, doi:10.3762/bjoc.20.240

• from p-fluoroaniline which can be explained by the π-donating effect of fluorine which facilitates the cyclization via the ortho-position in case of m-, but not of p-fluoroaniline. It is worth to be noted that the formation of 23d proceeded with excellent regioselectivity via carbon C-6 rather than C-2

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

• through the formation of novel reactive intermediates [15][16][17][18]. Fluorine-containing functional groups are essential structural motifs in the development of new bioactive compounds and functional materials. Compared to their non-fluorinated analogs, the presence of fluorine atoms in molecular

Access to optically active tetrafluoroethylenated amines based on [1,3]-proton shift reaction

• Yuta Kabumoto,
• Eiichiro Yoshimoto,
• Bing Xiaohuan,
• Masato Morita,
• Motohiro Yasui,
• Shigeyuki Yamada and
• Tsutomu Konno

Beilstein J. Org. Chem. 2024, 20, 2776–2783, doi:10.3762/bjoc.20.233

• amides in moderate three-step yields. Keywords: amine; chirality transfer; [1,3]-proton shift reaction; tetrafluoroethylene fragment; Introduction A fluorine atom has quite peculiar chemical and physical properties compared to others, and hence changes in molecular properties resulting from the

• introduction of fluorine atom(s) into organic molecules are also significantly unique, and often extremely noticeable even when the number of the atom introduced is small [1][2][3]. By skillfully utilizing such characteristics, fluorine-containing organic molecules have established themselves as indispensable

• compounds in various frontlines, such as medicinal, agrochemical, and material fields [4][5][6][7]. In particular, tetrafluoroethylenated compounds possessing two fluorine atoms on each of two adjacent carbons, have been attracting an enormous attention these days. This stems from the fact that substances

Synthesis of spiroindolenines through a one-pot multistep process mediated by visible light

• Francesco Gambuti,
• Jacopo Pizzorno,
• Chiara Lambruschini,
• Renata Riva and
• Lisa Moni

Beilstein J. Org. Chem. 2024, 20, 2722–2731, doi:10.3762/bjoc.20.230

• without further purification. Graphene oxide (GO) was purchased from Graphenea. All products were characterized by 1H,13C, 19F (when fluorine is present) NMR, IR and HRMS. General procedure for the one-pot synthesis of spiro[indole-isoquinoline] 3a: A solution of N-phenyltetrahydroisoquinoline (1 equiv

Synthesis of benzo[f]quinazoline-1,3(2H,4H)-diones

• Ruben Manuel Figueira de Abreu,
• Peter Ehlers and
• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 2708–2719, doi:10.3762/bjoc.20.228

• isolated in moderate to excellent yields (Scheme 3). The best yield was obtained for 5a with 99%. Several functional groups, such as methyl, N,N-dimethylamino, and trifluoromethyl, are tolerated by the developed procedure. However, a fluorine group was converted to a hydroxy functional group (5h), most

Synthesis of fluoroalkenes and fluoroenynes via cross-coupling reactions using novel multihalogenated vinyl ethers

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

Beilstein J. Org. Chem. 2024, 20, 2691–2703, doi:10.3762/bjoc.20.226

• synthetic methods for fluoroalkenes have attracted considerably and become increasingly necessary in pharmaceutical and industrial fields. Fluoroalkenes have been constructed in a variety of methods [4][5][6][7][8][9][10][11][12][13][14], and one of the methods is to make use of fluorine-containing building

• blocks. When using them as nucleophilic reagents [15][16][17][18][19][20], the reaction between anion species, such as fluorine-containing Horner–Wadsworth–Emmons reagents, and carbonyl compounds led to E-selective olefination (Scheme 1A) [15]. On the other hand, some reactions with electrophilic

• fluorine-containing building blocks have been developed [21][22][23][24][25]. Jubault and Poisson et al. reported SN2’ reactions of hydride or alcohols to electrophilic fluorine-containing alkenes gave the corresponding fluoroalkenes (Scheme 1B) [21]. In recent years, many fluorine-containing coupling

Synthesis and cytotoxicity studies of novel N-arylbenzo[h]quinazolin-2-amines

• Battini Veeraiah,
• Kishore Ramineni,
• Dabbugoddu Brahmaiah,
• Nangunoori Sampath Kumar,
• Hélène Solhi,
• Rémy Le Guevel,
• Chada Raji Reddy,
• Frédéric Justaud and
• René Grée

Beilstein J. Org. Chem. 2024, 20, 2592–2598, doi:10.3762/bjoc.20.218

• compounds with two substituents or with three fluorine atoms. All these compounds have been obtained in fair yields (51–70%) and they have spectral and analytical data in agreement with the indicated structures, as given in the experimental section and Supporting Information File 1. Cytotoxicity studies

Anion-dependent ion-pairing assemblies of triazatriangulenium cation that interferes with stacking structures

• Yohei Haketa,
• Takuma Matsuda and
• Hiromitsu Maeda

Beilstein J. Org. Chem. 2024, 20, 2567–2576, doi:10.3762/bjoc.20.215

• PF6− anions located above the TATA+ plane (Figure 3b,c and Figure 5b,c). Three of the fluorine atoms of BF4− and PF6− were pointed toward the TATA+ plane. The offset angles for Cl−, BF4−, and PF6− to the TATA+ central carbon were 87.7°, 78.1°, and 84.3°, respectively. The distances between fluorine

• ) packing structures and (ii) enlarged views for the columnar structures. In (i), cation and anion are represented in cyan and magenta colors, respectively. In (ii), brown, pink, yellow, blue, yellow green, orange, and green (spherical) refer to carbon, hydrogen, boron, nitrogen, fluorine, phosphorus, and

• +-Cl−, (b) 2+-BF4−, and (c) 2+-PF6−. Atom color code: yellow, green, orange, and green (spherical) refer to boron, fluorine, phosphorus, and chlorine, respectively. (i) Single-crystal X-ray structures and (ii) interaction energies for the pairs (a) 2+-Cl−, (b) 2+-BF4−, and (c) 2+-PF6−. In (i), the

A review of recent advances in electrochemical and photoelectrochemical late-stage functionalization classified by anodic oxidation, cathodic reduction, and paired electrolysis

• Nian Li,
• Ruzal Sitdikov,
• Ajit Prabhakar Kale,
• Joost Steverlynck,
• Bo Li and
• Magnus Rueping

Beilstein J. Org. Chem. 2024, 20, 2500–2566, doi:10.3762/bjoc.20.214

• ]. This electrochemical approach provides a convenient strategy for constructing 1,3-difluorinated molecules by employing Et3N·3HF as a nucleophilic fluorine source. Due to the mild reaction conditions, the LSF was demonstrated for complex natural precursors such as 5α-cholestan-3β-ol and androsterone

• another important transformation via anodic oxidation realized by the Baran group [36]. The choice of Selectfluor, which plays multiple roles, was crucial. In addition to functioning as a fluorine source, Selectfluor also acts as a mediator similar to quinuclidine and serves as an electrolyte. The method

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

• halogenated pyrans reveals deviation in the intra-annular torsion angles arising from repulsion between the axial fluorine at C2 and the axial halogen at C4, which increases with the size of the halogen at C4 (F < Cl < Br < I). Crystal packing arrangements of pyran inter-halides show hydrogen bond acceptor

• depending on the incorporated halogen on the pyran core at C4: −208.33 ppm for 12 (fluorine), −197.95 ppm for 13 (chlorine), −192.80 ppm for 14 (bromine), and −184.56 ppm for 15 (iodine). Similarly, the increase in chemical shift of F2 is smaller as exemplified with an upfield shift of −205.46 ppm for 12 to

• between 2 fluorine atoms have been reported in recent years [24][39], however, the 1,3-diaxial repulsion between fluorine and other halogens is quite uncommon [40][41]. As for the C5–C6 rotamer, all analogues exhibit a gt conformation except for trifluorinated 17, which possesses a tg conformation. An

Phenylseleno trifluoromethoxylation of alkenes

• Clément Delobel,
• Armen Panossian,
• Gilles Hanquet,
• Frédéric R. Leroux,
• Fabien Toulgoat and
• Thierry Billard

Beilstein J. Org. Chem. 2024, 20, 2434–2441, doi:10.3762/bjoc.20.207

• developed an electrophilic phenylseleno trifluoromethoxylation of alkenes, which leads to β-selenylated trifluoromethoxylated compounds or, upon subsequent reduction, to the trifluoromethoxylated ones. Keywords: DNTFB; electrophilic addition; fluorine; selenium; trifluoromethoxy; Introduction Due to the

• specific properties of the fluorine atom [1][2][3], fluorinated compounds are now present in a wide range of applications, from materials to life sciences [4][5][6][7][8][9][10][11]. In order to propose new molecules with specific properties for targeted applications, the development of new fluorinated

• resulting from the substitution of the CF3O group by the trifluoroacetoxy group was then observed. The activation of a fluorine atom from the CF3O group by H+ could be envisaged, which would then trigger the selenium attack to release difluorophosgene and HF, thus generating an episelenonium, which would

Facile preparation of fluorine-containing 2,3-epoxypropanoates and their epoxy ring-opening reactions with various nucleophiles

• Yutaro Miyashita,
• Sae Someya,
• Tomoko Kawasaki-Takasuka,
• Tomohiro Agou and
• Takashi Yamazaki

Beilstein J. Org. Chem. 2024, 20, 2421–2433, doi:10.3762/bjoc.20.206

• , University of Hyogo, 3-2-1 Koto, Kamigori-cho, Ako-gun, Hyogo 678-1297, Japan 10.3762/bjoc.20.206 Abstract We describe herein a facile method to access 2,3-epoxyesters with fluorine-containing substituents at their 3-position starting from the corresponding enoates by utilization of the low-costed and easy

• mainly afford 2-substituted 3-hydroxyesters usually in a highly anti selective manner. Keywords: α,β-unsaturated esters; epoxyesters; fluorine; Grignard-based cuprates; nucleophiles; Introduction Fluorine-containing compounds have been utilized in diverse fields due to their special character

• originating from unique fluorine atoms or fluorinated groups [1][2][3][4][5][6][7]. During our study in this area, ethyl 4,4,4-trifluorobut-2-enoate (1a) has been frequently employed as a potent and convenient Michael acceptor towards a variety of enolates [8][9][10][11][12][13][14][15] as well as

Efficient one-step synthesis of diarylacetic acids by electrochemical direct carboxylation of diarylmethanol compounds in DMSO

• Hisanori Senboku and
• Mizuki Hayama

Beilstein J. Org. Chem. 2024, 20, 2392–2400, doi:10.3762/bjoc.20.203

• , took place preferentially over electroreductive C(sp3)–O bond cleavage of 1b. It should also be noted that no aromatic carboxylic acids were detected by 1H NMR analysis. In contrast, the electrochemical carboxylation of 1c, containing a fluorine atom, gave a mixture of fluorine-containing carboxylic

• acid 2c and defluorinated carboxylic acid 2a. Fluorine-containing starting material 1c and defluorinated diphenylmethanol (1a) were detected by 1H NMR analysis. At the same time, it is presently unclear whether 2a was produced in a carboxylation–defluorination or defluorination–carboxylation sequence

Hydrogen-bond activation enables aziridination of unactivated olefins with simple iminoiodinanes

• Phong Thai,
• Lauv Patel,
• Diyasha Manna and
• David C. Powers

Beilstein J. Org. Chem. 2024, 20, 2305–2312, doi:10.3762/bjoc.20.197

• center [26][27]. Despite the prevalence of acid-activation in promoting carbon [28], oxygen [29][30], sulfur [31], chlorine [32], and fluorine [33] transfer reactions of hypervalent iodine compounds, these strategies have not been applied to activation of iminoiodinanes for nitrene transfer chemistry. We

gem-Difluorination of carbon–carbon triple bonds using Brønsted acid/Bu₄NBF₄ or electrogenerated acid

• Mizuki Yamaguchi,
• Hiroki Shimao,
• Kengo Hamasaki,
• Keiji Nishiwaki,
• Shigenori Kashimura and
• Kouichi Matsumoto

Beilstein J. Org. Chem. 2024, 20, 2261–2269, doi:10.3762/bjoc.20.194

• University, 3-4-1 Kowakae, Higashi-osaka, Osaka, 577-8502, Japan 10.3762/bjoc.20.194 Abstract gem-Difluorination of carbon–carbon triple bonds was conducted using Brønsted acids, such as Tf2NH and TfOH, combined with Bu4NBF4 as the fluorine source. The electrochemical oxidation of a Bu4NBF4/CH2Cl2 solution

• fluorobenziodoxole, are also utilized as F+ equivalents to introduce fluorine atoms into organic molecules. In addition, various trifluoromethylation reagents have been developed so far [5][6][7][8][9][10][11][12][13][14][15][16][17][18]. Transition-metal-catalyzed fluorination and trifluoromethylation methods have

• ) was reacted with the Brønsted acid (X equiv) and the fluorine source (Y equiv) in the solvent (4 mL) at temperature of T (°C) for Z hours. The chemical yield of the desired product, (5,5-difluorohexyl)benzene (2a), was evaluated for reaction optimization by using the 19F nuclear magnetic resonance

From perfluoroalkyl aryl sulfoxides to ortho thioethers

• Yang Li,
• Guillaume Dagousset,
• Emmanuel Magnier and
• Bruce Pégot

Beilstein J. Org. Chem. 2024, 20, 2108–2113, doi:10.3762/bjoc.20.181

• ][16], anilines [17], carbonyls [18][19][20][21], propargyl/allylsilanes [22][23][24][25][26][27][28][29][30][31][32][33][34], ynamides [35][36][37], and alkyl nitriles [38][39][40], were found to be suitable for this process. Whereas the addition of fluorine atoms to molecules is a well-established

• novel compounds. Acknowledgements We thank Matthias George for preparing some of the initial material during his master's degree. Funding Y.L. thanks the CNRS for Ph.D. grant. French Fluorine Network (GIS Fluor) is acknowledged for financial support.

Multicomponent syntheses of pyrazoles via (3 + 2)-cyclocondensation and (3 + 2)-cycloaddition key steps

• Ignaz Betcke,
• Alissa C. Götzinger,
• Maryna M. Kornet and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2024, 20, 2024–2077, doi:10.3762/bjoc.20.178

• hypothesized that the Michael addition occurs via the most nucleophilic nitrogen atom of the methylhydrazine at the β-fluorine atom of intermediate 92. An excess of hydrazine is used in the method, as hydrofluoric acid is formed during the reaction. Derivatives of α,β-unsaturated ketones, specifically 1,3-bis

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

• for 24 h. Careful investigation of the product structures by 1H and 19F NMR as well as GC–MS revealed exclusive substitution of fluorine rather than hydrogen, leading to a mixture of products in the ratio 0.15:1:1:0.15 (Scheme 25), with a combined yield of 50% for 4-iodotoluene and 75% for methyl 4

• ], while S-nucleophiles, namely thiophenolates, led to products upon fluorine atom substitution, which were isolated in low yield. Corresponding disulfides were isolated as major products, even when the reaction was carried out under inert atmosphere, suggesting a radical process. In summary, we compiled

A new platform for the synthesis of diketopyrrolopyrrole derivatives via nucleophilic aromatic substitution reactions

• Vitor A. S. Almodovar and
• Augusto C. Tomé

Beilstein J. Org. Chem. 2024, 20, 1933–1939, doi:10.3762/bjoc.20.169

• equivalents of the nucleophile, it is possible to promote the substitution of one or more fluorine atoms. Nucleophilic substitution of fluorine atoms often necessitates harsh conditions such as elevated temperatures, strong bases, or strong nucleophiles, but our findings demonstrate that this process can be

• the protons of the N–CH2C6F5 and N–CH2C6F4XR groups, respectively. All 19F NMR spectra confirmed the selective substitution of the 4-fluorine atoms (in one or in two rings) by the disappearance of the signal corresponding to the resonance of those atoms. Mass spectra of compounds 3a–f, 4a, 4d and 4f

Novel oxidative routes to N-arylpyridoindazolium salts

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

Beilstein J. Org. Chem. 2024, 20, 1906–1913, doi:10.3762/bjoc.20.166

• cyclization of perfluorinated phenylpyrilium salts using arylhydrazine [12]; the process is based on the fluorine nucleophilic substitution thus limiting its applicability to a wider range of substrates. Pyridyl-substituted diarylamines may be considered as the possible precursors for N-arylpyridoindazolium

The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162

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

• ; fluorobenziodoxoles; halogen bonding; hypervalent iodine; Selectfluor; Introduction An important strategy in the drug discovery process is the incorporation of fluorine into biologically active molecules because fluorine can improve bioactivity and pharmacokinetic properties [1]. Consequently, 22% of all small

• -molecule drugs contain at least one fluorine atom [2]. Hypervalent iodine(III) fluorides, such as difluoroiodotoluene 1 and fluoroiodane 2, have been key to the development of numerous, new synthetic procedures for C–F bond formation over the last decade. Since difluoroiodotoluene 1 has low chemical

•  2, entry 3) or at 40 °C for 6 hours (Table 2, entry 4). Finally, reducing the amount of Selectfluor to 1.5 equivalents led to an excellent 90% isolated yield and the conclusion that Selectfluor delivered one electrophilic fluorine (from the N–F) and one nucleophilic fluoride (from the

Syntheses and medicinal chemistry of spiro heterocyclic steroids

• Laura L. Romero-Hernández,
• Ana Isabel Ahuja-Casarín,
• Penélope Merino-Montiel,
• Sara Montiel-Smith,
• José Luis Vega-Báez and
• Jesús Sandoval-Ramírez

Beilstein J. Org. Chem. 2024, 20, 1713–1745, doi:10.3762/bjoc.20.152

• induce a more bioactive compound, fluorine atoms were introduced by acetylation and benzoylation of -NH at 152. Spiro compounds 152–154 were easily afforded in 34–62% overall yields (Scheme 40). The compounds showed excellent coenzymatic effects towards cellobiase activity produced by Chaetomium

• thermophilum and Thermomyces lanuginosus fungi. The activity was related to the presence of fluorine atoms, and the substitution of -NH with trifluoroacetyl group achieved the most active compound. Spirothiadiazine steroids Novel steroidal spiro-1,3,4-thiadiazines have been recently described through a one-pot

Regio- and stereochemical stability induced by anomeric and gauche effects in difluorinated pyrrolidines

• Ana Flávia Candida Silva,
• Francisco A. Martins and
• Matheus P. Freitas

Beilstein J. Org. Chem. 2024, 20, 1572–1579, doi:10.3762/bjoc.20.140

• nN→σ*CF electron delocalization, is particularly important in modulating the energetics of the α-fluoro isomers and imparts a strong conformational bias. In contrast, the fluorine gauche effect assumes a secondary role, as it is overshadowed by steric and electrostatic interactions, referred to as

• pervade biochemistry in peptides and proteins. The chemical and biological properties of substituted pyrrolidine derivatives, along with many other compounds, hinge on the relative stereochemistry. It is well established that the presence of fluorine in an organic molecule can significantly influence the

• , substituted 3-fluoropyrrolidines, particularly in the form of 2-carboxy derivatives (fluoroprolines), have been extensively explored. These compounds represent valuable nonnatural amino acids, and depending on the regio- and stereochemistry of fluorine substitution, fluoroproline substututions can enhance the

Benzylic C(sp³)–H fluorination

• Alexander P. Atkins,
• Alice C. Dean and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 1527–1547, doi:10.3762/bjoc.20.137

• , over recent years much attention has been focused on C(sp3)–H fluorination, and several methods that are selective for benzylic C–H bonds have been reported. These protocols operate via several distinct mechanistic pathways and involve a variety of fluorine sources with distinct reactivity profiles

• driven largely by the beneficial effects of including fluorine into bioactive molecules. These advantages include the modulation of potency, bioavailability and physical properties of drug and agrochemical compounds [1][2][3]. The significance of fluorination is reflected in the fact that a large number

• of agrochemicals contain fluorine, and that almost a quarter of drug molecules approved by the FDA between 2018 and 2022 contained at least one fluorine atom, for example belzutifan and quinofumelin, Figure 1A [4][5]. The fluorination of functionalised carbon centres is a reliable strategy to