2-Heteroarylethylamines in medicinal chemistry: a review of 2-phenethylamine satellite chemical space

• Carlos Nieto,
• Alejandro Manchado,
• Ángel García-González,
• David Díez and
• Narciso M. Garrido

Beilstein J. Org. Chem. 2024, 20, 1880–1893, doi:10.3762/bjoc.20.163

• 2-aminoethylpyrrole (Scheme 7) hits were elaborated and tested in a stopped-flow CO2 hydrase assay. Comparing this pyrrole family with original histamine inferred a decrease in selectivity towards the hCA VII isoform, while activity was not affected significantly. Tryptamine derivatives, i.e

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

• -free conditions. Although some new metal or Brønsted acid catalysts have been reported in the last few years, the main innovations can be found in the use of organic catalysts, enzymes, and compartmentations. A few reports on the in situ generation of reactants and on the reaction conducted under flow

• ]. In 2021, Poole et al. [34] reported the first GBB reaction performed under flow conditions. The method proved to be robust, efficient and scalable, and showed a broad functional group tolerance. A commercial apparatus was used and two stock solutions (the first consisting of the amines (1 equiv), the

• performed under flow conditions afforded the desired product also when the corresponding batch reaction failed. The authors provided no comment on whether the imine could already be formed in the stock solution before pumping into the reaction coil. A multigram synthesis was also performed, affording a GBB

Synthesis of polycyclic aromatic quinones by continuous flow electrochemical oxidation: anodic methoxylation of polycyclic aromatic phenols (PAPs)

• Hiwot M. Tiruye,
• Solon Economopoulos and
• Kåre B. Jørgensen

Beilstein J. Org. Chem. 2024, 20, 1746–1757, doi:10.3762/bjoc.20.153

• trap the phenoxonium cation formed in the oxidation as an acetal, that later were hydrolysed to the quinone. Formation of hydrogen gas as the cathode reaction caused challenges in the flow cell and were overcome by recycling the reaction mixture through the cell at increased flow rate several times

• estitmation of the HOMO/LUMO energies to shed more light on this transformation. The easy separation of the supporting electrolyte from the product will allow recycling and makes this a green transformation. Keywords: acetal formation; cyclic voltammetry; flow electrochemistry; green oxidation; polycyclic

• alternative to classical synthesis [25][26][27][28]. Electrochemical oxidation reactions are further used to emulate enzymatic oxidations of drugs and explore potential metabolites [29][30][31]. Electrochemical flow systems provide fast electrosynthesis with low cell resistance, large electrode area, and good

Supramolecular assemblies of amphiphilic donor–acceptor Stenhouse adducts as macroscopic soft scaffolds

• Ka-Lung Hung,
• Leong-Hung Cheung,
• Yikun Ren,
• Ming-Hin Chau,
• Yan-Yi Lam,
• Takashi Kajitani and
• Franco King-Chi Leung

Beilstein J. Org. Chem. 2024, 20, 1590–1603, doi:10.3762/bjoc.20.142

• applying the shear-flow method, negatively charged nanofibers of DA11 were assembled into a macroscopic soft scaffold when the solution was ejected into a shallow pool of calcium chloride solution (150 mM, Figure 4a). The high binding affinity between calcium ions and carboxylate groups enabled charge

• prepared by ejecting 5.0 wt % DAn solutions onto a bioinert glass-bottomed Petri dish by the shear-flow method, rinsing with PBS, and incubating with human-bone-marrow-derived mesenchymal stem cells (hBM-MSCs) at 37 °C and 5% CO2 for 3 days. hBM-MSCs have demonstrated importance in controlled

• (150 mM) before white-light irradiation and (b) DA11, (d) DA7, and (f) DA6 after white-light irradiation for 60 min. Macroscopic soft DAn scaffolds fabricated by the shear-flow method. Images taken during fluorescence microscopy. Photographs of freshly prepared (a) DA11, (c) DA10, (e) DA7, and (g) DA6

Electrocatalytic hydrogenation of cyanoarenes, nitroarenes, quinolines, and pyridines under mild conditions with a proton-exchange membrane reactor

• Koichi Mitsudo,
• Atsushi Osaki,
• Haruka Inoue,
• Eisuke Sato,
• Naoki Shida,
• Mahito Atobe and
• Seiji Suga

Beilstein J. Org. Chem. 2024, 20, 1560–1571, doi:10.3762/bjoc.20.139

• reactions. As PEM reactors are flow reactors, they have an advantage over batch reactors in terms of continuous production. Several reductive transformations taking advantage of the characteristics of the PEM reactor have been reported in recent years. For example, Atobe et al. reported the electrocatalytic

• suppress hydrogen generation, we varied the flow rate of the reaction solution (Table 4). The reaction time was set to 2.5 h (2.25 mmol, 8.3 F mol–1) and the flow rate of the reaction solution was changed from 0.25 to 1.0 mL min−1. As expected, increasing the flow rate increased the current efficiency and

• yield of 5a. With 0.75 mL min−1 of flow rate, 5a was obtained in 88% yield with 62% of current efficiency (Table 4, entry 3). In contrast to the previous report on electrocatalytic hydrogenation of nitrobenzene using a PEM reactor [21], cyclohexylamine was not observed in each reaction. Next, the scope

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

• continuous flow system (Figure 26) [71]. The authors were able to demonstrate rapid benzylic fluorination of 13 substrates, requiring residence times below 30 min. The use of photoexcited aryl ketones was further expanded in 2016 by Lectka and co-workers who reported the use of 5-dibenzosuberenone as a

• fluorination in continuous flow. Photochemical phenylalanine fluorination in peptides. Decatungstate-photocatalyzed versus AIBN-initiated selective benzylic fluorination. Benzylic fluorination using organic dye Acr+-Mes and Selectfluor. Palladium-catalysed benzylic C(sp3)–H fluorination with nucleophilic

Synthesis of cyclic β-1,6-oligosaccharides from glucosamine monomers by electrochemical polyglycosylation

• Md Azadur Rahman,
• Hirofumi Endo,
• Takashi Yamamoto,
• Shoma Okushiba,
• Norihiko Sasaki and
• Toshiki Nokami

Beilstein J. Org. Chem. 2024, 20, 1421–1427, doi:10.3762/bjoc.20.124

• was further washed with aqueous 1 M HCl solution and dried over Na2SO4. Then, the solvent was removed under reduced pressure, and the crude product (220 mg) was purified with recycling preparative gel permeation chromatography equipped with two series-connected JAIGEL-2HH columns (eluent: CHCl3, flow

Introduction of peripheral nitrogen atoms to cyclo-meta-phenylenes

• Koki Ikemoto and
• Hiroyuki Isobe

Beilstein J. Org. Chem. 2024, 20, 1207–1212, doi:10.3762/bjoc.20.103

• overnight to give 3a in 6% yield (272 mg, 0.592 mmol) after the extraction. The latter was purified by silica gel short path and GPC (column: YMC-GPC T30000-40 + T4000-40 + T2000-40, eluent: CHCl3, flow rate: 30 mL/min) to give 3a in 1% yield (52.8 mg, 0.115 mmol) and 3b in 3% yield (118 mg, 0.193 mmol). In

Cofactor-independent C–C bond cleavage reactions catalyzed by the AlpJ family of oxygenases in atypical angucycline biosynthesis

• Jinmin Gao,
• Liyuan Li,
• Shijie Shen,
• Guomin Ai,
• Bin Wang,
• Fang Guo,
• Tongjian Yang,
• Hui Han,
• Zhengren Xu,
• Guohui Pan and
• Keqiang Fan

Beilstein J. Org. Chem. 2024, 20, 1198–1206, doi:10.3762/bjoc.20.102

• ) and acetonitrile with 0.1% (v/v) trifluoroacetic acid (solvent B). A 20-min linear gradient from 25% (v/v) to 100% (v/v) solvent B was used with a flow rate of 1.0 mL⋅min−1. Absorbance at 266 and 313 nm was monitored. For SOD quench experiments, the reaction mixtures were analyzed on an Agilent 1260

• Infinity HPLC system with a diode array detector using an Agilent ZORBAX SB-C18 rapid resolution HT column (1.8 μm, 4.6 × 100 mm). A 10 min linear gradient from 20% (v/v) to 100% (v/v) solvent B was used with a flow rate of 1.5 mL⋅min−1. Full spectra from 190 to 640 nm were monitored. HPLC traces of

Two-fold addition reaction of silylene to C₆₀: structural and electronic properties of a bis-adduct

• Masahiro Kako,
• Masato Kai,
• Masanori Yasui,
• Michio Yamada,
• Yutaka Maeda and
• Takeshi Akasaka

Beilstein J. Org. Chem. 2024, 20, 1179–1188, doi:10.3762/bjoc.20.100

• were obtained using the liquid–liquid bilayer diffusion method with solutions of 3 in CS2 using hexane as a poor solvent at 0 °C. Single-crystal X-ray diffraction data of 3 were collected on a Rigaku Oxford Diffraction XtaLAB Synergy R DW system with a HyPix detector equipped with a nitrogen-gas flow

Manganese-catalyzed C–C and C–N bond formation with alcohols via borrowing hydrogen or hydrogen auto-transfer

• Mohd Farhan Ansari,
• Atul Kumar Maurya,
• Abhishek Kumar and
• Saravanakumar Elangovan

Beilstein J. Org. Chem. 2024, 20, 1111–1166, doi:10.3762/bjoc.20.98

• the manganese catalyst, a catalytic amount of t-BuONa (10 mol %) and an open reflux system (120 °C in toluene) under argon flow were required. Utilizing this unique method, many aromatic, aliphatic, and acyclic alcohols were cross-coupled, furnishing a library of disubstituted alcohols and ketones in

Auxiliary strategy for the general and practical synthesis of diaryliodonium(III) salts with diverse organocarboxylate counterions

• Naoki Miyamoto,
• Daichi Koseki,
• Kohei Sumida,
• Elghareeb E. Elboray,
• Naoko Takenaga,
• Ravi Kumar and
• Toshifumi Dohi

Beilstein J. Org. Chem. 2024, 20, 1020–1028, doi:10.3762/bjoc.20.90

• trifluoroacetic acid, followed by coupling with 1,3,5-trimethoxybenzene [18] (Scheme 1A). This process demonstrated tolerance for a wide range of electron-rich and electron-deficient (hetero)aryl iodine(III) compounds. Wirth and colleagues reported the flow synthesis of diaryliodonium(III) trifluoroacetates using

A Diels–Alder probe for discovery of natural products containing furan moieties

• Alyssa S. Eggly,
• Namuunzul Otgontseren,
• Carson B. Roberts,
• Amir Y. Alwali,
• Haylie E. Hennigan and
• Elizabeth I. Parkinson

Beilstein J. Org. Chem. 2024, 20, 1001–1010, doi:10.3762/bjoc.20.88

• oxygen atom in the ring destabilizing the diene HOMO. Thus, when it comes to substituents on a furan ring, it is better to place electron-withdrawing groups in the three and/or five positions of the furan to aid in the natural flow of the electrons [19]. Due to this reactivity, we expected that a Diels

Carbonylative synthesis and functionalization of indoles

• Alex De Salvo,
• Raffaella Mancuso and
• Xiao-Feng Wu

Beilstein J. Org. Chem. 2024, 20, 973–1000, doi:10.3762/bjoc.20.87

• indolo[1,2-c]quinazolin-6(5H)-one derivatives. Finally, starting from 1,2-bis(2-nitrophenyl)ethene and 1-methoxy-2-nitro-3-(2-nitrostyryl)benzene the related indolo[3,2-b]indoles were not observed (Scheme 17). One year later, by using continuous flow technology, Gutmann, Kappe and colleagues developed a

• -catalyzed reductive cyclization of 1,2-bis(2-nitrophenyl)ethene and 1,1-bis(2-nitrophenyl)ethene derivatives. Flow synthesis of 2-substituted indoles by reductive carbonylation. Pd-catalyzed synthesis of variously substituted 3H-indoles from nitrostyrenes by using Mo(CO)6 as CO source. Synthesis of indoles

Activity assays of NnlA homologs suggest the natural product N-nitroglycine is degraded by diverse bacteria

• Kara A. Strickland,
• Brenda Martinez Rodriguez,
• Ashley A. Holland,
• Shelby Wagner,
• Michelle Luna-Alva,
• David E. Graham and
• Jonathan D. Caranto

Beilstein J. Org. Chem. 2024, 20, 830–840, doi:10.3762/bjoc.20.75

• , 4.6 × 150 mm) and connected to an Agilent 6230 TOF mass spectrometer with electrospray ionization (ESI). Analyses used an isocratic mixture containing 65% water, 25% acetonitrile, and 10% isopropanol at a flow rate of 0.5 mL/min. The mass spectrometer was run in the negative ion mode with a probe

Advancements in hydrochlorination of alkenes

• Daniel S. Müller

Beilstein J. Org. Chem. 2024, 20, 787–814, doi:10.3762/bjoc.20.72

• -sensitive substrates. Another challenge, shared with Nicewicz's method [90], is the preparation of arylacridine 159 in a single step from the relatively expensive 9-chloroacridine through Pd-catalyzed cross-coupling with 2-chlorophenylboronic acid. Additionally, for large-scale reactions, a flow reactor is

New variochelins from soil-isolated Variovorax sp. H002

• Jabal Rahmat Haedar,
• Aya Yoshimura and
• Toshiyuki Wakimoto

Beilstein J. Org. Chem. 2024, 20, 692–700, doi:10.3762/bjoc.20.63

• kept at room temperature for one hour. The reaction mixtures were concentrated in vacuo, dissolved in acetone, and then injected into a GC–MS system, Zebron ZB-WAX (30 m × 0.25 mm ID × 0.25 µm, Phenomenex), using He as the gas source at a flow rate of 1.41 mL/min. The initial temperature (120 °C) was

• into a Cosmosil 5C18-MS-II column (10 mm ID × 250 mm, Nacalai Tesque) attached to an HPLC with an autosampler, at a flow rate of 0.8 mL/min at 40 °C. Each analysis was performed using an aqueous acetonitrile mobile phase. Biological activities of variochelins Assays for all compounds were performed in

Enhanced reactivity of Li⁺@C₆₀ toward thermal [2 + 2] cycloaddition by encapsulated Li⁺ Lewis acid

• Hiroshi Ueno,
• Yu Yamazaki,
• Hiroshi Okada,
• Fuminori Misaizu,
• Ken Kokubo and
• Hidehiro Sakurai

Beilstein J. Org. Chem. 2024, 20, 653–660, doi:10.3762/bjoc.20.58

• HPLC measurement. The solutions were subjected to analytical HPLC. HPLC profiles are shown in Supporting Information File 1. HPLC conditions: column: Buckyprep ø 4.6 × (10 + 250) mm; mobile phase: chlorobenzene/acetonitrile 95:5 containing 30 mM LiTFSI; flow rate: 1.5 mL/min; temperature: 50 °C

Isolation and structure determination of a new analog of polycavernosides from marine Okeania sp. cyanobacterium

• Kairi Umeda,
• Naoaki Kurisawa,
• Ghulam Jeelani,
• Tomoyoshi Nozaki,
• Kiyotake Suenaga and
• Arihiro Iwasaki

Beilstein J. Org. Chem. 2024, 20, 645–652, doi:10.3762/bjoc.20.57

• AFCS [Ø 11 × 300 mm; flow rate 5 mL/min; detection at 254 nm; solvent gradient condition, hexane/EtOAc 28:72 → 7:93] to give a fraction that contained compound 1 (17.5 mg, tR = 32.0 min). The fraction that contained 1 was further purified by HPLC [Cosmosil 5C18-MS-II (Ø 20 mm × 250 mm); solvent MeOH

• /H2O 85:15; flow rate 5 mL/min; detection UV 215 nm] to give a fraction that contained 1 (8.6 mg, last collected fraction). The fraction that contained 1 was further separated by HPLC [Cosmosil Cholester (Ø 20 mm × 250 mm); solvent MeCN/H2O 75:25; flow rate 5 mL/min; detection UV 254 nm] to give a

• fraction that contained 1 (0.6 mg, tR = 32.8 min). The fraction that contained 1 was further separated by HPLC [Cosmosil 5PE-MS (Ø 20 mm × 250 mm); solvent MeOH/H2O 85:15; flow rate 5 mL/min; detection UV 270 nm] to give 1 (0.5 mg, tR = 37.3 min). Polycavernoside E (1): colorless oil; [α]D26 −19 (c 0.04

A new analog of dihydroxybenzoic acid from Saccharopolyspora sp. KR21-0001

• Rattiya Janthanom,
• Yuta Kikuchi,
• Hiroki Kanto,
• Tomoyasu Hirose,
• Arisu Tahara,
• Takahiro Ishii,
• Arinthip Thamchaipenet and
• Yuki Inahashi

Beilstein J. Org. Chem. 2024, 20, 497–503, doi:10.3762/bjoc.20.44

• analyzed by LC–MS. The flow-through and 0% fractions were mixed and adjusted to pH 3 by adding formic acid (FA). Then, the mixture was purified by eluting with MeOH/H2O (0%, 50%, and 100%) with 0.05% of FA through a HP20 column (55 i.d. × 500 mm). The 50% fraction was concentrated in vacuo to remove MeOH

• %, 40%, 50%, 60%, 80%, and 100%) with 0.05% FA. The 20% fraction was purified by HPLC (Shimadzu, Columbia, MD, U.S.A.) with an ODS column (Pegasil ODS SP100, 20 i.d. × 250 mm) at a flow rate of 7 mL·min−1 and eluted with 20% MeOH with 0.05% FA (Scheme 1). The fraction with a retention time of 64.5 min

• was concentrated in vacuo to yield 1 (7.9 mg). LC–MS analysis Electrospray ionization-mass spectrometry (ESIMS) data was collected using a Triple TOF 5600+ LC–MS/MS System (AB Sciex, Framingham, MA, USA) with an ODS column (Capcell Core C18, 3.0 i.d. × 100 mm, 40 °C) (Osaka Soda, Japan) at a flow rate

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

• substrates using fluorine gas has been used successfully for the production of 5-fluorouracil (generic, anticancer) and voriconazole (V-FEND, Pfizer, antifungal) [33]. Methods have been developed for the selective monofluorination of 1,3-dicarbonyl derivatives by fluorine gas using batch and continuous flow

• , electrophilic reagent to be important. Given the structural similarity of 1,4-diazabicyclo[2.2.2]octane (DABCO) to the Selectfluor system, a 10% v/v mixture of fluorine in nitrogen was passed through a solution of 1a in acetonitrile containing one equivalent of DABCO, using a fluorination apparatus and gas flow

(E,Z)-1,1,1,4,4,4-Hexafluorobut-2-enes: hydrofluoroolefins halogenation/dehydrohalogenation cascade to reach new fluorinated allene

• Nataliia V. Kirij,
• Andrey A. Filatov,
• Yurii L. Yagupolskii,
• Sheng Peng and
• Lee Sprague

Beilstein J. Org. Chem. 2024, 20, 452–459, doi:10.3762/bjoc.20.40

• product 11 was removed from the reaction mixture at 20 °C for 2 hours with a slow flow of argon through the system. Unfortunately, we failed to completely separate it from the hexane and allene 11 was produced with 80–85% purity. We managed to partially solve this problem by replacing hexane with the

Green and sustainable approaches for the Friedel–Crafts reaction between aldehydes and indoles

• Periklis X. Kolagkis,
• Eirini M. Galathri and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2024, 20, 379–426, doi:10.3762/bjoc.20.36

• development of greener synthetic technologies, like photocatalysis, organocatalysis, the use of nanocatalysts, microwave irradiation, ball milling, continuous flow, and many more. Thus, in this review, we summarize the medicinal properties of BIMs and the developed BIM synthetic protocols, utilizing the

Discovery of unguisin J, a new cyclic peptide from Aspergillus heteromorphus CBS 117.55, and phylogeny-based bioinformatic analysis of UngA NRPS domains

• Sharmila Neupane,
• Marcelo Rodrigues de Amorim and
• Elizabeth Skellam

Beilstein J. Org. Chem. 2024, 20, 321–330, doi:10.3762/bjoc.20.32

• eluting with H2O + 0.1% formic acid and MeCN + 0.1% formic acid using a gradient from 90:10 to 10:90 of H2O/MeCN over 15 min, maintaining in 10:90 H2O/MeCN for 3 min, from 10:90 to 90:10 in 1 min, and maintaining at 90:10 for 1 min, using a flow rate of 1.0 mL/min. The PDA detector scanned between λ = 190

• and 700 nm. The MS was optimized using the following conditions: interface voltage 4.5 kV; interface temperature 350 °C; DL temperature 250 °C; heat block 200 °C; ESI mode, acquisition range 100 to 1000 Da; nebulizing gas 1.5 L min−1; drying gas flow 15 L min−1. The fractionation of the sample was

• performed on a Shimadzu LC-20AP preparative liquid chromatograph (SCL-40 System Controler Deliver and LH-40 Liquid Handler) coupled to a Shimadzu SPD-M40 Photo Diode Array Detector (PDA) system using a RP-18 column (Phenomenex, Kinetex 250 × 30 mm i.d., 5 µm, flow rate of 18.0 mL min−1). The purification of

Elucidating the glycan-binding specificity and structure of Cucumis melo agglutinin, a new R-type lectin

• Jon Lundstrøm,
• Emilie Gillon,
• Valérie Chazalet,
• Nicole Kerekes,
• Antonio Di Maio,
• Ten Feizi,
• Yan Liu,
• Annabelle Varrot and
• Daniel Bojar

Beilstein J. Org. Chem. 2024, 20, 306–320, doi:10.3762/bjoc.20.31

• -GalNAc (Lectinity, GlycoNZ, #0031-BP) was immobilized on CM5 chips (Cytiva #BR100012) that were coated previously with streptavidin (Sigma-Aldrich, Merck, #S4762), following standard protocol. Biotinylated GalNAc was diluted to 2 μg/mL in HBS-T before being injected into one of the flow cells of the chip

• . An immobilization level of 900 response units (RU) was obtained. A reference surface was always present in flow cell 1, allowing for the subtraction of bulk effects and non-specific interactions with streptavidin. The mammalian-produced CMA1 was injected in single cycle kinetic over the flow cell

• experiments, nine concentrations of LacNAc (Elicityl, #GLY008) from 10 to 0 mM with a dilution coefficient of two supplemented with a fixed concentration of 0.8 µM was injected into the cell surface in multiple cycle kinetic with an association time of 500 s and a dissociation time of 12 s at a flow rate of