Development and mechanistic studies of calcium–BINOL phosphate-catalyzed hydrocyanation of hydrazones

• Carola Tortora,
• Christian A. Fischer,
• Sascha Kohlbauer,
• Alexandru Zamfir,
• Gerd M. Ballmann,
• Jürgen Pahl,
• Sjoerd Harder and
• Svetlana B. Tsogoeva

Beilstein J. Org. Chem. 2025, 21, 755–765, doi:10.3762/bjoc.21.59

• through calcium catalysis [8][9][10]. Asymmetric synthesis has also been achieved via, e.g., 1,4-addition and [3 + 2] cycloaddition of 3-tetrasubstituted oxindoles with a calcium Pybox catalyst [11][12], or through enantioselective Friedel–Crafts and carbonyl–ene reactions [13]. Since the pioneering

Synthesis, structure, ionochromic and cytotoxic properties of new 2-(indolin-2-yl)-1,3-tropolones

• Yurii A. Sayapin,
• Eugeny A. Gusakov,
• Inna O. Tupaeva,
• Alexander D. Dubonosov,
• Igor V. Dorogan,
• Valery V. Tkachev,
• Anna S. Goncharova,
• Gennady V. Shilov,
• Natalia S. Kuznetsova,
• Svetlana Y. Filippova,
• Tatyana A. Krasnikova,
• Yanis A. Boumber,
• Alexey Y. Maksimov,
• Sergey M. Aldoshin and
• Vladimir I. Minkin

Beilstein J. Org. Chem. 2025, 21, 358–368, doi:10.3762/bjoc.21.26

• -methylquinazolinones [3], 2-methylbenzoxazinones [4], and 2-methylbenzoxa(thia)zoles [5] the interaction with sterically hindered 1,2-benzoquinones and 3,4,5,6-tetrachloro-1,2-benzoquinone proceeds with the expansion of the o-quinone ring and results in 2-hetaryl-substituted 1,3-tropolones 1 (Scheme 1), which exhibit

Red light excitation: illuminating photocatalysis in a new spectrum

• Lucas Fortier,
• Corentin Lefebvre and
• Norbert Hoffmann

Beilstein J. Org. Chem. 2025, 21, 296–326, doi:10.3762/bjoc.21.22

• band. These combined effects can be illustrated in the case of the [M(phen)3]2+ set with iron, ruthenium, and osmium (Figure 1). For a same phenanthroline ligand, these three complexes show an MLCT absorption band at different wavelengths, i.e., 522 nm for [Fe(phen)3]2+ [14], 449 nm for [Ru(phen)3]2

• + and 660 nm for [Os(phen)3]2+ [15]. In a same way, spin–orbit coupling, stemming from the relativistic effects, can be exploited in photoredox-catalyzed reaction [16]. Spin–orbit coupling promotes intersystem crossing (ISC) between the singlet and triplet excited states, and even allows for direct

• penetrate all the used materials and can initiate the reaction through the core of the reaction medium as the polymer forms, unlike blue light. This penetrating power of red light was also characterized by comparing the ruthenium complex [Ru(bpy)3]2+ absorbing at 450 nm with the osmium complex [Os(tpy)2]2

Cu(OTf)₂-catalyzed multicomponent reactions

• Sara Colombo,
• Camilla Loro,
• Egle M. Beccalli,
• Gianluigi Broggini and
• Marta Papis

Beilstein J. Org. Chem. 2025, 21, 122–145, doi:10.3762/bjoc.21.7

• process by using α-diazoketones, nitroalkenes and primary amines, in the presence of air as oxidant. The mechanism involved the formation of α-ketocarbene XXVI from α-diazoketone, able to react with the amine affording imine XXV after copper-catalyzed oxidative dehydrogenation. The subsequent [3 + 2

• [3 + 2] cycloaddition reaction between azodicarboxylates and nitrile ylides XXXVI as 1,3-dipoles. The latter are generated from diazoalkanes under the coordination of the copper catalyst to form a carbenoid species that undergoes nucleophilic attack of the nitriles. This transformation has

Recent advances in organocatalytic atroposelective reactions

• Henrich Szabados and
• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 55–121, doi:10.3762/bjoc.21.6

• followed by lactonization to Int-21 and Int-22 (Scheme 11c). Chi and co-workers showed that desymmetrization of urazoles can lead to axially chiral derivatives [31]. The NHC-catalyzed (3 + 2) annulation between α,β-unsaturated aldehydes 36 and urazoles 37 generates atropoisomers 38 with a C–N stereogenic

• of products in low to satisfactory yields, but having high enantiomeric purities. An organocatalytic asymmetric (3 + 2) cyclization of 3-arylindoles 154 with either achiral 155 or racemic 157 propargylic alcohols was reported by Wu et al. (Scheme 46) [74]. Utilizing CPA C37 with 3-arylindoles 154 and

• 161 were constructed by a (3 + 2) cycloaddition of isoindolinone-substitued propargylic alcohols 160 with bisindoles 159 mediated by CPA C39 (Scheme 47) [75]. These axially chiral spirocyclic products were prepared with good to very good yields and excellent enantiomeric purities. The slow

Non-covalent organocatalyzed enantioselective cyclization reactions of α,β-unsaturated imines

• Sergio Torres-Oya and
• Mercedes Zurro

Beilstein J. Org. Chem. 2024, 20, 3221–3255, doi:10.3762/bjoc.20.268

• -workers reported a cinchona alkaloid-derived thiourea-catalyzed regio- and stereoselective cycloaddition of 3-isothiocyanatooxindoles and imines containing two or three electron-deficient unsaturated bonds [25]. Firstly, the (3 + 2) cycloaddition of 3-isothiocyanatooxindoles 4 and aldimines 5 was explored

• (Scheme 3). The reaction of 3-isothiocyanatooxindoles 4 and ketimines 7 led to the (3 + 2) cycloaddition through the C=C bond of the α,β-unsaturated imine instead of the C=N bond, affording various spirocyclic derivatives 8 with excellent yields (92–98%), diastereoselectivities (15:1–20:1 dr), and

• -workers reported a dihydroquinine-derived squaramide-catalyzed (3 + 2) cycloaddition reaction of isocyanoacetates 26 and saccharin-derived 1-azadienes 14 [32]. In this work, the azadiene works as a C2 synthon, while the isocyanoacetate, bearing a protected carboxylic acid and a carbene-like divalent

Germanyl triazoles as a platform for CuAAC diversification and chemoselective orthogonal cross-coupling

• John M. Halford-McGuff,
• Thomas M. Richardson,
• Aidan P. McKay,
• Frederik Peschke,
• Glenn A. Burley and
• Allan J. B. Watson

Beilstein J. Org. Chem. 2024, 20, 3198–3204, doi:10.3762/bjoc.20.265

• potential as functional handles for downstream elaboration of CuAAC products. To date, the main use of germanyl alkynes in (3 + 2) cycloadditions has been limited to a small number of Huisgen (non-Cu-catalysed) reactions [68][69]. Zaitsev and co-workers reported the synthesis and CuAAC reactions of a

Multicomponent reactions driving the discovery and optimization of agents targeting central nervous system pathologies

• Lucía Campos-Prieto,
• Aitor García-Rey,
• Eddy Sotelo and
• Ana Mallo-Abreu

Beilstein J. Org. Chem. 2024, 20, 3151–3173, doi:10.3762/bjoc.20.261

• benzodioxepinones 12 in all cases (Scheme 11). The synthesized compounds demonstrated excellent drug-like features. Parkinson disease (PD) Knoevenagel–Michael addition/cyclization (MCR 3 + 2): Sirtuins, a group of enzymes that rely on NAD+ to function as protein deacetylases, have garnered attention across multiple

• of the nitrogen in lactams 11 with an oxygen in 12 to influence hydrogen-bond donating properties and synthesis of the benzodioxepinone derivatives via Passerini reaction. MCR 3 + 2 reaction to develop spirooxindole, spiroacenaphthylene, and bisbenzo[b]pyran compounds. Synthesis of ML192 analogs

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

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

• showed moderate or low antiproliferative activity against various cancer cell lines. 3-(2-Acetamido-4-oxo-4,5-dihydrothiazol-5-ylidene)indolin-2-one-N-glycosides The reaction of isatin-N-glycosides β-16a and β-16e with pseudo-thiohydantoin (47b) afforded β- and Z-configured 3-(2-acetamido-4-oxo-4,5

Copper-catalyzed yne-allylic substitutions: concept and recent developments

• Shuang Yang and
• Xinqiang Fang

Beilstein J. Org. Chem. 2024, 20, 2739–2775, doi:10.3762/bjoc.20.232

• sequence, [4 + 1] and [3 + 2] annulations involving yne-allylic substitutions have been released. These studies have shown the huge potential of this protocol in affording diversified molecular scaffolds, and more studies will be expected to demonstrate the value of this reaction. Copper-catalyzed allylic

• -ethynylthiophene esters. Proposed mechanism. [4 + 1] annulation of yne-allylic esters and cyclic 1,3-dicarbonyls. Asymmetric [4 + 1] annulation of yne-allylic esters. Proposed mechanism. Asymmetric [3 + 2] annulation of yne-allylic esters. Postulated annulation step. [4 + 1] Annulations of vinyl ethynylethylene

• consistent with the standard reaction conditions. However, nonlinear effect experiments confirmed that the active catalyst is a mono-copper species, so it is speculated that the dinuclear copper is the precursor of active single copper species (Scheme 33). Fang et al. [67] achieved the first asymmetric [3

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

• )-dione (4g). Compound 4g was obtained as a brown solid in 58% yield (58.3 mg, 184 µmol, Rf 0.19 (heptane/ethyl acetate 3:2)); mp 152–154 °C; IR (ATR) ν̃: 1695 (s), 1642 (vs), 1582 (s), 1493 (s), 1440 (s), 1421 (s), 1176 (m), 1079 (m), 756 (s) cm−1; 1H NMR (500 MHz, chloroform-d) δ 7.51–7.48 (m, 2H), 7.45

• acetate 3:2)); mp 187–189 °C; IR (ATR) ν̃: 1708 (s), 1654 (vs), 1574 (s), 1514 (s), 1506 (s), 1446 (s), 1423 (s), 1232 (s), 1158 (s) cm−1; 1H NMR (500 MHz, chloroform-d) δ 7.48–7.44 (m, 2H), 7.26–7.22 (m, 2H), 7.15–7.10 (m, 2H), 7.06–7.02 (m, 2H), 3.70 (s, 3H), 3.44 (s, 3H); 19F NMR (471 MHz, chloroform-d

• 54% yield (189 mg, 488 µmol, Rf 0.21 (heptane/ethyl acetate 3:2)); mp 162–164 °C; IR (ATR) ν̃: 1695 (s), 1640 (vs), 1582 (s), 1510 (s), 1446 (s), 1428 (s), 1219 (m), 813 (s) cm−1; 1H NMR (300 MHz, chloroform-d) δ 7.94–7.87 (m, 1H), 7.65–7.59 (m, 1H), 7.58 (s, 1H), 7.39–7.31 (m, 2H), 7.06–7.01 (m, 2H

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

• product (Scheme 30a). In the same year, the Xia group reported an iodide ion and PPh3-induced electrochemical oxidative [3 + 2] cycloaddition of carboxylic acids and isocyanoacetates [41]. The successful LSF of drug molecules such as sulbactam acid and oxaprozin demonstrated the potential applicability of

Visible-light-mediated flow protocol for Achmatowicz rearrangement

• Joachyutharayalu Oja,
• Sanjeev Kumar and
• Srihari Pabbaraja

Beilstein J. Org. Chem. 2024, 20, 2493–2499, doi:10.3762/bjoc.20.213

• , [Ru(bpy)3]2+ undergoes transition to [Ru(bpy)3]2+* which is quenched by persulfate resulting in [Ru(bpy)3]3+ along with the simultaneous generation of sulfate and a sulfate radical. SET from furfuryl alcohol closes the catalytic cycle of the PC and an intermediate A is generated with L (L = SO4−· or

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

• by use of Hex/CHCl3 3:2 as a solvent to afford 0.14 g (0.39 mmol) of the title compound 3aa in 78% yield as a sole stereoisomer. Rf 0.30 (Hex/AcOEt 2:1); mp 95–97 °C; 1H NMR (300.40 MHz, CDCl3) δ 3.70 (brs, 1H), 3.76 (s, 3H), 4.31–4.33 (m, 2H), 4.39 (brs, 1H), 5.14 (dd, J = 12.0, 21.3 Hz, 1H), 6.74

Deuterated reagents in multicomponent reactions to afford deuterium-labeled products

• Kevin Schofield,
• Shayna Maddern,
• Yueteng Zhang,
• Grace E. Mastin,
• Rachel Knight,
• Wei Wang,
• James Galligan and
• Christopher Hulme

Beilstein J. Org. Chem. 2024, 20, 2270–2279, doi:10.3762/bjoc.20.195

• aldehyde [10]. Latterly, Yamamoto utilized a 90% deuterated [D2]-isocyanide in a copper catalyzed [3 + 2] cycloaddition to afford a 60% deuterated [D2]-pyrrole [11]. The utility of the Leuckart–Wallach reaction towards the generation of isocyanides was first explored by Dömling [12], yet the use of such

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

• pyrazoles. The review will primarily focus on two major categories: two-carbon and three-carbon building blocks as key intermediates, while other special cases will be summarized separately. Review (3 + 2)-Cyclocondensation – C3-building blocks as key intermediates The majority of the numerous pyrazole

• give 1,5-diacyl-5-hydroxypyrazolines 131. Cleavage of the protecting group with potassium carbonate in methanol finally provides the corresponding 5-acyl NH-pyrazoles 132 (Scheme 46) [149]. A novel approach to synthesizing pyrazoles via the initial formation of isoxazoles 138 through (3 + 2

• with electrophiles, such as deuteration or electrophilic chlorination using N-chlorosuccinimide, in this consecutive three-component synthesis to give persubstituted pyrazoles 165 (Scheme 55) [162]. (3 + 2)-Cycloaddition – C2 building blocks as substrates 1,3-Dipolar cycloadditions are important

Harnessing the versatility of hydrazones through electrosynthetic oxidative transformations

• Aurélie Claraz

Beilstein J. Org. Chem. 2024, 20, 1988–2004, doi:10.3762/bjoc.20.175

• agrochemical industries. The (3 + 2)-cycloaddition between nitrile imines and alkenes represents one of the most efficient strategies to prepare these azacycles. However, conventional methods for the generation of the nitrile imine involved the use of unstable hydrazonoyl halides or the oxidation of aldehyde

• -derived hydrazones under harsh reaction conditions. In 2023, the group of Waldvogel presented a formal electrooxidative (3 + 2)-cycloaddition between aldehyde-derived hydrazones 72 and alkenes 73 to yield a large range of N-arylpyrazolines 74 under mild reaction conditions (Scheme 14) [58]. A biphasic

• situ cathodic generation of the base was supported by a control experiment in a divided cell, where no conversion was achieved. Final formal (3 + 2)-cycloaddition with the dipolarophiles 73 delivered the pyrazolines 74. It is interesting to note that a complementary (3 + 2)-cycloaddition between

Radical reactivity of antiaromatic Ni(II) norcorroles with azo radical initiators

• Siham Asyiqin Shafie,
• Ryo Nozawa,
• Hideaki Takano and
• Hiroshi Shinokubo

Beilstein J. Org. Chem. 2024, 20, 1967–1972, doi:10.3762/bjoc.20.172

• the electrophile [16][17][18]. In addition, C–C double bonds of the norcorrole skeleton outside the π-delocalization pathway exhibit a reactivity similar to an alkene to afford hydrogenated norcorroles by hydrogenation [19] or reduction with hydrazine [20] and [3 + 2]-cycloadducts with 1,3-dipoles [21

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, also called lanicemine, AZD6765 or AR-R15896AR, was described as a competitive ketamine alternative without psychotomimetic side effects, although potency and selectivity were significantly lower (Scheme 2) [8][9]. Dukat et al. [10] developed flexible 3-(2-aminoethyl)pyridine (AEP) analogs 3–5 as

• activity. 2-Aminoethylthiophene derivatives with therapeutic activity, part 1. 2-Aminoethylthiophene derivatives with therapeutic activity, part 2. 2-Aminoethylthiophene derivatives with therapeutic activity, part 3. 2-Aminoethylpyrrole derivatives with therapeutic activity. Histamine metabolic pathway. 2

• -Aminoethylimidazole derivatives with therapeutic activity, part 1. Krel is referred as histamine relative potency (basal reference 1.0). Conformationally restricted 2-aminoethylimidazole derivatives with therapeutic activity, part 2. 2-Aminoethylimidazole derivatives with therapeutic activity, part 3. 2

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

• a [1,5]-H shift [19], indazolo[3’,2’:2,3]imidazo[1,5-c]quinazolin-6(5H)-one 18 (Scheme 7) [20]. The favorable host–guest interaction between 14 and the reactants (demonstrated by 2D NMR and FTIR spectroscopy as well as by scanning electron micrography), combined with the acidity of the succinyl

Ugi bisamides based on pyrrolyl-β-chlorovinylaldehyde and their unusual transformations

• Alexander V. Tsygankov,
• Vladyslav O. Vereshchak,
• Tetiana O. Savluk,
• Serhiy M. Desenko,
• Valeriia V. Ananieva,
• Oleksandr V. Buravov,
• Yana I. Sakhno,
• Svitlana V. Shishkina and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2024, 20, 1773–1784, doi:10.3762/bjoc.20.156

• , and different convertible isocyanides gives rise to products of the classic Ugi reaction, ethyl (E)-4-(4-(R1-amino)-1-chloro-3-(2-chloro-N-(4-(R2)phenyl)acetamido)-4-oxobut-1-en-1-yl)-3,5-dimethyl-1H-pyrrole-2-carboxylates, which, however, exhibit unusual behavior in post-Ugi transformations. 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

• of these compounds via an intramolecular [3 + 2] cycloaddition reaction between (Z)-steroidal arylidene derivatives 42 and azomethine ylides (Scheme 13) [26]. The latter were generated in situ from sarcosine (MeNHCH2CO2H) and a mono- or dicarbonyl compound such as isatin, acenaphthenequinone, and

• 82 with concentrated sulfuric acid, cyclodehydration occurred, leading to the formation of 3-spiro[3’’’-(2’’’-phenyl-4’’’-oxo-1’’’,3’’’-thiazolidin-5’’-yl)-1’’,3’’,4’’-thiadiazolo[3’,4’-b]thiazolin]cholest-5-ene (83) in 60% yield (Scheme 24). Notably, stereochemical information at the newly formed

Generation of multimillion chemical space based on the parallel Groebke–Blackburn–Bienaymé reaction

• Evgen V. Govor,
• Vasyl Naumchyk,
• Ihor Nestorak,
• Dmytro S. Radchenko,
• Dmytro Dudenko,
• Yurii S. Moroz,
• Olexiy D. Kachkovsky and
• Oleksandr O. Grygorenko

Beilstein J. Org. Chem. 2024, 20, 1604–1613, doi:10.3762/bjoc.20.143

• ., 3-aminopyrazole (1{1}), 3-aminoisoxazole (1{2}), 2-aminothiazole (1{3}), 2-amino-1,3,4-thiadiazole (1{4}), or 2-aminotetrazole (1{5}) demonstrated poor conversion to the target products; 2-aminopyrimidines either gave isomeric mixtures (e.g., parent compound 1{6}, alkyl-substituted derivatives 1{7

• experience, 4-fluoro- and 4-chloro-2-fluoro-1-isocyanobenzenes (3{1} and 3{2}) showed poor performance and unsatisfactory results were also observed for isocyanocyclopropane (3{3}). Using the guidelines described above, we have updated the reactant lists with additional representatives and excluded those

Towards an asymmetric β-selective addition of azlactones to allenoates

• Behzad Nasiri,
• Ghaffar Pasdar,
• Paul Zebrowski,
• Katharina Röser,
• David Naderer and
• Mario Waser

Beilstein J. Org. Chem. 2024, 20, 1504–1509, doi:10.3762/bjoc.20.134

• ), catalyst B2 (10 mol % related to 1), and Cs2CO3 (3 equiv). Then the respective allenoate 3 (2 equiv) and toluene (0.05 M with respect to 1) were added and the mixture was stirred at room temperature for 24 h (Ar atmosphere). The crude product was passed through a short column of silicagel (rinsed with DCM