Investigations of amination reactions on an antimalarial 1,2,4-triazolo[4,3-a]pyrazine scaffold

• Henry S. T. Smith,
• Ben Giuliani,
• Kanchana Wijesekera,
• Kah Yean Lum,
• Sandra Duffy,
• Aaron Lock,
• Jonathan M. White,
• Vicky M. Avery and
• Rohan A. Davis

Beilstein J. Org. Chem. 2025, 21, 1126–1134, doi:10.3762/bjoc.21.90

• -position of the pyrazine ring [10][11]. During small-scale late-stage functionalisation of natural products, we have observed that amination or amidation with primary amines often involves less of a kinetic barrier than might otherwise be expected [12][13][14]. The use of readily available liquid amines in

• -chlorophenyl)-[1,2,4]triazolo[4,3-a]pyrazine were synthesised, purified (≥95% purity, determined by 1H and 13C NMR and HPLC–MS analysis) and assayed for in vitro antimalarial activity. Results and Discussion Synthesis of aminated triazolopyrazine analogues The amination of 5-chloro-3-(4-chlorophenyl)-[1,2,4

Recent advances in synthetic approaches for bioactive cinnamic acid derivatives

• Betty A. Kustiana,
• Galuh Widiyarti and
• Teni Ernawati

Beilstein J. Org. Chem. 2025, 21, 1031–1086, doi:10.3762/bjoc.21.85

Pd-Catalyzed asymmetric allylic amination with isatin using a P,olefin-type chiral ligand with C–N bond axial chirality

• Natsume Akimoto,
• Kaho Takaya,
• Yoshio Kasashima,
• Kohei Watanabe,
• Yasushi Yoshida and
• Takashi Mino

Beilstein J. Org. Chem. 2025, 21, 1018–1023, doi:10.3762/bjoc.21.83

• asymmetric allylic amination of allylic esters with isatin derivatives 11 as nucleophiles. The reaction proceeds efficiently, yielding the products (S)-13 with good-to-high enantioselectivity. A scale-up reaction was also successfully conducted at a 1 mmol scale. Additionally, when malononitrile was added to

• the resulting product (S)-13a in the presence of FeCl3 as the catalyst, the corresponding malononitrile derivative (S)-16 was obtained without any loss in optical purity. Keywords: asymmetric allylic amination; axial chirality; isatin; palladium catalysis; P,olefin-type chiral ligand; Introduction

• activity against Huh7.5-FGR-JC1-Rluc2A cells, which carry HCV gt 2a [13]. Therefore, developing asymmetric reactions that simultaneously form a carbon–nitrogen bond and construct a chiral center is of great importance. Although a relatively large number of asymmetric allylic amination reactions using

Studies on the syntheses of β-carboline alkaloids brevicarine and brevicolline

• Benedek Batizi,
• Patrik Pollák,
• András Dancsó,
• Péter Keglevich,
• Gyula Simig,
• Balázs Volk and
• Mátyás Milen

Beilstein J. Org. Chem. 2025, 21, 955–963, doi:10.3762/bjoc.21.79

• -monomethylation of the primary amino group of compound 25 by alkylation with methyl iodide or by Eschweiler–Clarke reductive amination with formaldehyde and formic acid were unsuccessful, because the dimethylated byproduct was also formed, even when one equivalent alkylating agent was used. Finally, our efforts

Recent advances in controllable/divergent synthesis

• Jilei Cao,
• Leiyang Bai and
• Xuefeng Jiang

Beilstein J. Org. Chem. 2025, 21, 890–914, doi:10.3762/bjoc.21.73

• represents a highly challenging direct C(sp3)–H asymmetric amination. Mechanistic insights: When using a bulky, electron-rich chiral bisphosphine ligand L6, the glycine ester substrate coordinates with the copper catalyst to form a key intermediate complex Int-26. The sterically hindered and electron-rich

• achieved selective synthesis of either enantiomer of a target product by controlling the reaction duration (Scheme 13) [42]. When performing the asymmetric intermolecular allylic amination of 6-hydroxyisoquinoline (49) with tert-butyl(1-phenylallyl)carbonate ((rac)-50) using an Ir catalyst derived from [Ir

• in the absence of a Brønsted acid additive, the opposite enantiomer 52 was obtained. Mechanistically, an initial kinetic resolution (KR) of (rac)-50 occurs via an Ir-catalyzed asymmetric allylic amination. Due to the higher reactivity of (S)-50, it reacts with 6-hydroxyisoquinoline within 6 minutes

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

• ; hydrazones; isocyanides; Introduction Catalytic applications of non-toxic earth abundant metals like calcium are currently on the rise [1][2][3][4]. Prominent recent examples that witness the versatility of calcium catalysis include calcium-catalyzed amination of π-activated alcohols [5], the Beckmann

Entry to 2-aminoprolines via electrochemical decarboxylative amidation of N‑acetylamino malonic acid monoesters

• Olesja Koleda,
• Janis Sadauskis,
• Darja Antonenko,
• Edvards Janis Treijs,
• Raivis Davis Steberis and
• Edgars Suna

Beilstein J. Org. Chem. 2025, 21, 630–638, doi:10.3762/bjoc.21.50

• chiral nitrogen nucleophile as shown below. To the best of our knowledge, the electrosynthesis of gem-α,α-diamino acid derivatives 6 has not been accomplished, and all published electrochemical amination examples under Hofer–Moest conditions [5] targeted either N-substituted heteroarenes [6] or aminals

• was not extracted from background-corrected voltammograms. All CV graphs are plotted using IUPAC polarographic convention. Selected examples of α,α-disubstituted cyclic amino acids in drug design. Electrochemical decarboxylative amination reactions. A) Cyclic voltammograms of 6a and 9a at 3 mM and 6

Cryptophycin unit B analogues

• Thomas Schachtsiek,
• Jona Voss,
• Maren Hamsen,
• Beate Neumann,
• Hans-Georg Stammler and
• Norbert Sewald

Beilstein J. Org. Chem. 2025, 21, 526–532, doi:10.3762/bjoc.21.40

• 8 was obtained in good yield of 61% through reductive amination with excess formaldehyde and NaBH3CN as reductant, the selective installation of only one methyl group, providing monomethyl aniline 7, proved to be more troublesome. Either reductive amination using the same protocol, but under strict

Synthesis of N-acetyl diazocine derivatives via cross-coupling reaction

• Thomas Brandt,
• Pascal Lentes,
• Jeremy Rudtke,
• Michael Hösgen,
• Christian Näther and
• Rainer Herges

Beilstein J. Org. Chem. 2025, 21, 490–499, doi:10.3762/bjoc.21.36

• amination is a versatile and powerful tool for C–N bond formation and widely applied in the synthesis of new pharmaceutical substances [29][30][31]. Furthermore, azobenzenes [32][33], as well as diazocines [34][35], have been derivatized via Buchwald–Hartwig amination. The Buchwald–Hartwig amination of

• -acetyl diazocines 2 and 3 via Buchwald–Hartwig amination. Equivalents are normalized to the used amount of N-acetyl diazocine starting material. Photophysical properties of N-acetyl diazocines 1-4, 7–14, 17, 19–21, and 23 in acetonitrile. Photophysical properties of N-acetyl diazocines 1, 13, and 21 in

Synthesis of electrophile-tethered preQ₁ analogs for covalent attachment to preQ₁ RNA

• Laurin Flemmich and
• Ronald Micura

Beilstein J. Org. Chem. 2025, 21, 483–489, doi:10.3762/bjoc.21.35

• reductive amination to form the hydroxyalkyl handles, which were further converted to the haloalkyl or mesyloxyalkyl-modified target compounds. In addition, we report hydrogenation conditions for preQ0 and DPQ0 that allow for cleaner and faster access to preQ1 compared to existing routes and provide the

• of the electrophile. We thus identified aldehydes 9 and 10 as suitable branching points, which were easily derivatized to their aminomethyl-modified preQ1 analogs by reductive amination (Scheme 3). Their syntheses by Raney-Ni reduction of nitriles 7 and 8, previously described by Gangjee and co

• -workers [33], proceeded cleanly in our hands. In the case of compound 4a, the chloropropyl moiety was directly installed by reductive amination of 9 with 3-chloropropylamine hydrochloride under basic conditions. A two-step reaction sequence, however, was necessary to generate derivatives 4b–e and 3a

Beyond symmetric self-assembly and effective molarity: unlocking functional enzyme mimics with robust organic cages

• Keith G. Andrews

Beilstein J. Org. Chem. 2025, 21, 421–443, doi:10.3762/bjoc.21.30

• reductive amination to stabilize imine cages, and the resulting amine cages gain solubility from increased flexibility at the cost of losing some structural rigidity [42][43][44]. Metastable conformations – programming cavity shape and symmetry: Unlike non-covalent/dative assemblies, covalently linked cages

Identification and removal of a cryptic impurity in pomalidomide-PEG based PROTAC

• Bingnan Wang,
• Yong Lu and
• Chuo Chen

Beilstein J. Org. Chem. 2025, 21, 407–411, doi:10.3762/bjoc.21.28

• synthesis of iVeliparib-AP6 [5] starts with a nucleophilic aromatic substitution (SNAr) reaction wherein 4-fluorothalidomide (1) reacts with amino-PEG7-OH 2 to give alcohol 3 (Scheme 1). Subsequent alcohol oxidation followed by reductive amination of the resulting aldehyde 4 with veliparib [6][7] provides

Recent advances in electrochemical copper catalysis for modern organic synthesis

• Yemin Kim and
• Won Jun Jang

Beilstein J. Org. Chem. 2025, 21, 155–178, doi:10.3762/bjoc.21.9

• the product are accessible by adjusting the two distinct chiral catalysts. C–N Bond formation In 2018, Mei et al. developed the electrochemical C–H amination of arenes with amine electrophiles using copper catalysis, which provided a step-economical approach for the synthesis of aromatic amines by

• . Subsequent intramolecular amine transfer to the radical cation intermediate 53, followed by ligand exchange, yields amination product 49 and Cu(I) species 55. Cu(II) catalyst 50 is regenerated by anodic oxidation, thereby completing the catalytic cycle. In 2019, Nicholls et al. reported a Cu-catalyzed

• directed C–H amination of benzamides with secondary amine electrophiles independently (Figure 11) [61]. In 2023, De Sarkar and Baidya reported the Cu-catalyzed electrocatalytic azidation of N-arylenamines, followed by denitrogenative annulation for quinoxaline synthesis (Figure 12) [62]. Only 0.5 mol

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

• Michael-type addition of 5-aminoindazole to afford the first coupling product XXXVIII. The subsequent intramolecular amination and dehydration then leads to the final product (Scheme 31) [50]. Polycyclic spiroindoline-3,4’-pyrano[3,2-b]pyran-4-ones 43 were synthesized exploiting the three-component

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

• purities in this process (Scheme 20). Chiral Brønsted acid-catalyzed atroposelective reactions Chiral Brønsted acids became prominent organocatalysts that also promote the syntheses of axially chiral compounds. The amination of aromatic biaryls 65a–g with dibenzylazodicarboxylate catalyzed by

• amines 76 in the C–H amination reaction with CPA C25, the authors were able to prepare axially chiral para-amination products 78 (Scheme 25) [49]. Such amination products 78 were prepared with high levels of yields and showed remarkable enantiomeric purities. Interestingly, when a phenyl substituent was

• , not the organocatalyst nor the product being formed, effectively absorb the light. An atroposelective C–H amination was done with the help of SPINOL-derived chiral phosphoric acids C51, C40, and C42 (Scheme 66) [96]. It was a reaction of naphthalenyldiazene carboxylates 222 with derivatives of

Facile one-pot reduction of β-nitrostyrenes to phenethylamines using sodium borohydride and copper(II) chloride

• Laura D’Andrea and
• Simon Jademyr

Beilstein J. Org. Chem. 2025, 21, 39–46, doi:10.3762/bjoc.21.4

• based on the reductive amination of phenyl-2-propanone by use of Al/Hg amalgam. The latter procedure involves numerous drawbacks, such as environmental concerns for the use of mercury, contamination of the final products, the need of special safety precautions, and adequate disposal techniques [9][10

Emerging trends in the optimization of organic synthesis through high-throughput tools and machine learning

• Pablo Quijano Velasco,
• Kedar Hippalgaonkar and
• Balamurugan Ramalingam

Beilstein J. Org. Chem. 2025, 21, 10–38, doi:10.3762/bjoc.21.3

• –Hartwig amination, and Ullmann coupling. These experiments showcased a conversion rate that outperformed existing reference systems and provided at least six times the efficiency in the experimentation, besides synthesis planning, optimization, and downstream workup tasks. The throughput of SynBot is

• medium for enhancing the optimization of the Buchwald–Hartwig amination intermediate, which is crucial for synthesizing the drug olanzapine [47]. The reactor setup was integrated with spectroscopic and chromatographic in-line analytical tools, enabling real-time monitoring of products and reaction

• various reaction categories. The system consists of a liquid–liquid separator and an in-line/online analytical tool to facilitate closed-loop autonomous optimization. The capability of the system was demonstrated in the optimization of C–C and C–N cross-coupling, olefination, reductive amination

Reactivity of hypervalent iodine(III) reagents bearing a benzylamine with sulfenate salts

• Beatriz Dedeiras,
• Catarina S. Caldeira,
• José C. Cunha,
• Clara S. B. Gomes and
• M. Manuel B. Marques

Beilstein J. Org. Chem. 2024, 20, 3281–3289, doi:10.3762/bjoc.20.272

• . A plausible mechanism is proposed, suggesting a possible radical pathway. Keywords: electrophilic amination; hypervalent iodine reagents; sulfinamide; sulfonamide; Introduction Iodine(III) compounds, known as λ3-iodanes, have been extensively applied in organic synthesis. Although initially used

• VIII (named BBX), and investigated its reactivity on the α-amination of indanone-based β-ketoesters (Scheme 1) [4]. Very recently, Minakata’s group also reported iodine(III) reagents with transferable amino groups, particularly a benziodoxolone bearing a transferable NH2 group (IX) [20]. HIRs have been

• ) [32][33]. To investigate the reactivity of the BBXs in this electrophilic amination reaction, the generated compound 4 was subjected to a retro-Michael addition to produce the sulfenate anion intermediate, followed by the addition of BBX 2. Based on our experience with HIRs, the reaction of 2 with

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

• include arylation, iodination, alkynylation, thiophenolation, amination, and esterification, were carried out. Among these reactions, esterification was achieved in moderate yield under metal-free conditions by reacting the synthesized naproxen methyl ester (2-methoxyphenyl)iodonium

Multicomponent synthesis of α-branched amines using organozinc reagents generated from alkyl bromides

• Baptiste Leroux,
• Alexis Beaufils,
• Federico Banchini,
• Olivier Jackowski,
• Alejandro Perez-Luna,
• Fabrice Chemla,
• Marc Presset and
• Erwan Le Gall

Beilstein J. Org. Chem. 2024, 20, 2834–2839, doi:10.3762/bjoc.20.239

• alkyl iodides [24]. It was indeed noticed that the reactivity of primary iodides in the multicomponent carbonyl alkylative amination (CAA) reaction was quite sluggish compared to the secondary counterparts. In addition, primary alkyl bromides were found to be almost inactive in the process. Therefore

Synthesis of tricarbonylated propargylamine and conversion to 2,5-disubstituted oxazole-4-carboxylates

• Kento Iwai,
• Akari Hikasa,
• Kotaro Yoshioka,
• Shinki Tani,
• Kazuto Umezu and
• Nagatoshi Nishiwaki

Beilstein J. Org. Chem. 2024, 20, 2827–2833, doi:10.3762/bjoc.20.238

• ] because of their easily modifiable dipeptide frameworks. Several methods exist for accessing PCPAs, such as the amination of 1-halo-1-alkynes [16][17], tandem reactions of α-imino esters with nucleophiles and electrophiles [18], and the nucleophilic addition of an acetylide to α-carbonylated N-acylimines

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

• monofluoroalkylations. Proposed mechanism. Aymmetric yne-allylic substitution of yne-allylic esters with anthrones. Aymmetric yne-allylic substitution of yne-allylic esters with coumarins. Aymmetric yne-allylic substitution of with coumarins by Lin. Proposed mechanism. Amination by alkynylcopper driven dearomatization

• and rearomatization. Arylation by alkynylcopper driven dearomatization and rearomatization. Remote substitution/cyclization/1,5-H shift process. Proposed mechanism. Arylation or amination by alkynylcopper driven dearomatization and rearomatization. Remote nucleophilic substitution of 5

5th International Symposium on Synthesis and Catalysis (ISySyCat2023)

• Anthony J. Burke and
• Elisabete P. Carreiro

Beilstein J. Org. Chem. 2024, 20, 2704–2707, doi:10.3762/bjoc.20.227

• ) derivatives, which possess recognized pharmacological properties [12]. They used sequential reactions catalyzed by palladium and copper. The process involves an initial amination, which can be carried out via either the Buchwald–Hartwig or the Chan–Lam reaction, followed by a palladium-catalyzed

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

• amination: Direct and selective CH-aminations and amidations are challenging reactions. In this context, the regioselective sulfonamidation of (hetero)aromatic groups was achieved by the Lei group via dehydrogenative aryl C–H/N–H cross-coupling [9]. A crucial step in this transformation is the generation of

• significant potential for further industrial and medicinal chemistry applications (Scheme 5). Furthermore, Ackermann and coworkers described a straightforward C(sp3)–H amination of 1,3-diarylpropenes with sulfonamides via direct oxidation of allylic C(sp3)–H bonds [13]. During the reaction process, a radical

• have been developed, the combination of electrochemistry with organocatalysis is generally less explored. In this context, Wang et al. combined organocatalysis and electrochemistry for the benzyl amination via C–H/N–H dehydrogenative cross-coupling of alkyl arenes with azoles [39]. According to the

Homogeneous continuous flow nitration of O-methylisouronium sulfate and its optimization by kinetic modeling

• Jiapeng Guo,
• Weike Su and
• An Su

Beilstein J. Org. Chem. 2024, 20, 2408–2420, doi:10.3762/bjoc.20.205

• the residence time to 12.36 min amplified the error to approximately 8% (Figure 7c). A similar increase in error with prolonged residence time was noted in Kappe et al.’s kinetic modeling of the Buchwald–Hartwig amination reaction [41], where the theoretical and experimental values diverged by 4.1