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

Catalysing (organo-)catalysis: Trends in the application of machine learning to enantioselective organocatalysis

• Stefan P. Schmid,
• Leon Schlosser,
• Frank Glorius and
• Kjell Jorner

Beilstein J. Org. Chem. 2024, 20, 2280–2304, doi:10.3762/bjoc.20.196

• [92] and a phase-transfer catalysed oxidative amination reaction [93]. In the latter, NCI descriptors were both used to simplify previously existing MLR models and also led to a hypothesis of key NCIs in the transition state. Whereas these descriptors require the selection of a suitable probe model

Factors influencing the performance of organocatalysts immobilised on solid supports: A review

• Zsuzsanna Fehér,
• Dóra Richter,
• Gyula Dargó and
• József Kupai

Beilstein J. Org. Chem. 2024, 20, 2129–2142, doi:10.3762/bjoc.20.183

• cases, the support surface can even impede unwanted side reactions. Pericàs and co-workers immobilised a thiourea organocatalyst on PS (28) and applied it in the enantioselective α-amination of 1,3-dicarbonyl compounds [36]. Unlike homogeneous thioureas, catalyst 28 is not irreversibly deactivated by

• . α-Amination of ethyl 2-oxocyclopentanecarboxylate catalysed by PS-THU which could be recycled over 9 reaction cycles. Preparation of supported catalysts C29–C31 from cinchona squaramides 29–31 modified with a primary amino group. Application of PGMA-supported organocatalysts C29–C31 in the

Negishi-coupling-enabled synthesis of α-heteroaryl-α-amino acid building blocks for DNA-encoded chemical library applications

• Matteo Gasparetto,
• Balázs Fődi and
• Gellért Sipos

Beilstein J. Org. Chem. 2024, 20, 1922–1932, doi:10.3762/bjoc.20.168

• ][28]. However, the selectivity of these photoredox reactions is driven by the structural properties of the heteroaromatic ring. During the preparation of this article, the Meggers group published an outstanding enantioselective iron-catalyzed α-amination pathway (Scheme 1b) [29]. The method is widely

Solvent-dependent chemoselective synthesis of different isoquinolinones mediated by the hypervalent iodine(III) reagent PISA

• Ze-Nan Hu,
• Yan-Hui Wang,
• Jia-Bing Wu,
• Ze Chen,
• Dou Hong and
• Chi Zhang

Beilstein J. Org. Chem. 2024, 20, 1914–1921, doi:10.3762/bjoc.20.167

• isoquinolinone derivatives. The method provides highly chemoselective access to 3- or 4-substituted isoquinolinone derivatives by reacting o-alkenylbenzamide derivatives with PISA in either acetonitrile or wet hexafluoro-2-isopropanol. Keywords: annulation; C–H amination; hypervalent iodine reagent; iodine(III

• zwitterionic water-soluble hypervalent iodine reagent (phenyliodonio)sulfamate (PISA). In water, PISA is strongly acidic, and the pH value can reach 2.05 in a saturated aqueous solution. With PISA, various indoles have been synthesized via C–H amination of 2-alkenylanilines involving an aryl migration

• , isopropyl, cyclopropyl, phenyl, or hydrogen, respectively, the intramolecular amination smoothly gave the corresponding 4-substituted isoquinolinone products 2b,c,d–f in 51–94% yield. Notably, when 1c was used as the substrate, the cycloisomerization product 2c' was observed in 31% yield besides 2c in 51

Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations

• Ryo Tanifuji and
• Hiroki Oguri

Beilstein J. Org. Chem. 2024, 20, 1693–1712, doi:10.3762/bjoc.20.151

• pentacyclic secondary amine 97 bearing the ester linker in the C1 side chain in one pot. After removal of SfmC by precipitation and centrifugation, the reaction mixture containing secondary amine 97 was subjected to the reductive amination using 2-picoline borane as a hydride source, yielding tertiary amine

Methyltransferases from RiPP pathways: shaping the landscape of natural product chemistry

• Maria-Paula Schröder,
• Isabel P.-M. Pfeiffer and
• Silja Mordhorst

Beilstein J. Org. Chem. 2024, 20, 1652–1670, doi:10.3762/bjoc.20.147

• three main routes for the synthesis of methylated peptides: chemical synthesis [33][34], in vitro ribosomal synthesis [35], and enzymatic synthesis. Chemical synthesis. Three main categories of reactions are commonly used: reductive amination, reductive ring openings, and the use of methylating agents

• [34]. In reductive amination, the substrate is usually an aldehyde or amine. After the formation of the iminium ion, it is reduced with the appropriate reagent to form the N-methylated amino acid. Different methods have been established using for example benzaldehyde as a protection group, sodium

Synthesis of 2-benzyl N-substituted anilines via imine condensation–isoaromatization of (E)-2-arylidene-3-cyclohexenones and primary amines

• Lu Li,
• Na Li,
• Xiao-Tian Mo,
• Ming-Wei Yuan,
• Lin Jiang and
• Ming-Long Yuan

Beilstein J. Org. Chem. 2024, 20, 1468–1475, doi:10.3762/bjoc.20.130

• substrates [7][8]. Pre-functionalized arenes are essential precusors in all of these general approaches. 2-Cyclohexenones are fundamental and versatile organic synthetic materials [9][10]. They have been applied as an ideal arylation platform to construct functionalized anilines via an amination

• –dehydrogenative aromatization strategy with amines as nucleophiles [11][12]. For instance, the groups of Deng and Li reported the Pd catalyzed oxidative coupling of 2-cyclohexenones with amines [13]. Later, the same group demonstrated the direct amination of phenols by reductive coupling of in situ generated 2

• anilines [19] (Scheme 1, (3)). To date, although plentiful amination–aromatization approaches for the preparation of anilines have been well-established, to develop novel and efficient synthetic methods still remains highly desirable. In continuation of our recent studies on synthetic applications of