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

Predicting bond dissociation energies of cyclic hypervalent halogen reagents using DFT calculations and graph attention network model

• Yingbo Shao,
• Zhiyuan Ren,
• Zhihui Han,
• Li Chen,
• Yao Li and
• Xiao-Song Xue

Beilstein J. Org. Chem. 2024, 20, 1444–1452, doi:10.3762/bjoc.20.127

• applications [27][28][29][30]. For example, hypervalent bromine(III) reagents enable C–H amination and alkene aziridination reactions without the need for additional Lewis acid activation [31][32][33]. However, challenges in the synthesis and stabilization of cyclic hypervalent bromine and chlorine reagents

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

• , hydroaminomethylation, reduction of nitriles and nitro compounds or through reductive amination of carbonyl derivatives [26][27][28][29][30]. However, for example, cross-coupling reactions with alkyl or aryl halides generate considerable amounts of waste (Scheme 2A). Even though many different approaches exist for

Structure–property relationships in dicyanopyrazinoquinoxalines and their hydrogen-bonding-capable dihydropyrazinoquinoxalinedione derivatives

• Tural N. Akhmedov,
• Ajeet Kumar,
• Daken J. Starkenburg,
• Kyle J. Chesney,
• Khalil A. Abboud,
• Novruz G. Akhmedov,
• Jiangeng Xue and
• Ronald K. Castellano

Beilstein J. Org. Chem. 2024, 20, 1037–1052, doi:10.3762/bjoc.20.92

• functionality as well as Buchwald–Hartwig amination involving aryl halides. Thermal studies Thermal stabilities of DCPQs 1a–6a and DPQDs 1b–7b were evaluated using thermogravimetric analysis (TGA; Figure 2 and Table S4 in Supporting Information File 1). The thermal stability of the DCPQs is attributed to their

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

• isolated product was an indol-3-one derivative (Scheme 14). Another example for the synthesis of 3-substituted indoles was described by Hsieh and Dong [35]. They synthesized 3-arylindoles by palladium-catalyzed C–H bond amination via reduction of nitroalkenes using carbon monoxide as reducing agent. The

• palladium-catalyzed reductive N-heteroannulation. Synthesis of 3-arylindoles by palladium-catalyzed C–H bond amination via reduction of nitroalkenes. Synthesis of 2,2′-bi-1H-indoles, 2,3′-bi-1H-indoles, 3,3′-bi-1H-indoles, indolo[3,2-b]indoles, indolo[2,3-b]indoles, and 4,4′-diaza-3,3′-bi-1H-indole. Pd

(Bio)isosteres of ortho- and meta-substituted benzenes

• H. Erik Diepers and
• Johannes C. L. Walker

Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78

• . Bennet and co-workers also reported the synthesis of 1-amino-1,2-BCPs (±)-11a–e via a similar strategy (Scheme 1C) [29]. They were able to prepare differently-substituted [1.1.1]propellanes 3b–f and subject these to strain-release amination reactions. The synthesis was shown to tolerate typical alcohol

• cyclopropanation [44] (to (±)-66) of α-hydroxy silyl enol ethers (±)-65 followed by an acid-catalysed pinacol rearrangement to (±)-67. As exemplary derivatizations of 5-oxo-BCH (±)-67, 1,5-BCHs (±)-68, (±)-69 and (±)-70 were accessed by reductive amination, ketone reduction, and Horner–Wadsworth–Emmons olefination

• -cubanes (Scheme 9B) [51]. Partial deprotection of diester 88 led to acid 89 as a key intermediate and in situ activation of the acid as the hypervalent iodine complex enabled a photoredox decarboxylative amination to 1,2-cubane 90. Alternatively, conversion of the acid moiety of 89 to redox active esters

Mechanisms for radical reactions initiating from N-hydroxyphthalimide esters

• Carlos R. Azpilcueta-Nicolas and
• Jean-Philip Lumb

Beilstein J. Org. Chem. 2024, 20, 346–378, doi:10.3762/bjoc.20.35

• forming an iminium intermediate 101. Finally, nucleophilic addition of phthalimide anion 102 afforded the amination product 103. Bosque and Bach reported the use of 3-acetoxyquinuclidine (q-Ac) as a catalytic donor for the activation of TCNHPI esters derived from α-amino acids [72] (Scheme 20). Treatment

Substitution reactions in the acenaphthene analog of quino[7,8-h]quinoline and an unusual synthesis of the corresponding acenaphthylenes by tele-elimination

• Ekaterina V. Kolupaeva,
• Narek A. Dzhangiryan,
• Alexander F. Pozharskii,
• Oleg P. Demidov and
• Valery A. Ozeryanskii

Beilstein J. Org. Chem. 2024, 20, 243–253, doi:10.3762/bjoc.20.24

• studied for the first time. In addition to the pronounced tendency of the title compound to form associates with an intramolecular hydrogen bond of the NHN type (new examples with the participation of pyridine rings, including self-associates are shown) and its inertness to amination reactions of the

• effect of functional groups on the further chemistry and basicity of the newly synthesized derivatives is also considered. Results and Discussion Amination, dehydrogenation, and supramolecular aggregation Direct amination of quinoquinoline 5 could potentially lead to 2(11)-substituted amines 6 (Figure 1

• ), the basicity of which must obviously be higher than that of the starting heterocycle 5. To this end, we conducted a series of experiments on its oxidative amination by varying the reaction conditions (time, temperature, addition of n-butyllithium to increase the nucleophilicity of amines), and