Synthesis of HBC fluorophores with an electrophilic handle for covalent attachment to Pepper RNA

• Raphael Bereiter and
• Ronald Micura

Beilstein J. Org. Chem. 2025, 21, 727–735, doi:10.3762/bjoc.21.56

• was impractical for the HBC derivative with a C4-handle (N-(4-bromobutyl)-HBC) due to intramolecular cyclization with the amine. To prevent intramolecular cyclization, we considered the 4-bromobutyl HBC ether 11 as a potential candidate with a 4-atom spacer. Accordingly, 4-hydroxybenzaldehyde was

Origami with small molecules: exploiting the C–F bond as a conformational tool

• Patrick Ryan,
• Ramsha Iftikhar and
• Luke Hunter

Beilstein J. Org. Chem. 2025, 21, 680–716, doi:10.3762/bjoc.21.54

• positioned beta to nitrogen, the fundamental stereoelectronic interactions that arise (I–III, Figure 11) are conceptually similar to those that we have already seen with oxygen-containing molecules. The dominant interaction is an electrostatic attraction between the amine, which is typically protonated at

• elucidate the bioactive conformations, of other simple linear amines too. A gauche alignment of the vicinal C–N and C–F bonds is consistently seen [156], whether the scaffold is a primary amine (e.g., tetrafluorovaline, 91 [157]), a secondary amine (e.g., N-methyl-ᴅ-aspartate(92) [158][159]), or a tertiary

• amine (e.g., a fluorinated analogue of the antidepressant drug, citalopram 93 [160]). We now turn our attention to cyclic amines. Fluorine has been shown to be capable of modifing the conformations of a variety of N-heterocycles, ranging in size from four- to eight-membered rings [48][161][162][163]. In

Recent advances in allylation of chiral secondary alkylcopper species

• Minjae Kim,
• Gwanggyun Kim,
• Doyoon Kim,
• Jun Hee Lee and
• Seung Hwan Cho

Beilstein J. Org. Chem. 2025, 21, 639–658, doi:10.3762/bjoc.21.51

• wide range of 1,1-diborylalkanes bearing an N-tosyl-protected amine as well as alkene and alkyne moieties underwent efficient coupling with allylic bromides. A notable advantage of this synthetic approach is that it provides a distinct alternative to traditional CuH-catalyzed allylic alkylation

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

• [7][8] (Figure 2, reactions 1 and 2, respectively). Results and Discussion N-Acetylamino malonic acid monoester 9a possessing a tosyl-protected tethered amine was selected as a model substrate for the development of the intramolecular amidation under Hofer–Moest conditions. The acid 9a was prepared

Formaldehyde surrogates in multicomponent reactions

• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Bernhard Westermann

Beilstein J. Org. Chem. 2025, 21, 564–595, doi:10.3762/bjoc.21.45

• the alkene moiety of the amine. The resulting stabilized carbocation 15 is then captured by formaldehyde (generated in situ from DMSO) leading to an intermediate oxocarbenium 16 that undergoes a cyclization to obtain the sulfenylated oxazinane derivative 13. In isotope labelling experiments using DMSO

• available from the reaction between aldehydes and amines (primary or secondary), the reaction is called AAA coupling: amine–aldehyde–alkyne coupling (Scheme 19). In this context, the use of formaldehyde as a C1 building block is suitable despite the unstable aminol intermediate. There are several examples

• . These are the basis for the AHA coupling: amine–haloalkane–alkyne coupling for the synthesis of propargylamines by the activation of both C–H and C–X bonds by metal catalysis (Scheme 20). In general, the activation of both CH and CX bonds is accomplished by homogeneous metal catalysis with CuCl being

Study of the interaction of 2H-furo[3,2-b]pyran-2-ones with nitrogen-containing nucleophiles

• Constantine V. Milyutin,
• Andrey N. Komogortsev and
• Boris V. Lichitsky

Beilstein J. Org. Chem. 2025, 21, 556–563, doi:10.3762/bjoc.21.44

• that, the use of 3-fold excess of amine 2a led to the same results. Apparently, the stability of salt 3a is connected with high acidity of the starting furanone 1a and its recovery is only possible under the action of strong acids (HCl, H2SO4). Further, we investigated the chemical behavior of

• intramolecular hydrogen bond between the NH-unit and the carbonyl group. The presented results indicate that the reaction of the aliphatic amine doesn’t lead to recyclization of the studied heterocyclic system. Further, we hypothesized that synthesis of the enamine 4a can be realized in one-pot variant without

• isolation of intermediate salt 3a. Indeed, the reflux of starting compound 1a with amine 2a in AcOH for 24 h led to formation of product 4a with 62% yield. Using various furanones 1 and amines we attempted to synthesize analogues of compound 4a based on the above procedure. It was found that the presence of

Asymmetric synthesis of β-amino cyanoesters with contiguous tetrasubstituted carbon centers by halogen-bonding catalysis with chiral halonium salt

• Yasushi Yoshida,
• Maho Aono,
• Takashi Mino and
• Masami Sakamoto

Beilstein J. Org. Chem. 2025, 21, 547–555, doi:10.3762/bjoc.21.43

• -workers developed chiral amine 1 with an electron-deficient iodine atom, which catalyzed the Mannich reaction in excellent yields and enantioselectivities [17]. In 2020, Huber and co-workers reported the bis(iodoimidazolium) 2-catalyzed Mukaiyama–aldol reaction of carbonyl compounds with enol silyl ethers

Vinylogous functionalization of 4-alkylidene-5-aminopyrazoles with methyl trifluoropyruvates

• Judit Hostalet-Romero,
• Laura Carceller-Ferrer,
• Gonzalo Blay,
• Amparo Sanz-Marco,
• José R. Pedro and
• Carlos Vila

Beilstein J. Org. Chem. 2025, 21, 533–540, doi:10.3762/bjoc.21.41

• -aminopyrazole 2. Compounds 3ab and 3ad were obtained in a comparable yield (54 and 46%) from 1,3-dimethyl-1H-pyrazol-5-amine (2b) or 3-methyl-1-(p-tolyl)-1H-pyrazol-5-amine (2d). On the other hand, 1,3-diphenyl-1H-pyrazol-5-amine (2c) provided the corresponding product 3ac in much lower yield (16%). If a tert

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

• of, firstly, m-chloro-p-(methylamino) derivative 1 to dissect the structure–activity relationship between the primary (IC50(CCRF-CEM) = 0.58 nM), secondary, and tertiary amine (IC50(CCRF-CEM) = 54 pM) derivatives [20]. Secondly, p-(dimethylamino) derivative 2 was synthesised to investigate the effect

• formate, and thirdly ring closure to obtain the epoxides 26 and 2 in 89% and 14% yield over three steps each, respectively. While the synthesis of tertiary amine 2 was finished, final Alloc cleavage from 26 under Tsuji–Trost-like conditions [19] provided secondary amine 1 in 74% yield. The cytotoxicity of

• values of the primary (IC50 (CCRF-CEM) = 580 pM) and tertiary (IC50 (CCRF-CEM) = 54 pM) amine derivatives (Figure 1B) [20][35], showing a strict increase in cytotoxicity with increasing degree of aniline methylation. The same trend was also observed for unit D derivatives modified with amino groups [19

Synthesis of the aggregation pheromone of Tribolium castaneum

• Biyu An,
• Xueyang Wang,
• Ao Jiao,
• Qinghua Bian and
• Jiangchun Zhong

Beilstein J. Org. Chem. 2025, 21, 510–514, doi:10.3762/bjoc.21.38

• -amine reduction and tosylation from diethyl (S)-2-(hex-5-en-2-yl)malonate ((S)-6). The stereocenter in geminal ester (S)-6 could be derived from (R)-2-methyloxirane ((R)-2) via a ring-opening reaction and a stereospecific inversion of the chiral secondary tosylate (R)-5. Following the similar procedure

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

• . Using diphenylamine as a more electron-rich amine resulted in the formation of diphenylamino-substituted N-acetyl diazocine 20 in a significantly lower yield of 25% starting from the bromide 2 and 47% starting from the iodo precursor 3 (Table 5). Deprotection of carbamate 19 with trifluoroacetic acid

• (9) in ortho- and para-positions. The increase is even stronger if electron-withdrawing pyridine- (14), cyano- (23) or the strong +M amino substituents (21) are attached to the N-acetyl diazocine in meta-position. In contrast to the extended half-life of the unsubstituted amine 21 the Boc-protected

• 19 and the diphenyl-substituted amine 20 show half-lives not significantly longer than the parent N-acetyl diazocine 1. Given the water solubility and the excellent switching behavior of parent 1 in aqueous media [3][13][20], the photochemical properties of water-soluble substituted N-acetyl

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

• were required to obtain the corresponding mesylate 3b. Similar to 11, compound 12 was isolated as its trifluoroacetate salt. Selective Boc protection of the aliphatic amine gave 13, which was selectively O-mesylated to give compound 14. Compound 14 was found to slowly undergo intramolecular cyclization

• by displacement of the mesyl group to give a six-membered cyclic carbamate, a reactivity that has been described earlier [34]. Thus, care was taken to quickly isolate compound 14 and use it immediately in the next step. Deblocking of the secondary amine by treatment with trifluoroacetic acid afforded

• 3b in almost quantitative yield. The bis(3-bromopropyl)-modified ligand 3c was generated by heating preQ1 together with bis(3-hydroxypropyl)amine. It is noteworthy that the amine exchange reaction is thought to proceed via a purine methide intermediate [11]. Subsequent treatment of the diol with

Photomechanochemistry: harnessing mechanical forces to enhance photochemical reactions

• Francesco Mele,
• Ana M. Constantin,
• Andrea Porcheddu,
• Raimondo Maggi,
• Giovanni Maestri,
• Nicola Della Ca’ and
• Luca Capaldo

Beilstein J. Org. Chem. 2025, 21, 458–472, doi:10.3762/bjoc.21.33

• (12.3, 0.2 mmol), tosyl chloride (12.4, 2 equiv), and tris(4-methoxyphenyl)amine (10 mol %) was milled in the presence of 100 wt % of SAOED at 30 Hz for 3 h, sulfone 12.5 was obtained in 89% yield after isolation. The synthesis of 12.5 was scaled up to 15 mmol scale, obtaining the desired product in a

New tandem Ugi/intramolecular Diels–Alder reaction based on vinylfuran and 1,3-butadienylfuran derivatives

• Yuriy I. Horak,
• Roman Z. Lytvyn,
• Andrii R. Vakhula,
• Yuriy V. Homza,
• Nazariy T. Pokhodylo and
• Mykola D. Obushak

Beilstein J. Org. Chem. 2025, 21, 444–450, doi:10.3762/bjoc.21.31

• insufficiently studied furo[2,3-f]isoindole derivatives. Ugi adducts formed from (E)-3-(furan-2-yl)acrylaldehyde, maleic acid monoanilide, isonitrile, and an amine spontaneously underwent the IMDAV reaction with a high level of stereoselectivity, leading to single pairs of enantiomers of 4,4a,5,6,7,7a-hexahydro

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

• structures would require fewest augmentations. Otte has levied similar techniques to generate soluble amine-based organic cages with the same symmetry possibilities, using the three edge pieces to provide internal vectors to generate “catalytic triad” mimics [42][43][44]. Synthesis of robust organic cages

• 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

• drug”) class of PROTAC molecules with a PEG linker is frequently used to promote targeted protein degradation. The standard protocol for their synthesis involves nucleophilic aromatic substitution of 4-fluorothalidomide with a PEG-amine. We report herein the identification of a commonly ignored

The effect of neighbouring group participation and possible long range remote group participation in O-glycosylation

• Rituparna Das and
• Balaram Mukhopadhyay

Beilstein J. Org. Chem. 2025, 21, 369–406, doi:10.3762/bjoc.21.27

• neighbouring group participation for the formation of the acetoxonium ion intermediate was more favourable in the locked systems like o-substituted benzoyl groups instead of aliphatic protections. Many protecting groups have been developed for the protection of the amine functionality of nucleosides like 2

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

• study found that by using [Os(phen)3]2+ as the photocatalyst and 660 nm red light, the reaction exhibited greater functional group tolerance, handling a variety of electron-deficient, neutral and rich (hetero)aryl bromides 9 and primary and secondary amine-based nucleophiles 10 with minimal degradation

• ). The mechanism of the reaction presented by the authors involves two different catalytic cycles as presented in Scheme 3c. After excitation of the osmium complex 13, this latter is reduced via the use of a tertiary amine to give the active species 14 able to oxidize the formed nickel complex 15 in the

• light (λ = 750 nm), followed by triplet energy transfer to molecular oxygen, generating singlet oxygen as the active species. Similarly as in the case of the Furuyama et al. study, the singlet oxygen subsequently oxidizes the amine substrate to an iminium ion, which reacts with a cyanide nucleophile to

Molecular diversity of the reactions of MBH carbonates of isatins and various nucleophiles

• Zi-Ying Xiao,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2025, 21, 286–295, doi:10.3762/bjoc.21.21

• substitution products 5a–n in high yields (Scheme 2). The substituents showed a marginal effect on the yields. In addition, a secondary arylamine such N-methylaniline and aliphatic amine (n-butylamine) also gave the expected products 5m and 5n in satisfactory yields. It should be pointed out that no base

• crystal structure of compound 8a. Reaction of arylamines and MBH carbonates of isatins. Reaction conditions: MBH carbonate of isatin (0.1 mmol), aromatic amine (0.1 mmol), DMAP (0.02 mmol, 20 mol %), toluene (5.0 mL), rt, 1 h; yields refer to isolated yields. Reaction of arylamines and MBH maleimides of

• isatins. Reaction conditions: MBH maleimide of isatin (0.1 mmol), aromatic amine (0.1 mmol), toluene (5.0 mL), 65 °C, 1 h; yields refer to isolated yields. Reactions of MBH carbonates of isatins and triphenylphosphine. Reaction conditions: MBH carbonate of isatin (0.1 mmol), triphenylphosphine (0.1 mmol

Dioxazolones as electrophilic amide sources in copper-catalyzed and -mediated transformations

• Seungmin Lee,
• Minsuk Kim,
• Hyewon Han and
• Jongwoo Son

Beilstein J. Org. Chem. 2025, 21, 200–216, doi:10.3762/bjoc.21.12

• dioxazolone 7. Subsequently, nitrene insertion of INT-12 into the Cu–C bond, forms INT-13, which then undergoes isomerization and protodemetalation, followed by catalyst regeneration, as suggested by the DFT calculations. Finally, the nucleophilic addition of the amine to the electrophilic intermediate INT-15

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

• Figure 11. Initially, the Cu(II) catalyst 50 coordinates with substrate 47 and amine electrophile 48 to generate Cu(II) intermediate 51, which is then oxidized by the iodine radical to form Cu(III) complex 52. Cu(III) complex 52 undergoes electron transfer to produce radical cation intermediate 53

• . 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

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

• counteranion. The use of a carbamate among the substrates instead of the amine allowed the synthesis of propargylcarbamates 11. This reaction, effective only for the aromatic aldehydes, did not require other co-catalysts or ligands (Scheme 8) [21]. Three-component reactions of alkynes, alkyltrifluoroborates

• Pd-catalyzed cross-coupling reactions, allowing the formation of C–C and C–N bonds in the o-position of the aryl chalcogen compounds. α-Aminophosphonates 14 were the result of a one-pot condensation of an aldehyde, a primary amine and phosphite P(OMe)3 with copper triflate acting as Lewis acid

• reaction between the anhydride and the amine suggested the subsequent reaction with the ketone to give an imine intermediate XXIV. This latter can undergo intramolecular nucleophilic attack affording the quinazolinone derivative 26 (Scheme 20) [37]. Polysubstituted pyrroles 27 were obtained in a cascade

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

Hot shape transformation: the role of PSar dehydration in stomatocyte morphogenesis

• Remi Peters,
• Levy A. Charleston,
• Karinan van Eck,
• Teun van Berlo and
• Daniela A. Wilson

Beilstein J. Org. Chem. 2025, 21, 47–54, doi:10.3762/bjoc.21.5

• glutamate) (PBLG) as the hydrophobic block, which was done to prevent ending on a primary amine in the final product which could disrupt self-assembly due to its ionizable nature. Subsequently, PBLG served as a macroinitiator for the polymerization of sarcosine NCA, yielding the final polymer with high

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

• ]. One of the most studied and inexpensive routes to synthesize substituted phenethylamines focuses on the reduction of their α,β-unsaturated nitroalkene analogue (β-nitrostyrene), where both the double bond and the nitro group need to be reduced to deliver the corresponding primary amine. Their

• precipitated under stirring with an excess of 2 N HCl in diethyl ether solution and the vessel was cooled to 5 °C. The solid was filtered, washed with cold diethyl ether, and dried under reduced pressure as the amine hydrochloride salt. (II) An excess of 4 N HCl in dioxane solution was added and the filtrate

• was stirred for 30 minutes. The residue was concentrated under reduced pressure, suspended in dry cold acetone, and stirred vigorously for 1 hour. The suspension was filtered and washed with a minimum amount of cold acetone to deliver the product as hydrochloride salt. 2-Phenylethan-1-amine