Enhancing chemical synthesis planning: automated quantum mechanics-based regioselectivity prediction for C–H activation with directing groups

• Julius Seumer,
• Nicolai Ree and
• Jan H. Jensen

Beilstein J. Org. Chem. 2025, 21, 1171–1182, doi:10.3762/bjoc.21.94

• reactions, the regioselectivity is not only determined by the activation energy for the rate-determining step but also by the proximity of an intramolecular reaction partner, here the secondary amine. From this in-depth analysis, we conclude that our QM workflow only predicted the wrong reaction site for

A multicomponent reaction-initiated synthesis of imidazopyridine-fused isoquinolinones

• Ashutosh Nath,
• John Mark Awad and
• Wei Zhang

Beilstein J. Org. Chem. 2025, 21, 1161–1169, doi:10.3762/bjoc.21.92

• reaction followed by the cleavage of the alkyl group to give intermediate II as a free amine. Annulation of II with CDI gave product B which is an HIV reverse transcriptase inhibitor (Scheme 1B) [17]. We have reported a three-component [3 + 2] cycloaddition followed by IMDA reaction for making heterocyclic

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

• scaffold for aminations with 14 commercially available primary amines. Reacting scaffold 1 with excess primary amine at room temperature for 16 h generated the desired amine analogues in respectable yields (18–87%) and high purity (≥95%) following chromatography workup. The structures of the 14 previously

• undescribed amine analogues 2–15 were fully characterised following 1D/2D NMR, UV, and HRMS data analyses. X-ray crystallographic analysis of crystals obtained from the aminated products 2, 7, 10, and 15 are also reported here. The new library of amine-substituted triazolopyrazines was screened against the

• Plasmodium falciparum 3D7 strain. The tertiary alkylamine products 10–14 displayed antimalarial activity with IC50 values ranging from 9.90 to 23.30 µM against P. falciparum 3D7, with compounds 10–12 demonstrating no toxicity at 80 µM against the human embryonic kidney cell line HEK293. Keywords: amine

A versatile route towards 6-arylpipecolic acids

• Erich Gebel,
• Cornelia Göcke,
• Carolin Gruner and
• Norbert Sewald

Beilstein J. Org. Chem. 2025, 21, 1104–1115, doi:10.3762/bjoc.21.88

• Erich Gebel Cornelia Gocke Carolin Gruner Norbert Sewald Department of Chemistry, Organic and Bioorganic Chemistry, Bielefeld University, Universitätsstraße 25, D-33615 Bielefeld, Germany 10.3762/bjoc.21.88 Abstract Pipecolic acid is known as a non-proteinogenic amino acid with a secondary amine

• . This tendency of amine bases in cross-coupling reactions aligns with the literature [44][45][46], reporting that they are either superior to or significantly outperformed by oxygen-based bases, depending on the conditions and substrates. K2CO3 was found to be the most suitable base, having similar

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

• -dithiocyanatopyrimidine (NDTP) as the coupling reagent for cinnamic acid amidation with swift reaction time (Scheme 4) [22]. The reaction of cinnamic acid (7) with NDTP resulted in the active acyl thioester 11 followed by a reaction with an amine to give the corresponding amide 10. The byproduct of the coupling reagent

• activate the carboxyl group of cinnamic acid (7) to generate the reactive silyl ester 30, which converted to the corresponding amide 29 upon reaction with an amine on a gram-scale operation (Scheme 10) [42]. Ramachandran and co-workers (2020) performed the amidation of cinnamic acid (7) by utilizing

• stoichiometric amine–BH3 reagent via triacyloxyborane–amine complex 33 to obtain the corresponding amides 31 and 32 in good yields (Scheme 11) [43]. Moreover, acid halides are widely applied for esterification and amidation. For example, Pattarawarapan and co-workers (2020) reported the amidation of cinnamic

Recent total synthesis of natural products leveraging a strategy of enamide cyclization

• Chun-Yu Mi,
• Jia-Yuan Zhai and
• Xiao-Ming Zhang

Beilstein J. Org. Chem. 2025, 21, 999–1009, doi:10.3762/bjoc.21.81

• intermediate would meet challenges associated with the instability of enolate derivatives. In their recent study, they successfully developed such a polycyclization taking advantage of a novel spiropyrroline-derived oxazole (SPDO) ligand (L3). As shown in Scheme 7, one-pot condensation of primary amine 40, β

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

• synthesis of brevicarine (2) (Scheme 5) started with the known synthesis of 5 from 3, followed by catalytic reduction of the triple bond of phthaloyl intermediate 5 to give compound 24. Removal of the phthalimide group with methylamine resulted in amine 25. Alternatively, the removal of the phthaloyl moiety

• from compound 5 to amine 6 using methylamine instead of the highly toxic and environmentally harmful methylhydrazine, which was used earlier [9], has been developed as a greener approach, followed by catalytic reduction of the triple bond also leading to compound 25. Our experiments for the N

• were crowned by success. In order to completely avoid the possibility of overmethylation [37], the methyl group was introduced by N-formylation of the primary amine group of 25 to give congener 26, followed by reduction of the formyl group with borane–dimethyl sulfide complex [38] to result in

Study of tribenzo[b,d,f]azepine as donor in D–A photocatalysts

• Katy Medrano-Uribe,
• Jorge Humbrías-Martín and
• Luca Dell’Amico

Beilstein J. Org. Chem. 2025, 21, 935–944, doi:10.3762/bjoc.21.76

• behavior is supported by the DFT studies, which suggested a better spatial separation between the HOMO and LUMO. As expected, the HOMO–LUMO energy gap followed a trend that is dependent on the electron-donating capacity of the nitrogen heterocycles and amine present in compounds 5e (2.9 eV), 5d (3.5 eV

Silver(I) triflate-catalyzed post-Ugi synthesis of pyrazolodiazepines

• Muhammad Hasan,
• Anatoly A. Peshkov,
• Syed Anis Ali Shah,
• Andrey Belyaev,
• Chang-Keun Lim,
• Shunyi Wang and
• Vsevolod A. Peshkov

Beilstein J. Org. Chem. 2025, 21, 915–925, doi:10.3762/bjoc.21.74

• [20][21][22][23]. For example, the Ugi four-component reaction (U4CR), involving a carbonyl compound, a primary amine, a carboxylic acid, and an isocyanide, provides a straightforward method for constructing dipeptide-like adducts [24][25][26][27]. These adducts can subsequently be rigidified into

• pyrazolodiazepines 16a–d were obtained in consistently high yields of 84–96%. Notably, the synthesis of the parent pyrazolodiazepine 16a was scaled up to 3.5 mmol without a substantial decrease in isolated yield. To explore the influence of the amine component on the process, an extensive subset of aniline-derived

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

• -migration to form borate ester 86, which then reacts with another molecule of CH2BrLi to form the more stable borate Int-80. Subsequently, a C-1,2-migration leads to the formation of the double-insertion product 84. If the amine portion is more electron-deficient or has more delocalized nitrogen electrons

• species Int-83. Subsequently, in the presence of a base, the amine undergoes nucleophilic attack on the coordinated CO, generating (carbamoyl)copper complex Int-84. Then, alkyl bromide undergoes a single-electron-transfer (SET) process with Int-84, forming intermediate Int-85 and an alkyl radical, which

• is captured by CO to yield an acyl radical. Alternatively, under the action of a base, the amine can undergo anionic ligand exchange with (carbonyl)copper species Int-83, generating an electron-rich amino copper(I) species Int-84', which activates alkyl bromide through an SET process, followed by

Unraveling cooperative interactions between complexed ions in dual-host strategy for cesium salt separation

• Zhihua Liu,
• Ya-Zhi Chen,
• Ji Wang,
• Qingling Nie,
• Wei Zhao and
• Biao Wu

Beilstein J. Org. Chem. 2025, 21, 845–853, doi:10.3762/bjoc.21.68

• highly efficient Cs3PO4 extraction. Results and Discussion The tripodal hexaurea receptor L is comprised of a central tren (tris(2-aminoethyl)amine) core and three arms of ortho-phenylene bis(urea) units, which can fold inward to encapsulate an anion inside the cavity through up to 12 hydrogen bonds [30

4-(1-Methylamino)ethylidene-1,5-disubstituted pyrrolidine-2,3-diones: synthesis, anti-inflammatory effect and in silico approaches

• Nguyen Tran Nguyen,
• Vo Viet Dai,
• Luc Van Meervelt,
• Do Thi Thao and
• Nguyen Minh Thong

Beilstein J. Org. Chem. 2025, 21, 817–829, doi:10.3762/bjoc.21.65

• single-crystal X-ray diffraction [19]. According to a previous publication, the condensation between pyrrolidine-2,3-diones and an amine as nucleophile normally occurred at the 3-position of nitrogen-containing heterocyclic ring which results in the corresponding enamine product [18]. However, the

• addition, even though there was an excess of water as compared to methylamine in the reaction mixture, the nucleophilicity of water molecules is lower than that of the aliphatic amine [22]. Hence, the transimination reaction [23] has occurred reversibly in which the imine (C=N) linkage-containing resonance

Regioselective formal hydrocyanation of allenes: synthesis of β,γ-unsaturated nitriles with α-all-carbon quaternary centers

• Seeun Lim,
• Teresa Kim and
• Yunmi Lee

Beilstein J. Org. Chem. 2025, 21, 800–806, doi:10.3762/bjoc.21.63

• % yield under basic conditions using sodium hydroxide and tert-butanol. The reduction of nitrile 3q with lithium aluminum hydride generated amine 7 in an 85% yield, whereas the selective hydrogenation of the alkene moiety of 3q using a Pd/C catalyst in a H2 gas environment smoothly produced product 8 in a

New advances in asymmetric organocatalysis II

• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 766–769, doi:10.3762/bjoc.21.60

• describes the enantioselective Michael addition of pyrazoline-5-ones to α,β-unsaturated ketones. The enantioselectivity and chemical efficiency of this transformation were achieved with a cinchona-alkaloid-derived primary-amine–Brønsted acid composite [22]. A good demonstration of how organocatalysis

• progressed from the original amine catalysts is the work of Shirakawa and co-workers. In this contribution, the authors employed a binaphthalene-derived sulfide organocatalyst for enantioselective bromolactonizations of α- and β-substituted 5-hexenoic acids to produce the corresponding chiral lactones [23

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