Chiral phosphoric acid-catalyzed asymmetric synthesis of helically chiral, planarly chiral and inherently chiral molecules

• Wei Liu and
• Xiaoyu Yang

Beilstein J. Org. Chem. 2025, 21, 1864–1889, doi:10.3762/bjoc.21.145

• interactions with the enehydrazine intermediate, which is essential for achieving high levels of stereocontrol. Using the optimal catalyst CPA 1, a series of aza[6]helicenes 3a,b was synthesized with excellent enantioselectivity and high yield. However, this method demonstrated notably reduced efficiency and

• acid substrates 43 which, upon treatment with ynamide 44, yielded the vinyl acetate intermediate INT-A (Scheme 13). Subsequently, the one-pot CPA-catalyzed intramolecular esterification of this intermediate afforded the planarly chiral macrocycles 45 with good yield and high enantioselectivity

• 71 yielded the cyclic intermediate INT-B, which then underwent addition with aniline co-catalyst 73 to form INT-C. The CPA-enabled release of CO2 from INT-C yielded the imine-containing intermediate INT-D, which underwent iterative addition with INT-B, followed by release of CO2 to afford INT-E. The

Systematic pore lipophilization to enhance the efficiency of an amine-based MOF catalyst in the solvent-free Knoevenagel reaction

• Pricilla Matseketsa,
• Margret Kumbirayi Ruwimbo Pagare and
• Tendai Gadzikwa

Beilstein J. Org. Chem. 2025, 21, 1854–1863, doi:10.3762/bjoc.21.144

• and the amine catalyst (Scheme 1A) [47][48]. However, there is another possible mechanism where malononitrile is deprotonated by the amine catalyst. Here, the resulting carbanion would attack benzaldehyde to form 2-(hydroxy(phenyl)methyl)malononitrile (HPMM) as an intermediate that then loses a water

• intermediate depending on the lipophilicity of the pores. Under solvent-free conditions, we observed the formation of 2-(hydroxy(phenyl)methyl)malononitrile (HPMM, Figure 5), an intermediate which is subsequently dehydrated to yield the main product (BMN) as the reaction progresses [53]. Looking at the ratio

• of final product to intermediate (BMN:HPMM), we observed that relatively more of the hydroxy intermediate was observed with the unfunctionalized KSU-1 catalyst (Figure 5) when compared to the lipophilicized catalysts, with the amount of HPMM decreasing with increasing aliphatic chain surface area

Photoswitches beyond azobenzene: a beginner’s guide

• Michela Marcon,
• Christoph Haag and
• Burkhard König

Beilstein J. Org. Chem. 2025, 21, 1808–1853, doi:10.3762/bjoc.21.143

• -nitrobenzyl bromide (47) with 50 or with 52, after its reduction with NaBH4. The intermediate products are then treated with lead in a buffered basic environment to get the final product in low yield accompanied by two by-products, 54a,b. For the O-heterodiazocine, reduction with triphenylphosphine and a

Fe-catalyzed efficient synthesis of 2,4- and 4-substituted quinolines via C(sp²)–C(sp²) bond scission of styrenes

• Prafull A. Jagtap,
• Manish M. Petkar,
• Vaishnavi R. Sawant and
• Bhalchandra M. Bhanage

Beilstein J. Org. Chem. 2025, 21, 1799–1807, doi:10.3762/bjoc.21.142

• the FeIII species. An alternative mechanism involving a concerted [4 + 2] cycloaddition between the aza-butadiene moiety in II and the alkene, leading to intermediate IV, cannot be ruled out. Conclusion In summary, we have successfully developed a highly efficient method for the oxidative C–C bond

Synthesis of chiral cyclohexane-linked bisimidazolines

• Changmeng Xi,
• Qingshan Sun and
• Jiaxi Xu

Beilstein J. Org. Chem. 2025, 21, 1786–1790, doi:10.3762/bjoc.21.140

• nucleophilically attacks the phosphonium in A to generate intermediate B by loss of triphenylphosphine oxide and triflic acid. The nucleophilic sulfonamide in B intramolecularily attacks the generated imine moiety in B to form intermediate C, in which triflic acid may protonate the imine moiety in B to assist the

• nucleophilic attack. Intermediate C further transforms to imidazoline product 5 by loss of triphenylphosphine oxide and triflic acid. Conclusion Both chiral bisoxazolines and bisimidazolines are efficient and widely applied chiral ligands in metal-catalyzed asymmetric organic reactions. Several chiral

Preparation of a furfural-derived enantioenriched vinyloxazoline building block and exploring its reactivity

• Madara Darzina,
• Anna Lielpetere and
• Aigars Jirgensons

Beilstein J. Org. Chem. 2025, 21, 1737–1741, doi:10.3762/bjoc.21.136

• ][24] (Scheme 1). The proposed strategy relied on the N-deprotection of the intermediate ester 3d inducing O-to-N rearrangement to form amide 5 as a precursor of vinyloxazoline 6. For this purpose, Alloc (allyloxycarbonyl) turned out to be a suitable N-protecting group as it was compatible with the

• oxidation in methanol in batch electrolysis conditions, providing unsaturated esters S-3d and R-3d, respectively (Scheme 2). The previously used one-reactor two-step conditions were found to be productive for the electrosynthesis of S-3d, requiring the addition of acetic acid for the intermediate spiroketal

• -wise process [22]. The first step involves addition of the oxazoline nitrogen to TsNCO leading to a zwitterionic intermediate A, which undergoes 1,4-conjugate addition forming a cyclic intermediate B. Subsequently, the electron-rich double bond in intermediate B reacts with a second equivalent of TsNCO

Convenient alternative synthesis of the Malassezia-derived virulence factor malassezione and related compounds

• Karu Ramesh and
• Stephen L. Bearne

Beilstein J. Org. Chem. 2025, 21, 1730–1736, doi:10.3762/bjoc.21.135

• advisable to stockpile the penultimate synthetic intermediate 23 and subsequently conduct the deprotection on the smaller scale. Conclusion Overall, we have developed a facile synthesis of the natural product malassezione, utilizing an EDC-mediated coupling of N-Boc-protected indole-3-acetic acid. The use

Approaches to stereoselective 1,1'-glycosylation

• Daniele Zucchetta and
• Alla Zamyatina

Beilstein J. Org. Chem. 2025, 21, 1700–1718, doi:10.3762/bjoc.21.133

• configuration has been explained by the formation of a picolinium adduct, resulting from the trapping of the acidic by-product TMSOTf by the pyridine moiety of the picoloyl group during glycosylation [69]. The resulting intermediate, a picolinium-stabilized TMS-glycoside, exhibits high configurational stability

Structural analysis of stereoselective galactose pyruvylation toward the synthesis of bacterial capsular polysaccharides

• Tsun-Yi Chiang,
• Mei-Huei Lin,
• Chun-Wei Chang,
• Jinq-Chyi Lee and
• Cheng-Chung Wang

Beilstein J. Org. Chem. 2025, 21, 1671–1677, doi:10.3762/bjoc.21.131

• Program, Taiwan International Graduate Program (TIGP), Academia Sinica, Taipei 115, Taiwan 10.3762/bjoc.21.131 Abstract Pyruvate ketal is a biologically essential moiety due to its key role as an intermediate in metabolic pathways, serving as a key precursor for the synthesis of various essential

• to synthesize a pyruvate ketal-containing PS A1 precursor associated with the commensal anaerobic bacteria capsule (Scheme 1) [7][8][9][10][11]. The target structure was β-ᴅ-Galf-(1→3)-α-ᴅ-Gal-(1→3)-β-ᴅ-Gal. This molecule acts as a critical intermediate for synthesizing various O4-linked PS A1

Influence of the cation in hypophosphite-mediated catalyst-free reductive amination

• Natalia Lebedeva,
• Fedor Kliuev,
• Olesya Zvereva,
• Klim Biriukov,
• Evgeniya Podyacheva,
• Maria Godovikova,
• Oleg I. Afanasyev and
• Denis Chusov

Beilstein J. Org. Chem. 2025, 21, 1661–1670, doi:10.3762/bjoc.21.130

• reaction medium, thereby preventing their reduction. This fact and the result of the control experiment where Schiff base was used as a starting material (Scheme 3a) demonstrated that Schiff base was not an intermediate in the developed reaction. The reactions between carbonyl compounds and secondary

• amines proceeded forming products in moderate to high yields. In this process enamine can be the intermediate. Therefore, enamine was tested in the control experiment and the corresponding product was obtained in moderate yield (49%). To validate the experiment with enamine the reductive amination with

• equal amounts of the corresponding carbonyl compound and amine was carried out and the product was obtained in 69% yield (Scheme 3b). Therefore, enamine could be considered as an intermediate or resting state of the reaction, but more likely the real intermediate is an iminium cation or hemiaminal. To

Formal synthesis of a selective estrogen receptor modulator with tetrahydrofluorenone structure using [3 + 2 + 1] cycloaddition of yne-vinylcyclopropanes and CO

• Jing Zhang,
• Guanyu Zhang,
• Hongxi Bai and
• Zhi-Xiang Yu

Beilstein J. Org. Chem. 2025, 21, 1639–1644, doi:10.3762/bjoc.21.127

• is the retrosynthetic analysis for the key intermediate 1, which can reach the final compound VI via chlorination and demethylation [19]. Target molecule 1 can be accessed by decarboxylation reaction from compound 13, prepared by an intramolecular Heck reaction between the β-ketoester and the vinyl

Transition-state aromaticity and its relationship with reactivity in pericyclic reactions

• Israel Fernández

Beilstein J. Org. Chem. 2025, 21, 1613–1626, doi:10.3762/bjoc.21.125

• ) of the butadiene + ethylene reaction proceeds with a lower barrier (up to 7 kcal/mol) than the corresponding stepwise pathway leading to a diradical intermediate (Scheme 1a) [19][20]. Similar preferences for concerted pathways over stepwise mechanisms were also found for dipolar cycloadditions and

• [81]. From a mechanistic point of view, this process involves the initial formation of a bent-allene intermediate, which leads to the final reaction product via hydrogen shifts (Scheme 2) [82]. The so-called Bergman cyclization of cis-3-hexene-1,5-diynes [83][84], which is suggested to proceed through

3-Aryl-2H-azirines as annulation reagents in the Ni(II)-catalyzed synthesis of 1H-benzo[4,5]thieno[3,2-b]pyrroles

• Julia I. Pavlenko,
• Pavel A. Sakharov,
• Anastasiya V. Agafonova,
• Derenik A. Isadzhanyan,
• Alexander F. Khlebnikov and
• Mikhail S. Novikov

Beilstein J. Org. Chem. 2025, 21, 1595–1602, doi:10.3762/bjoc.21.123

• intermediate formation of free radical species [9]. A similar reaction of N-acetyl substituted indole 9c produced [3 + 2] cycloaddition products 12 in even lower yield (4%). However, the main reaction product turned out to be unstable compound 13, which, nevertheless, was isolated in 40% yield as a single

• mechanisms of the formation of azirindine 16 under Ni(II)- and Cu(I)-catalysis. Oxidative dimerization of non-aromatic cyclic enols has been previously observed in their reactions with 3-arylazirines catalyzed by Cu(I) and Cu(II) complexes and was attributed to the recombination of intermediate free radicals

Facile synthesis of hydantoin/1,2,4-oxadiazoline spiro-compounds via 1,3-dipolar cycloaddition of nitrile oxides to 5-iminohydantoins

• Juliana V. Petrova,
• Varvara T. Tkachenko,
• Victor A. Tafeenko,
• Anna S. Pestretsova,
• Vadim S. Pokrovsky,
• Maxim E. Kukushkin and
• Elena K. Beloglazkina

Beilstein J. Org. Chem. 2025, 21, 1552–1560, doi:10.3762/bjoc.21.118

• bioactive fragments into a single molecule through a spacer. An alternative strategy of combining heterocyclic pharmacophores is to incorporate them into a spiro-jointed structure that lacks any intermediate link between the active parts [17]. Despite the fact that these strategies share numerous

General method for the synthesis of enaminones via photocatalysis

• Paula Pérez-Ramos,
• Raquel G. Soengas and
• Humberto Rodríguez-Solla

Beilstein J. Org. Chem. 2025, 21, 1535–1543, doi:10.3762/bjoc.21.116

• -mediated reaction for the synthesis of enaminones from 3-bromochromones (Scheme 1D). Initially, a Ni(II)-catalyzed hydroamination protocol affords the intermediate 2-amino-3-bromochromanones, which upon photocatalytic dehalogenation and subsequent opening of the heterocyclic ring provide the corresponding

• semipreparative scale for the reaction of 3-bromochromone (7a, 5.0 mmol) to afford enaminone 9a in a 68% isolated yield (Scheme 3). In terms of the reaction mechanism, TEMPO completely inhibited the reaction, implying the possibility of a radical intermediate in the reaction (Scheme 4A). Moreover, the TEMPO

Ambident reactivity of enolizable 5-mercapto-1H-tetrazoles in trapping reactions with in situ-generated thiocarbonyl S-methanides derived from sterically crowded cycloaliphatic thioketones

• Grzegorz Mlostoń,
• Małgorzata Celeda,
• Marcin Palusiak,
• Heinz Heimgartner,
• Marta Denel-Bobrowska and
• Agnieszka B. Olejniczak

Beilstein J. Org. Chem. 2025, 21, 1508–1519, doi:10.3762/bjoc.21.113

• terminal S‒CH2 position, leading to the formation of the sulfonium cation 11 and the delocalized heterocyclic anion 12 (Scheme 6). In the next step, competitive addition of both intermediate species yields either thioaminals 9 or dithioacetals 10. However, a slow isomerization of the thermodynamically less

Heterologous biosynthesis of cotylenol and concise synthesis of fusicoccane diterpenoids

• Ye Yuan,
• Zhenhua Guan,
• Xue-Jie Zhang,
• Nanyu Yao,
• Wenling Yuan,
• Yonghui Zhang,
• Ying Ye and
• Zheng Xiang

Beilstein J. Org. Chem. 2025, 21, 1489–1495, doi:10.3762/bjoc.21.111

• pathway of brassicicenes in Aspergillus oryzae and harnessing the promiscuity of a cytochrome P450 from the biosynthesis of fusicoccin A (Figure 1b). A key intermediate, brassicicenes I (5), was further used to achieve the collective synthesis of alterbrassicicene E (6), brassicicenes A (7) and R (8

• cotylenin A and cotylenol (Figure 3a). Oxidation of brassicicene I with Dess–Martin reagent afforded intermediate 9 in 92% yield. The tertiary hydroxy group of compound 9 was further protected with a TMS group to provide compound 10 in 90% yield, a key intermediate in the synthesis of cotylenol and

• oxaziridine [25], furnishing intermediate 18 in 72% yield. After deprotection of the TBS and TES groups, brassicicene R (8) was obtained in 70% yield. Therefore, alterbrassicicene E (6) and brassicicenes A (7) and R (8) were synthesized from brassicicene I over 4 or 5 chemical steps. Conclusion In summary

Photoredox-catalyzed arylation of isonitriles by diaryliodonium salts towards benzamides

• Nadezhda M. Metalnikova,
• Nikita S. Antonkin,
• Tuan K. Nguyen,
• Natalia S. Soldatova,
• Alexander V. Nyuchev,
• Mikhail A. Kinzhalov and
• Pavel S. Postnikov

Beilstein J. Org. Chem. 2025, 21, 1480–1488, doi:10.3762/bjoc.21.110

• resulting aryl radical is subsequently captured by an isonitrile molecule, forming an imidoyl radical intermediate X1. The intermediate X1 facilitates the reduction of the Ru(III) species back to Ru(II) thereby completing the photoredox cycle, with the formation of the cationic intermediate X2. We propose

Microwave-enhanced additive-free C–H amination of benzoxazoles catalysed by supported copper

• Andrei Paraschiv,
• Valentina Maruzzo,
• Filippo Pettazzi,
• Stefano Magliocco,
• Paolo Inaudi,
• Daria Brambilla,
• Gloria Berlier,
• Giancarlo Cravotto and
• Katia Martina

Beilstein J. Org. Chem. 2025, 21, 1462–1476, doi:10.3762/bjoc.21.108

• with the vessel pressurised under nitrogen (Table 2, entry 7). Under these conditions, the yield was 58%, demonstrating the superiority of an open vessel in a multimode cavity for this reaction. Since Cu salts facilitate both the nucleophilic attack of piperidine on benzoxazole to form the intermediate

• contrast, the presence of Cu facilitated the conversion of the intermediate to the desired aromatic benzoxazole 2a, demonstrating copper’s dual role as a Lewis acid in enhancing nucleophilic attack, and as an efficient catalyst for ring-closing oxidative rearomatisation. Of the conditions tested, the use

• of CuCl2 in toluene showed limited effectiveness, achieving 82% conversion but only a 28% yield of the final product. The remaining resulting mixture included 35% of the intermediate 2a-o and 19% of the hydrolysed product 2a-o-hydrol. However, the reaction performance in acetonitrile improved

Tautomerism and switching in 7-hydroxy-8-(azophenyl)quinoline and similar compounds

• Lidia Zaharieva,
• Vera Deneva,
• Fadhil S. Kamounah,
• Nikolay Vassilev,
• Ivan Angelov,
• Michael Pittelkow and
• Liudmil Antonov

Beilstein J. Org. Chem. 2025, 21, 1404–1421, doi:10.3762/bjoc.21.105

• , populating both KE and KK, which undergo ground-state PT to E and K, respectively. Therefore, it is crucial to have the intermediate keto tautomers KE and KK higher in energy in the ground state, comparing to the paired terminal E and K, respectively, in order to provide efficient switching. The additional

Oxetanes: formation, reactivity and total syntheses of natural products

• Peter Gabko,
• Martin Kalník and
• Maroš Bella

Beilstein J. Org. Chem. 2025, 21, 1324–1373, doi:10.3762/bjoc.21.101

• /RPC mechanism starts with a single-electron oxidation of the cobalt catalyst followed by a reaction with the siloxane to generate a cobalt–hydride complex. Subsequent hydride transfer to the alkene produces radical pair 23 which collapses to alkylcobalt intermediate 24. Another single-electron

• intramolecular E2 elimination. Finally, the importance and power of the intramolecular Williamson etherification has also been demonstrated by the kilogram-scale synthesis of oxetane intermediate 41, which is a key intermediate in the preparation of the previously mentioned IDO1 inhibitor 2 (Scheme 9) [16

• , and 6-endo cyclization pathways – this may be attributed to precoordination of the Cu(I) catalyst to the alkoxide, which facilitates oxidative addition into the C–Br bond and results in the formation of a favorable five-membered Cu-containing intermediate [48]. Ten years later, while developing the

Recent advances in amidyl radical-mediated photocatalytic direct intermolecular hydrogen atom transfer

• Hao-Sen Wang,
• Lin Li,
• Xin Chen,
• Jian-Li Wu,
• Kai Sun,
• Xiao-Lan Chen,
• Ling-Bo Qu and
• Bing Yu

Beilstein J. Org. Chem. 2025, 21, 1306–1323, doi:10.3762/bjoc.21.100

• it into the byproduct 46 and generating a carbon-centered radical 62. Species 62 is trapped by heteroarene 60, leading to the formation of the intermediate 63. This intermediate 63 undergoes SET and proton transfer with the assistance of O-anion 64 and the Br-5CzBN+• radical cation, delivering the

• abstracts a hydrogen atom from substrate 1 through HAT, producing an α-amido-acridinyl radical intermediate 92 and a substrate-derived carbon-centered radical 4. Radical 4 undergoes regioselective addition to the acceptor, forming transient radical adduct 93. A concomitant SET from 92 to 93 generates a

Recent advances and future challenges in the bottom-up synthesis of azulene-embedded nanographenes

• Bartłomiej Pigulski

Beilstein J. Org. Chem. 2025, 21, 1272–1305, doi:10.3762/bjoc.21.99

• -known Ziegler–Hafner azulene synthesis [35]. The key step in this method involves the synthesis of the intermediate pentafulvene, which is subsequently cyclized to yield the target azulene. An example of this strategy is the synthesis of the azulene-embedded isomer of benzo[a]pyrene which was reported

• acenes from anthracene to pentacene (57a–d) in rather low yields (16–38%). The synthetic pathway leading to the hexacene isomer 60 was more complex due to the high reactivity of intermediate pentacenes. Instead, pentacene-6,13-dione 58 was subjected to the reaction with di-n-butylacetylene (56) giving

• constructed by condensation of dialdehyde 160 with compounds 161–163 yielding diketones 164–166. Next, diketones 164–166 were subjected to nucleophilic addition reaction by lithiated triisopropylsilyl (TIPS) acetylene, followed by SnCl2-mediated reduction of the intermediate diols. Finally, azulene-embedded

Recent advances in oxidative radical difunctionalization of N-arylacrylamides enabled by carbon radical reagents

• Jiangfei Chen,
• Yi-Lin Qu,
• Ming Yuan,
• Xiang-Mei Wu,
• Heng-Pei Jiang,
• Ying Fu and
• Shengrong Guo

Beilstein J. Org. Chem. 2025, 21, 1207–1271, doi:10.3762/bjoc.21.98

• radical A. This is followed by the conversion of a substrate containing C(sp3)–H bonds adjacent to an oxygen atom into an alkyl radical intermediate B. The alkyl radical intermediate then adds to the C=C bond of N-arylacrylamide, generating a second alkyl radical intermediate C, which undergoes

• intramolecular cyclization to form a benzene ring radical intermediate D. Finally, hydrogen abstraction from the radical intermediate by Fe3+(OH) leads to the formation of oxindole compounds 5. A similar reaction was reported by Liang’s group in the same year, as shown in Scheme 4. The study introduced a metal

• intermediate 12. Subsequent intramolecular cyclization and oxidative aromatization lead to the final isoxazoline-featured oxindole 9. In 2017, Li’s group reported an oxidative divergent bicyclization of 1,n-enynes through α-C(sp3)–H functionalization of alkyl nitriles using a Sc(OTf)3 and Ag2O system (Scheme 7

Synthesis of β-ketophosphonates through aerobic copper(II)-mediated phosphorylation of enol acetates

• Alexander S. Budnikov,
• Igor B. Krylov,
• Fedor K. Monin,
• Valentina M. Merkulova,
• Alexey I. Ilovaisky,
• Liu Yan,
• Bing Yu and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2025, 21, 1192–1200, doi:10.3762/bjoc.21.96

• radicals and product 3 can be described by several pathways. The direct oxidation of 2 by Cu(II) A leads to the formation of P-centered radical E and Cu(I) B. Under air atmosphere, the formed Cu(I) species B can react with molecular oxygen resulting in the formation of peroxycopper intermediate C [75][76

• hydroperoxide transfer from copper complex D with the formation of intermediate H and, therefore, regenerating Cu(I) B. Alternatively, the latter can be formed by oxidation of benzylic radical G with the formation of carbocation I. However, given that in the absence of oxygen the β-ketophosphonate was formed