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

• incorporated into cyclization reactions. The iminium species generated from enamides via nucleophilic addition or substitution are capable of engaging in further electrophilic additions or isomerization processes. Exploiting the multiple reactivities of enamides facilitates the development of diverse

• iminium intermediates can serve as electrophiles. Due to the presence of an amide, the resulting iminiums from the enamides can be stabilized to take part in the second nucleophilic addition, though direct isomerization of the iminiums to the enamides is also possible (Figure 1). Guided by these

• . Cyclization/isomerization – collective total synthesis of fawcettimine-type alkaloids The bicyclic decahydroquinoline enamide motif can serve as a versatile precursor to access different types of tricyclic N-heterocycles. As demonstrated in the above work from She’s group, the aza-Prins cyclization renders

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

• C(sp3)–C(sp3) coupling via distal stereocontrol, efficiently producing C3-alkylated pyrrolidines, while the nickel catalytic system afforded C2-alkylated pyrrolidines through a tandem alkene isomerization/hydroalkylation process. This method utilized readily accessible catalysts, chiral BOX ligands

• insertion to achieve C3 selectivity, whereas nickel catalysis involved alkene isomerization to generate a (2,3-dihydropyrrolyl) intermediate Int-35, followed by C2-selective coupling. In 2024, the Zheng group reported a catalyst-controlled cyclization reaction of bicyclo[1.1.0]butanes (BCBs) 32 with α

Cu–Bpin-mediated dimerization of 4,4-dichloro-2-butenoic acid derivatives enables the synthesis of densely functionalized cyclopropanes

• Patricia Gómez-Roibás,
• Andrea Chaves-Pouso and
• Martín Fañanás-Mastral

Beilstein J. Org. Chem. 2025, 21, 877–883, doi:10.3762/bjoc.21.71

• summary, we have discovered an unanticipated Cu–Bpin-promoted diastereoselective dimerization of 4,4-dichloro-2-butenoic acid derivatives. The reaction occurs via initial Cu–Bpin insertion followed by keto–enol isomerization and salt metathesis to generate a lithium enolate which is then trapped by a

Light-enabled intramolecular [2 + 2] cycloaddition via photoactivation of simple alkenylboronic esters

• Lewis McGhie,
• Hannah M. Kortman,
• Jenna Rumpf,
• Peter H. Seeberger and
• John J. Molloy

Beilstein J. Org. Chem. 2025, 21, 854–863, doi:10.3762/bjoc.21.69

• isomerization of alkenes [18][19], [2 + 2] cycloadditions [20][21][22][23][24], and dearomative [4 + 2] cycloadditions [25][26][27]. When considering conjugated alkenes, the triplet excited state energy and excited state lifetime are intrinsically linked to the degree of conjugation and substitution of a

• reactivity in EnT catalysis has also been intensively pursued (Figure 1B). The controlled geometric isomerization of boron-containing conjugated dienes [42], styrenes [43][44][45] and β-boryl acrylates [46][47] has been established with great effect, while elegant [2 + 2] cycloaddition strategies to readily

• . Herein, we demonstrate the sensitization of alkenylboronates to enable efficient intramolecular [2 + 2] cycloaddition using high energy photosensitizers (Figure 1C). Sensitization was quickly established and explored through the use of alkene scrambling (geometrical isomerization) reaction probes, to

Substituent effects in N-acetylated phenylazopyrazole photoswitches

• Radek Tovtik,
• Dennis Marzin,
• Pia Weigel,
• Stefano Crespi and
• Nadja A. Simeth

Beilstein J. Org. Chem. 2025, 21, 830–838, doi:10.3762/bjoc.21.66

• discovered that simple acylation of the pyrazole moiety leads to increased quantum yields of isomerization, long Z-isomer life-times, good spectral separation, and high photostability. Keywords: azobenzenes; azopyrazoles; photochromism; photoswitches; substituent effects; Introduction Organic photoswitches

• hyperchromic effects compared for NH- and NMe-PAP-H. Photochemical isomerization Upon irradiation with a 365 nm LED (exemplarily displayed for NMe-PAP-CN in Figure 2), we observed a decrease of the π→π* band for the E isomers. Simultaneously the π→π* bands around 253–369 nm and the n→π* bands around 426–457

• spectral separation of the isomers. Since we encountered fast back isomerization only for NAc-PAP-OH (vide infra), the PSDs could only be determined from the UV–vis spectra. NAc-PAPs showed high to quantitative formation of the Z-configurated isomers. For example, NAc-PAP-Br showed an isomerization

Synthesis and photoinduced switching properties of C₇-heteroatom containing push–pull norbornadiene derivatives

• Daniel Krappmann and
• Andreas Hirsch

Beilstein J. Org. Chem. 2025, 21, 807–816, doi:10.3762/bjoc.21.64

• heat, catalysis, or an electrochemical input [4][5][6], the stored energy can be released converting the molecule back in the parent form (Figure 1). Typical MOST systems are azobenzenes (E/Z-isomerization) [7][8][9][10], the isomerization of dihydroazulenes/vinylheptafulvenes [11][12][13], conversion

• , it is essential not only to achieve a high storage density and good quantum efficiency for the isomerization process but also to ensure large half-lifes and durability in switching reliability [20]. By making structural adjustments to the parent carbon scaffold, it is possible to target specific

• products alongside the formation of the desired QCs [32][34][35][36][37][38]. Despite this, the focus has largely been on symmetrical 2,3-substituted derivatives, with reports primarily on the reversible isomerization of oxa-NBD to oxa-QC derivatives [39]. Asymmetrical push–pull derivatives have received

Development and mechanistic studies of calcium–BINOL phosphate-catalyzed hydrocyanation of hydrazones

• Carola Tortora,
• Christian A. Fischer,
• Sascha Kohlbauer,
• Alexandru Zamfir,
• Gerd M. Ballmann,
• Jürgen Pahl,
• Sjoerd Harder and
• Svetlana B. Tsogoeva

Beilstein J. Org. Chem. 2025, 21, 755–765, doi:10.3762/bjoc.21.59

• the R-product from E-hydrazone is slightly lower in energy (Table 3). However, the activation barrier for the rate-limiting step is 0.4 kcal·mol−1 lower for the pathway shown in Figure 2 and that yields the S-product from the Z-hydrazone. As the activation barrier to thermal E/Z-isomerization is more

Copper-catalyzed domino cyclization of anilines and cyclobutanone oxime: a scalable and versatile route to spirotetrahydroquinoline derivatives

• Qingqing Jiang,
• Xinyi Lei,
• Pan Gao and
• Yu Yuan

Beilstein J. Org. Chem. 2025, 21, 749–754, doi:10.3762/bjoc.21.58

• , we conducted a 5.0 mmol scale reaction and obtained the target product 3aa in 82% yield (Scheme 3). Based on previous reports, a plausible mechanism was proposed. In the presence of a copper catalyst, aniline reacts with cyclobutanone oxime to form an imine intermediate, which undergoes isomerization

Orthogonal photoswitching of heterobivalent azobenzene glycoclusters: the effect of glycoligand orientation in bacterial adhesion

• Leon M. Friedrich and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2025, 21, 736–748, doi:10.3762/bjoc.21.57

• ]. Specifically, the reversible E/Z isomerization of the azo group in azobenzene glycosides is suited to control the spatial presentation of glycoligands and, for example, switch carbohydrate-specific bacterial adhesion on and off [20][21][22][23]. Indeed, glycoazobenzene derivatives are excellent tools to

• other hand, leads to a PSS with more E isomer, namely an E/Z ratio of 85:15. Irradiation of 3 and 4 with light of 520 nm effects an E to Z isomerization with an E/Z ratio of 23:77 in both cases, since 520 nm light addresses the bathochromically shifted n–π* band of the E isomers due to the ortho-fluoro

• hypothesize that isomerization of the azo group in the tested azobenzene glycoconjugates controls the orientation of the attached glycoligand and therefore, different glycoazobenzene isomers show various affinities for the bacterial lectin FimH as reflected by the measured RIP values. This is clearly seen

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

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

• subsequently activated with light at the site of illness with high spatiotemporal resolution. Thus, collateral damage in the surrounding healthy tissue can be avoided. In addition, the quantitative thermal back-isomerization from the active E to the inactive Z configuration prevents contamination and

• efficiency. In any case the light-induced geometry change via isomerization should selectively control the interaction between the inhibitor and the receptor [21]. Currently there is only one example reported in the literature for the incorporation of N-acetyl diazocines into biologically active molecules

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

•  2). However, if maleic acid was used instead of its monoanilide, then an aromatic furan product was obtained (Scheme 3). Most likely, the presence of a carboxyl group near the hydrogen in the 3-position of the furan ring contributes to its shift and isomerization to a more thermodynamically

Synthesis, structure, ionochromic and cytotoxic properties of new 2-(indolin-2-yl)-1,3-tropolones

• Yurii A. Sayapin,
• Eugeny A. Gusakov,
• Inna O. Tupaeva,
• Alexander D. Dubonosov,
• Igor V. Dorogan,
• Valery V. Tkachev,
• Anna S. Goncharova,
• Gennady V. Shilov,
• Natalia S. Kuznetsova,
• Svetlana Y. Filippova,
• Tatyana A. Krasnikova,
• Yanis A. Boumber,
• Alexey Y. Maksimov,
• Sergey M. Aldoshin and
• Vladimir I. Minkin

Beilstein J. Org. Chem. 2025, 21, 358–368, doi:10.3762/bjoc.21.26

• reactions of 2-methylquinolines with 3,5-di-(tert-butyl)-1,2-benzoquinone [1] and benzophenones with o-chloranil [15]. The norcaradiene derivatives 5, formed in the next step by the intramolecular cyclization reaction of 4, undergo thermal isomerization into 2,3-dihydrotropolones 6. The formation of 2

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

• have been obtained by DABCO-catalyzed dimerization of MBH carbonates of isatin in ODCB at high temperature (150 °C), which could be converted to bisspirooxindole derivatives via the isomerization of the double bond and a sequential thermal 6π-electrocyclic ring-closure process [30]. Here, the novel

Effect of substitution position of aryl groups on the thermal back reactivity of aza-diarylethene photoswitches and prediction by density functional theory

• Misato Suganuma,
• Daichi Kitagawa,
• Shota Hamatani and
• Seiya Kobatake

Beilstein J. Org. Chem. 2025, 21, 242–252, doi:10.3762/bjoc.21.16

• -withdrawing substituents on the N-aryl moieties enhanced the thermal stability of the Z-isomers while maintaining the advantageous photoswitching properties upon irradiation with red light [52]. The effect of substituents on the thermal cis–trans isomerization of azobenzenes has also been widely studied, and

• time scale [54]. Langton and co-workers demonstrated that the thermal isomerization rate of azobenzenes can be tuned over a time scale spanning 107 seconds by introducing appropriate chalcogens and halogens at the ortho-position of the benzene rings [55]. Thus, investigation of the strategies to

Streamlined modular synthesis of saframycin substructure via copper-catalyzed three-component assembly and gold-promoted 6-endo cyclization

• Asahi Kanno,
• Ryo Tanifuji,
• Satoshi Yoshida,
• Sota Sato,
• Saori Maki-Yonekura,
• Kiyofumi Takaba,
• Jungmin Kang,
• Kensuke Tono,
• Koji Yonekura and
• Hiroki Oguri

Beilstein J. Org. Chem. 2025, 21, 226–233, doi:10.3762/bjoc.21.14

• reaction involves an in situ generation of the iminium cation A followed by isomerization to the thermodynamically more stable iminium cation B. Subsequent nucleophilic attack of a copper acetylide enabled regioselective C–C bond formation at the C11 position. After removal of the cyclic acetal, the

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

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

• formation releasing Cu(OTf)2. The final bicyclic product 33 arises from isomerization and water elimination. Recently, Singh's research group developed a cascade process to access imidazo[1,2-a]pyridines-linked isoxazoles 35. Isoxazole carbaldehydes treated with 2-aminopyridines and isonitriles in the

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

• activation of propargylic aldehydes with catalyst Int-1. Another critical feature was the ability of the organocatalyst to promote the Z-selective isomerization of Int-2 to Int-3. In a related fashion, Wang and co-workers developed an atroposelective heterocycloaddition [19]. The iminium-activated alkynals 4

• reaction pathway was proposed [56]. The first step is a CPA C27-catalyzed condensation giving rise to the imine intermediate followed by isomerization to the enamine stabilized by CPA. An enantioselective intramolecular cyclization followed by dehydration then afford the aromatic ring and desired product

• consists of isomerization and another catalyst activation promoting an intramolecular Michael addition. The organocatalyst is freed, and cyclization product Int-62 undergoes racemization to form Int-64. The identical intermediate Int-64 is formed by catalyst activation and direct nucleophilic addition. In

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

• four-step process involves allylation, Claisen rearrangement, isomerization, and oxidative dimerization. Each reaction step was optimized independently by using either online HPLC or in-line benchtop NMR spectroscopy to afford an overall yield of 67% in 66 iterative experiments over four linear

Non-covalent organocatalyzed enantioselective cyclization reactions of α,β-unsaturated imines

• Sergio Torres-Oya and
• Mercedes Zurro

Beilstein J. Org. Chem. 2024, 20, 3221–3255, doi:10.3762/bjoc.20.268

• acid activates both the enol form of the azlactone and the α,β-unsaturated imine, facilitating the asymmetric [4 + 2] cyclization reaction. The authors proposed the formation of intermediate B which subsequently undergoes an isomerization to give the chiral dihydropyridinone derivative 49. An

Synthesis of 2H-azirine-2,2-dicarboxylic acids and their derivatives

• Anastasiya V. Agafonova,
• Mikhail S. Novikov and
• Alexander F. Khlebnikov

Beilstein J. Org. Chem. 2024, 20, 3191–3197, doi:10.3762/bjoc.20.264

• their amides, esters, and azides by FeCl2-catalyzed isomerization of 3-aryl-5-chloroisoxazole-4-carbonyl chlorides into 3-aryl-2H-azirine-2,2-dicarbonyl dichlorides followed by their reaction with nucleophiles are reported. Two approaches to the preparation of 3-aryl-5-chloroisoxazole-4-carbonyl

• chlorides have been developed. Keywords: azirine-2,2-dicarboxamides; azirine-2,2-dicarboxylic acids; isomerization; isoxazoles; Introduction The isomerization of isoxazoles, containing a heteroatomic substituent at C5, to 2H-azirines is a powerful method for the preparation of 2H-azirine-2-carboxylic acid

• derivatives [1]. In particular, the catalytic isomerization of 5-chloroisoxazoles allows the generation of azirine-2-carbonyl chlorides, which can be easily converted into a variety of azirine-2-carboxylic acid derivatives by reactions with nucleophilic reagents. Using this approach, numerous 2-(1H-pyrazol-1

Synthesis of extended fluorinated tripeptides based on the tetrahydropyridazine scaffold

• Thierry Milcent,
• Pascal Retailleau,
• Benoit Crousse and
• Sandrine Ongeri

Beilstein J. Org. Chem. 2024, 20, 3174–3181, doi:10.3762/bjoc.20.262

• hydrazine [36], allowed the expected compounds 6e and 6f to be obtained in good yields. This methodology was applied to the previous hydrazides 5a–d giving the corresponding compounds 6a–d in similar yields. As expected, no isomerization occurred during the oxidation, leading exclusively to the imine and

Enantioselective regiospecific addition of propargyltrichlorosilane to aldehydes catalyzed by biisoquinoline N,N’-dioxide

• Noble Brako,
• Sreerag Moorkkannur Narayanan,
• Amber Burns,
• Layla Auter,
• Valentino Cesiliano,
• Rajeev Prabhakar and
• Norito Takenaka

Beilstein J. Org. Chem. 2024, 20, 3069–3076, doi:10.3762/bjoc.20.255

• % yield with 61:39–92:8 enantiomeric ratios. Furthermore, possible mechanisms of propargyl–allenyl isomerization of propargyltrichlorosilane were computationally investigated. Keywords: α-allenic alcohol; computational chemistry; Lewis base catalysis; organocatalysis; propargyltrichlorosilane

• significantly suppressed the isomerization [46]. In this study, however, we could not prepare isomerically pure propargyltrichlorosilane on a preparative scale from propargyl chloride and CuCl by following Kobayashi’s protocol [45] (propargyltrichlorosilane/allenyltrichlorosilane = 10:1) while we fully

• inherently present in chlorosilane reagents. Given our observation regarding propargyl–allenyl isomerization as discussed above, we wanted to avoid its use. Thus, we briefly tested whether 1) it is necessary for achieving a reasonable reaction rate, and 2) if it could be substituted with 4 Å molecular sieves

Extension of the π-system of monoaryl-substituted norbornadienes with acetylene bridges: influence on the photochemical conversion and storage of light energy

• Robin Schulte,
• Dustin Schade,
• Thomas Paululat,
• Till J. B. Zähringer,
• Christoph Kerzig and
• Heiko Ihmels

Beilstein J. Org. Chem. 2024, 20, 3061–3068, doi:10.3762/bjoc.20.254

• )2 and the corresponding arylnorbornadienes without an acetylene bridge, such as 1o, leading to efficient and quantitative conversion to the quadricylanes (Scheme 4) [38]. Hence, we assumed that triplet-sensitized isomerization of the mono-, bis-, and tris-norbornadiene derivatives with an

• by 1H NMR spectroscopy. Initially, all derivatives showed the isomerization reactions to the corresponding quadricyclane derivatives, as identified by the characteristic 1H NMR signal pattern of the quadricyclane fragment with five multiplets at around 1.6 ppm, 1.7 ppm, 1.8 ppm, 2.1 ppm, and 2.2 ppm