Total synthesis of natural products based on hydrogenation of aromatic rings

• Haoxiang Wu and
• Xiangbing Qi

Beilstein J. Org. Chem. 2026, 22, 88–122, doi:10.3762/bjoc.22.4

• (Scheme 31) [102]. In the presence of NBS as the oxidant, precursor 206 undergoes an aza-Achmatowicz rearrangement to give the monobrominated intermediate 207, which upon treatment with NaHCO3 furnishes the spirocyclic scaffold 208. From this versatile intermediate, a range of oxindole natural products

An Fe(II)-catalyzed synthesis of spiro[indoline-3,2'-pyrrolidine] derivatives

• Elizaveta V. Gradova,
• Nikita A. Ozhegov,
• Roman O. Shcherbakov,
• Alexander G. Tkachenko,
• Larisa Y. Nesterova,
• Elena Y. Mendogralo and
• Maxim G. Uchuskin

Beilstein J. Org. Chem. 2025, 21, 2383–2388, doi:10.3762/bjoc.21.183

• under heating furnished chiral spiroindolylpyrroles in excellent yields and enantioselectivity (Scheme 1, path d) [11]. Moreover, a copper-catalyzed reaction of oxindole-derived alkenes with acetophenone O-acetyl oxime has also been employed to construct the spiroindolylpyrrole scaffold (Scheme 1, path

Preparation of spirocyclic oxindoles by cyclisation of an oxime to a nitrone and dipolar cycloaddition

• Beth L. Ritchie,
• Alexandra Longcake and
• Iain Coldham

Beilstein J. Org. Chem. 2025, 21, 1890–1896, doi:10.3762/bjoc.21.146

• condensation, cyclisation, and cycloaddition as an efficient strategy for the rapid formation of complex spirocyclic products that could have value for the formation of novel, bioactive oxindoles. Keywords: cascade; cycloaddition; oxindole; spirocycle; stereochemistry; Introduction The Alstonia alkaloids are

• , sore throats, toothache, ulcers, and snake bites [1]. The medicinal qualities of these plants are ascribed to the presence of alkaloids, and they are rich in many different indole and oxindole alkaloids [2]. About 100 Alstonia alkaloids are known, with more being isolated on a regular basis [3][4

• is in part due to limitations in the quantities obtained in the extraction processes. Other selected examples shown in Figure 1 all contain the same spirocyclic oxindole with a bridged azabicyclo[3.2.1]octane moiety. Several methods to access spirocyclic oxindole alkaloids have been reported [7][8][9

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

• oxindole [3][8][9], chrysenequinone [10], cycloheptatriene [11][12], thiazole [13], and matrine-type alkaloids [14]. The hybrid pharmacophore design is a frequently employed approach in the development of potential antitumor and other drugs [15][16]. This method involves the merging of two distinct

• examples of oxindole/1,2,4-oxadiazole [20] and hydantoin/1,2,4-triazoline [22] spiro-compounds. Synthesis of dipolarophiles (5-iminohydantoins 2a–i). Preparation of the dipole precursors 4a–d. 32CA reactions of nitrile oxides with 5-iminohydantoins (synthesis of spiro-compounds 5a–l). Isolated yields are

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

• 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

• subsequently adds to the activated alkene of N-arylacrylamide, followed by intramolecular cyclization, ultimately leading to the formation of the hydroxy-containing oxindole via the loss of a hydrogen radical. In 2016, Han and colleagues developed a novel methodology in which TBHP served dual roles as both

• 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

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

• . Diverse functionalized 3-substituted oxindole derivatives were successfully prepared in satisfactory yields and with high diastereoselectivity. In addition, the base-promoted dimerization of MBH carbonates of isatin afforded the ethylene-bridged bis(3-methylene)oxindole derivatives with nearly 4:1

• reactions of isatins with alkyl acrylates, acrylonitrile, and other activated alkenes [26][27][28][29]. Due to the stronger electron-withdrawing effect of the oxindole motif, MBH carbonates of isatins showed higher reactivity than that of the normal MBH carbonates of normal ketones [30][31][32][33][34][35

• - and P-containing nucleophiles to MBH carbonates of isatins and convenient synthesis of diverse functionalized 3-substituted oxindole derivatives. Results and Discussion Initially, the reaction conditions were briefly examined by using MBH nitrile of isatin 1a and p-toluidine (2a) as model reaction. It

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

• derivative, yielding a 3-alkylidene-substituted oxindole XXXIX that, after coordination with Cu(OTf)2, is able to react with the enolic form of kojic acid to generate the C-alkylated intermediate XL. Subsequent intramolecular nucleophilic attack of the enolic hydroxy group to the copper-activated cyano group

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

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

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

• trifluoromethylated acrylamides 36 under environmentally friendly conditions [66]. When the reaction mixture of acrylamides 36 and diaryliodonium tetrafluoroborates 26 dissolved in water was irradiated with light of 390 nm wavelength, the desired oxindole products 37 were obtained in good yields (Scheme 14). The

• electron-donating substituents at the para-position of the N-arylacrylamide led to good yields. In cases of meta-substitution, a mixture of C6 and C4-substituted oxindole products were obtained, whereas ortho-substitution resulted in the desired oxindoles in moderate yields. Nitrogen substitution was also

N-Glycosides of indigo, indirubin, and isoindigo: blue, red, and yellow sugars and their cancerostatic activity

• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 2840–2869, doi:10.3762/bjoc.20.240

• -glycosides Sassatelli et al. reported the synthesis of isoindigo-N-glycosides β-57a–c by reaction of benzyl-protected isatin-N-glycosides β-56a–c with oxindole (55) (Scheme 35) [53][54][55]. Deprotection by BBr3 afforded β-58a–c. Isatins 56 were prepared by glycosylation of indoline, benzylation, and

• 4-oxobutanoic acid side chain at the 5'-position, was prepared by reaction of the corresponding oxindole with isatin-N-glycoside 56a. The in vitro antiproliferative activities of compounds β-57a–c and β-58a–d were studied toward a panel of human solid cancer cell lines (PC 3, DLD-1, MCF-7, M4Beu

• ‘-diglycosides In our group, the synthesis of N,N’-diglycosylated isoindigos was studied. In contrast to isatin-N-glycosides, oxindole-N-glycosides are not readily available. Therefore, reductive dimerization of isatin-N-glycosides was considered as a strategy for the synthesis of the target compounds. Isatin-N

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

• a new family of isatin-based α-acetamide carboxamide oxindole hybrids using the versatile Ugi four-component reaction [18]. Sixteen hybrids were prepared by reacting 5-amino-1-benzyl-3,3-dimethoxyindolin-2-one, benzyl isocyanide, carboxylic acids, and aldehyde/ketone derivatives, catalyzed by ZnF2

Synthetic applications of the Cannizzaro reaction

• Bhaskar Chatterjee,
• Dhananjoy Mondal and
• Smritilekha Bera

Beilstein J. Org. Chem. 2024, 20, 1376–1395, doi:10.3762/bjoc.20.120

• ). Huang et al. set up a clean crossed-Cannizzaro-aldol reaction strategy of isatin derivatives 88 and 90 with paraformaldehyde under microwave irradiation to furnish 3,3-disubstituted oxindole derivatives 89a–h and 91a–d [92]. The representative 3-hydroxymethyloxindole adducts with varying substituents

The Ugi4CR as effective tool to access promising anticancer isatin-based α-acetamide carboxamide oxindole hybrids

• Carolina S. Marques,
• Aday González-Bakker and
• José M. Padrón

Beilstein J. Org. Chem. 2024, 20, 1213–1220, doi:10.3762/bjoc.20.104

• , we highlight the reputation of this reaction approach to access number and scaffold diversity of a library of isatin-based α-acetamide carboxamide oxindole hybrids, promising anticancer agents, in a mild and fast sustainable reaction process. The library was tested against six human solid tumor cell

• lines, among them, non-small cell lung carcinoma, cervical adenocarcinoma, breast cancer and colon adenocarcinoma. The most potent compounds 8d, 8h and 8k showed GI50 values in the range of 1–10 μM. Keywords: cancer; GI50; isatin; oxindole; Ugi4CR; Introduction Meticulous attention has been given by

• adducts, with stereochemistry control [4][5]. Unquestionable potential of application in the pharmaceutical industry is recognizable by the number of APIs obtained by this reaction approach [6][7]. The oxindole framework is a privileged unit, recognized massively by its extensive biological applications

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

• products (Scheme 59). The same year, Balaraman and co-workers reported the selective C-alkylation of oxindole with unactivated secondary alcohols catalyzed by a phosphine-free NNN-Mn(II) catalyst [89]. Various cyclic and aliphatic secondary alcohols were coupled with different oxindoles using 2 mol % of

• previous C–C bond forming mechanism, the base-assisted aldol condensation of the ketone with the oxindole generated the unsaturated C-alkylated intermediate and H2O. Finally, the unsaturated product is hydrogenated to the saturated C-alkylated product by the manganese hydride complex Mn23-c with

• in methanol at 110 °C for 24 h under a N2 atmosphere, giving the desired products with 60 to 99% yields (Scheme 64). In 2023, Elias et al. reported that an air-stable, phosphine-free manganese complex generated from 8-quinoline could α-alkylate 2-oxindole with primary and secondary alcohols [92

Construction of diazepine-containing spiroindolines via annulation reaction of α-halogenated N-acylhydrazones and isatin-derived MBH carbonates

• Xing Liu,
• Wenjing Shi,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2023, 19, 1923–1932, doi:10.3762/bjoc.19.143

• cyclic 1,2-diazepine ring and the methylene unit is connected to the 3-positon of the oxindole moiety. On the basis of the current results and previous works [54][55][56][57][58][59][60][61], a reaction mechanism for the formation of the spiro[indoline-3,5'-[1,2]diazepines] has been proposed and is

N-Boc-α-diazo glutarimide as efficient reagent for assembling N-heterocycle-glutarimide diads via Rh(II)-catalyzed N–H insertion reaction

• Grigory Kantin,
• Pavel Golubev,
• Alexander Sapegin,
• Alexander Bunev and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2023, 19, 1841–1848, doi:10.3762/bjoc.19.136

• group (Figure 2). We observed formation of complex mixtures in the case of δ-valerolactam, glutarimide and oxindole. This observation can be attributed to the competing direction of the attack of the carbenoid onto the carbonyl oxygen atom resulting in unstable intermediates. In the reaction with 5

Selective construction of dispiro[indoline-3,2'-quinoline-3',3''-indoline] and dispiro[indoline-3,2'-pyrrole-3',3''-indoline] via three-component reaction

• Ziying Xiao,
• Fengshun Xu,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2023, 19, 1234–1242, doi:10.3762/bjoc.19.91

• nitrostyrenes with previously prepared oxindole-functionalized dihydrobenzofuranones (reaction 2 in Scheme 1) [52]. We reported a piperidine-promoted domino reaction of thiophenols and two molecules of 3-phenacylideneoxindoles to give multifunctionalized dispirocyclopentanebisoxindoles (reaction 3 in Scheme 1

• indicated that only one diastereoisomer was predominately produced in the reaction, while the other possible diastereomers were not detected. This result shows that this reaction has a high diastereoselectivity due to the large steric effect of two oxindole scaffolds and the thermodynamically controlling

• effect. The single crystal structure of compound 3a was determined by X-ray crystallographic diffraction (Figure 1). From Figure 1 it can be seen that the two scaffolds of oxindole at neighboring positions are in trans-configuration. The ethoxycarbonyl group is also in trans-position to the carbonyl

Aromatic C–H bond functionalization through organocatalyzed asymmetric intermolecular aza-Friedel–Crafts reaction: a recent update

• Anup Biswas

Beilstein J. Org. Chem. 2023, 19, 956–981, doi:10.3762/bjoc.19.72

• . As the electron-demanding reaction partner, isatin-derived N-Boc-substituted ketimines 49 were employed which effectively functionalized the C6–H bond of substrate 4 to construct 3-oxindole derivatives 50 bearing an indole-substituted aza-quaternary stereocenter at its C3 position. 2,3-Dialkyl

• aromatic substitution involved isatin-derived ketimines 49 as the electron-demanding partner to achieve this aromatic p-C–H bond functionalization framing an all substituted stereocenter at the C3 position of the oxindole scaffold in the products 60. A very low reaction temperature (−55/−60 °C) was ideal

• ketimines 49 to construct an aza-quaternary stereocenter at the C3 position of oxindole scaffolds 61 bearing a β-naphtholyl substituent (Scheme 16b) [44]. In 2020, Meng, Chan, Zhao and co-workers reported another C3-selective aza-Friedel–Crafts reaction of 4-aminoindole derivatives 63 utilizing N-Boc-α

Eschenmoser coupling reactions starting from primary thioamides. When do they work and when not?

• Lukáš Marek,
• Jiří Váňa,
• Jan Svoboda and
• Jiří Hanusek

Beilstein J. Org. Chem. 2023, 19, 808–819, doi:10.3762/bjoc.19.61

• give the zwitterionic intermediates 6a,b'' necessary for successful ECR. On the other hand, without any base only thiazoles 7a,b are formed probably from isomeric forms 6a,b' of the starting salts 6a,b. In contrast to the tricyclic intermediate 16 formed from oxindole α-thioiminium salt (15), which in

NaI/PPh₃-catalyzed visible-light-mediated decarboxylative radical cascade cyclization of N-arylacrylamides for the efficient synthesis of quaternary oxindoles

• Dan Liu,
• Yue Zhao and
• Frederic W. Patureau

Beilstein J. Org. Chem. 2023, 19, 57–65, doi:10.3762/bjoc.19.5

• afforded various functionalized oxindoles featuring a C3 quaternary stereogenic center. Mechanistic experiments suggest a radical mechanism. Keywords: decarboxylative cascade cyclization; iodide catalysis; metal-free photocatalysis; oxindole; phosphine catalysis; Introduction Radical-initiated cascade

• attention due to their propensity to build important oxindole scaffolds. These are broadly found in natural products, pharmaceuticals, and bioactive molecules (Figure 1) [7][8][9][10][11][12][13]. Although a number of synthetic approaches have already been explored [14][15][16][17][18][19][20], these

• reported a Ru(bpy)3Cl2-catalyzed synthesis of N-Boc proline oxindole derivatives under visible-light assistance [47]. Therein, N-hydroxyphthalimide (NPhth) esters were utilized as alkyl radical precursors, which can be readily prepared from highly available carboxylic acids. In 2015, Cheng and co-workers

One-pot double annulations to confer diastereoselective spirooxindolepyrrolothiazoles

• Juan Lu,
• Bin Yao,
• Desheng Zhan,
• Zhuo Sun,
• Yun Ji and
• Xiaofeng Zhang

Beilstein J. Org. Chem. 2022, 18, 1607–1616, doi:10.3762/bjoc.18.171

• introduced in this study. Subsequently one equivalent of aldehyde and olefinic oxindole in situ were followed by decarboxylative 1,3-dipolar cycloaddition for diastereoselective synthesis of spirooxindolepyrrolothiazoles with generating 5 new bonds, 5 stereocenters and two heterocycles (Scheme 1C and Scheme

• olefinic oxindole 4a shown in Table 1. In our continuous effort on the reaction optimization of benign solvents, we firstly evaluated the influence of reaction time and protic solvents such as EtOH, iPrOH and MeOH at 25 °C for 6 h, which only results in slightly different LC yield (93–95%) of compound 3a

• (Table 1, entries 2–4) superior to 86% yield for 3 h (Table 1 entry 1), and followed by decarboxylative [3 + 2] cycloaddition with the second equivalent of compound 1a and olefinic oxindole 4a under reflux heating for 12 h. It indicates that the one-pot reaction process with EtOH and iPrOH afforded the

A facile approach to spiro[dihydrofuran-2,3'-oxindoles] via formal [4 + 1] annulation reaction of fused 1H-pyrrole-2,3-diones with diazooxindoles

• Pavel A. Topanov,
• Anna A. Maslivets,
• Maksim V. Dmitriev,
• Irina V. Mashevskaya,
• Yurii V. Shklyaev and
• Andrey N. Maslivets

Beilstein J. Org. Chem. 2022, 18, 1532–1538, doi:10.3762/bjoc.18.162

• constructing spirooxindole systems by employing different approaches [6][7][8][9][10][11][12]. Cyclopiazonic acid derivatives such as aspergillins A–E [13] (Figure 1) and speradines C and F [14][15] are secondary metabolites of fungi, and include a furan fragment spiro-fused with 2-oxindole. Cyclopiamides I

• and J [16] were also isolated from the fungus Penicillium commune and contain a furan fragment spiro-annulated by 2-oxindole. These compounds exhibit anticancer [13] and antimicrobial [17] activities. One of the expeditious methods for obtaining dihydrofurans is the cycloaddition reaction of diazo

• ] (Scheme 1). Thus, in the present work, we report a simple, catalyst-free diastereoselective method for the synthesis of dihydrofurans spiro-annulated with an oxindole moiety for the first time. The essence of the method is the use of [e]-fused 1H-pyrrole-2,3-diones (FPDs) as the enone component in a

Vicinal ketoesters – key intermediates in the total synthesis of natural products

• Marc Paul Beller and
• Ulrich Koert

Beilstein J. Org. Chem. 2022, 18, 1236–1248, doi:10.3762/bjoc.18.129

• for different purposes in the syntheses of a range of oxindole alkaloids. The start of the synthesis of (rac)-corynoxine (76) was the conversion of tryptamine (70) to oxindole 71, which was used in a chemoselective Mannich reaction with aldehyde 72, introducing the α-ketoester moiety (Scheme 12) [27

Copper-catalyzed multicomponent reactions for the efficient synthesis of diverse spirotetrahydrocarbazoles

• Shao-Cong Zhan,
• Ren-Jie Fang,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2022, 18, 796–808, doi:10.3762/bjoc.18.80

• ’, 1j’ were successfully isolated and fully characterized. Notably, the relative configuration of major isomer 1f (CCDC 2109575) was determined by X-ray crystallographic analysis, in which the m-chlorophenyl, benzoyl and the phenyl group in oxindole are in cis-configuration. It has been known that the

• benzoyl group and the phenyl group in oxindole stand in cis-position in the starting 3-phenacylideneoxindoles [75]. Therefore, a concerted Diels–Alder reaction should be involved in this three-component reaction. On the basis of this success, we further considered whether other dienophiles could be

• group in the oxindole scaffold, while these two groups exist in trans-configuration in the minor isomer 2g’. 5-Arylidene-1,3-dimethylbarbituric acids, as good dienophiles, could also react smoothly in such a catalytic system (Scheme 4a). Firstly, the three-component reaction of 2-methylindole, 5