Chitosan-supported CuI-catalyzed cascade reaction of 2-halobenzoic acids and amidines for the synthesis of quinazolinones

• Xuhong Zhao,
• Weishuang Li,
• Mengli Yang,
• Bojie Li,
• Yaoyao Zhang,
• Lizhen Huang and
• Lei Zhu

Beilstein J. Org. Chem. 2025, 21, 839–844, doi:10.3762/bjoc.21.67

• obtained (Table 1, entry 19). With the optimized conditions in hand, we explored the substrate scope of the CS@CuI-catalyzed cascade reactions of 2-halobenzoic acids (including 2-iodobenzoic acid and 2-bromobenzoic acid) with amidines (Scheme 2). Initially, when the amidine substituent (R2) is a methyl

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

• concerns and improved reaction control can be addressed, paving the way for more efficient and sustainable synthetic methodologies. Keywords: cascade reactions; formaldehyde surrogates; green chemistry; heterocycles; multicomponent reactions; Introduction Organic chemistry is a mature discipline that has

• temperatures, no specifically prepared solvents), one-pot, batch processes leading to tandem or cascade reactions, resource efficiency through the application of the 12 principles of Green Chemistry, and readily available starting materials such as waste materials from food production processes [1][2][3]. In

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

• can engage in electron-transfer mechanisms to enable radical cascade reactions under red-light irradiation (Scheme 9) [37]. These zinc(II)-based porphyrin catalysts operate via an oxidative quenching cycle, directly facilitating the transfer of an electron from the excited state of the porphyrin 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

• involvement of a fluorescent intermediate in the cascade synthetic process. Keywords: cascade reactions; copper-catalyzed three-component coupling; gold-mediated 6-endo hydroamination; tandem cyclizations; tetrahydroisoquinoline alkaloids; Introduction The bis-tetrahydroisoquinoline (THIQ) alkaloid family

Efficacy of radical reactions of isocyanides with heteroatom radicals in organic synthesis

• Akiya Ogawa and
• Yuki Yamamoto

Beilstein J. Org. Chem. 2024, 20, 2114–2128, doi:10.3762/bjoc.20.182

• (R = EWG-C6H4, E = PhS and PhTe) in moderate to high yields [30]. Very few examples of intermolecular cascade reactions with imidoyl radicals as key intermediates have been reported. The intermolecular cascade reaction of diselenide, electron-deficient acetylene, and isocyanide under photoirradiation

Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations

• Ryo Tanifuji and
• Hiroki Oguri

Beilstein J. Org. Chem. 2024, 20, 1693–1712, doi:10.3762/bjoc.20.151

• pathways are described with a focus on the biosynthetic intermediates and enzymatic transformations that enable cascade reactions and pinpoint modifications. This focus highlights how these biosynthetic pathways are applicable to the development of streamlined chemo-enzymatic synthesis processes. The

Evaluation of the enantioselectivity of new chiral ligands based on imidazolidin-4-one derivatives

• Jan Bartáček,
• Karel Chlumský,
• Jan Mrkvička,
• Lucie Paloušová,
• Miloš Sedlák and
• Pavel Drabina

Beilstein J. Org. Chem. 2024, 20, 684–691, doi:10.3762/bjoc.20.62

• -tetrazole, which was successfully used in many asymmetric reactions via “enamine activation”, especially in asymmetric aldol reactions [20][21][22][23]. Moreover, compound IV was previously included in a study dealing with asymmetric cascade reactions (based on aldol reactions) of aldehydes with α-keto

Visible-light-induced radical cascade cyclization: a catalyst-free synthetic approach to trifluoromethylated heterocycles

• Chuan Yang,
• Wei Shi,
• Jian Tian,
• Lin Guo,
• Yating Zhao and
• Wujiong Xia

Beilstein J. Org. Chem. 2024, 20, 118–124, doi:10.3762/bjoc.20.12

• ], Friedel–Crafts acylation [12], radical cascade reactions [2][13], and photoinduced radical cyclizations [14][15][16][17]. However, these methods often suffer from drawbacks such as harsh reaction conditions and the requirement of transition-metal catalysts. Although photocatalyzed cyclization reactions

Anion–π catalysis on carbon allotropes

• M. Ángeles Gutiérrez López,
• Mei-Ling Tan,
• Giacomo Renno,
• Augustina Jozeliūnaitė,
• J. Jonathan Nué-Martinez,
• Javier Lopez-Andarias,
• Naomi Sakai and
• Stefan Matile

Beilstein J. Org. Chem. 2023, 19, 1881–1894, doi:10.3762/bjoc.19.140

• catalysis. Moreover, epoxide opening polyether cyclizations are among the most impressive cascade reactions in nature [71][72][73]. Best known is the hypothetical cascade XII in the biosynthesis of brevetoxin B [74]. It affords eleven fused ethers by violating the Eschenmoser–Dunitz–Baldwin guidelines [75

Acetaldehyde in the Enders triple cascade reaction via acetaldehyde dimethyl acetal

• Alessandro Brusa,
• Debora Iapadre,
• Maria Edith Casacchia,
• Alessio Carioscia,
• Giuliana Giorgianni,
• Giandomenico Magagnano,
• Fabio Pesciaioli and
• Armando Carlone

Beilstein J. Org. Chem. 2023, 19, 1243–1250, doi:10.3762/bjoc.19.92

• organic synthesis to build complex scaffolds starting from simple starting materials. The Enders three-component cascade reaction was a cornerstone in the field and a plethora of organocatalyzed cascade reactions followed. However, acetaldehyde was not shown as a successful reaction partner, probably

• reason, the use of MCRs is appealing in the construction of natural or synthetic products [2][3][4][5] or libraries of compounds [2], and is generally considered an advantage in organic synthesis for atom economy, waste reduction and time saving. Cascade reactions are defined as chemical processes in

• which two or more bond-forming steps happen under identical reaction conditions, and where a subsequent transformation takes place at the functionality obtained in the former bond-forming event. Cascade reactions are valuable tools for streamlining the synthesis of structurally complex molecules in a

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

• spirooxindoles, in which the in situ-generated Michael adduct of 3-ethoxycarbonylmethyleneoxindole underwent a Mannich reaction and annulation reaction with in situ-generated aldimines (reaction 1 in Scheme 1) [50][51]. Tanaka reported chiral quinidine derivative-catalyzed Michael–Henry cascade reactions of

• , 1526, 1545, 1368, 1285, 1145, 1025, 956, 882 cm−1; HRMS (ESI-TOF): [M + H]+ calcd. for C48H44ClN3O5, 760.2937; found, 760.2921. Crystal structure of dispiro compound 3a. Crystal structure of compound 4a. Representative cascade reactions of Michael adducts of 3-methyleneoxindoles. Proposed reaction

Nucleophile-induced ring contraction in pyrrolo[2,1-c][1,4]benzothiazines: access to pyrrolo[2,1-b][1,3]benzothiazoles

• Ekaterina A. Lystsova,
• Maksim V. Dmitriev,
• Andrey N. Maslivets and
• Ekaterina E. Khramtsova

Beilstein J. Org. Chem. 2023, 19, 646–657, doi:10.3762/bjoc.19.46

• to the PBTA scaffold is an annulation of benzothiazoles with a pyrrole moiety (Scheme 1). It includes intramolecular cyclizations of benzothiazoles bearing a 3'-chloro substituent at C2 position (Scheme 1, entries 1 and 2) [5][6][7], intramolecular catalytic carbene cascade reactions of propargyl 1,3

• ] and reactions of 3-acyl-2,3-dihydro-1,3-benzothiazole-2-carbonitriles with acetylenedicarboxylate (Scheme 1, entry 9) [4]. The second group of approaches to the PBTA scaffold is an annulation of o-aminothiophenol with a pyrrolothiazole moiety (Scheme 2). It includes catalytic cascade reactions of o

• -aminothiophenol with donor–acceptor cyclopropanes (Scheme 2, entry 10) [27], condensations of o-aminothiophenol with 4-oxo acids or their derivatives (Scheme 2, entry 11) [2][28][29][30][31] and cascade reactions of o-aminothiophenol, furfural and anhydrides of 2,3-unsaturated carboxylic acids (Scheme 2, entry 12

Germacrene B – a central intermediate in sesquiterpene biosynthesis

• Houchao Xu and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2023, 19, 186–203, doi:10.3762/bjoc.19.18

• farnesylfarnesyl diphosphate (FFPP) can serve as a precursor to triterpenes [5], a compound class that was believed to be solely derived from squalene. Terpene synthases convert these linear precursors through cationic cascade reactions into terpene hydrocarbons or alcohols [6][7][8]. For type I terpene synthases

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

• ][10][11][12][13]. Selected photocatalytic decarboxylative radical cascade reactions of N-arylamides. Arylamide substrate scope with isolated yields of products. Alkyl radical precursor scope with isolated yields of products. Selected mechanistic experiments. Optimization tablea. Supporting

• 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

• reactions constitute a powerful synthetic approach to construct multiple C–C or C–X bonds in one pot. As such, these tend to allow facile access to many complex natural molecules and drugs [1][2][3][4][5][6]. Recently, radical-initiated cascade cyclizations involving acrylamides have attracted considerable

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

• nitrogen-based heterocycles, such as multicomponent reactions (MCRs) [18][19][20][21][22][23], one-pot cascade reactions [24][25][26][27][28][29][30][31][32] as good examples of PASE synthesis. We have reported a series of multicomponent reactions, like Groebke–Blackburn–Bienayme for making BET inhibitors

• UMB32 and UMB136 [33][34]. Zhang developed 4-aminoquinolines for the synthesis of fluorinated analogues of acetylcholinesterase (AChE) inhibitors [35] in cascade reactions, such as one-step syntheses of quinolines. Quinolin-4-ols involving histone acetyltransferases (HAT) inhibitors [36][37], as well as

Oxa-Michael-initiated cascade reactions of levoglucosenone

• Julian Klepp,
• Thomas Bousfield,
• Hugh Cummins,
• Sarah V. A.-M. Legendre,
• Jason E. Camp and
• Ben W. Greatrex

Beilstein J. Org. Chem. 2022, 18, 1457–1462, doi:10.3762/bjoc.18.151

• , United Kingdom 10.3762/bjoc.18.151 Abstract The reactions of aromatic aldehydes and levoglucosenone promoted by methoxide gives bridged α,β-unsaturated ketones, formed by a series of oxa-Michael-initiated cascade reactions in yields of up to 91% (14 examples). A complex series of equilibria operate

• during the reaction, and the formation of the bridged species is thermodynamically favored, except in the case of 5-methylfurfural and pyrrole-2-carboxaldehyde. This is the first report detailing this type of aldol/Michael cascade involving oxa-Michael initiation. Keywords: cascade reactions; green

Make or break: the thermodynamic equilibrium of polyphosphate kinase-catalysed reactions

• Michael Keppler,
• Sandra Moser,
• Henning J. Jessen,
• Christoph Held and
• Jennifer N. Andexer

Beilstein J. Org. Chem. 2022, 18, 1278–1288, doi:10.3762/bjoc.18.134

• frequently used in ATP regeneration systems as well as in cascade reactions for NTP biosynthesis [22][23][39][44][50][58][59][60]. Therefore, the results presented here can serve to further tune and improve these multi-enzyme reactions and the yield of biomimetic NTP synthesis systems. Usually, reactions for

Enzymes in biosynthesis

• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2022, 18, 1131–1132, doi:10.3762/bjoc.18.116

• proceed through multistep cationic cascade reactions and usually produce a polycyclic terpene hydrocarbon or alcohol with multiple stereogenic centers. While these transformations require only a single enzyme, polyketide and nonribosomal peptide biosyntheses are catalyzed by megasynthases that follow an

Tosylhydrazine-promoted self-conjugate reduction–Michael/aldol reaction of 3-phenacylideneoxindoles towards dispirocyclopentanebisoxindole derivatives

• Sayan Pramanik and
• Chhanda Mukhopadhyay

Beilstein J. Org. Chem. 2022, 18, 469–478, doi:10.3762/bjoc.18.49

• generation of new cascade reactions to construct carbo- and heterocyclic moieties [27][28], we aimed to synthesize dispirocyclopentanebisoxindoles in one pot operation using a new protocol. Chemical hydrogenation of double bonded compounds like α,β-unsaturated ketones, approaching to saturated ketones, is an

Asymmetric organocatalytic Michael addition of cyclopentane-1,2-dione to alkylidene oxindole

• Estelle Silm,
• Ivar Järving and
• Tõnis Kanger

Beilstein J. Org. Chem. 2022, 18, 167–173, doi:10.3762/bjoc.18.18

• substituted cyclopentane diones were uninvestigated until 2014 when we showed that CPD undergoes a Michael addition with nitrostyrenes [22]. Subsequently, different cascade reactions for CPD have been developed: with highly reactive (E)-2-oxobut-3-enoates [23], α,β-unsaturated aldehydes [24] and alkylidene

Iron-catalyzed domino coupling reactions of π-systems

• Austin Pounder and
• William Tam

Beilstein J. Org. Chem. 2021, 17, 2848–2893, doi:10.3762/bjoc.17.196

• production of byproducts. Iron catalysis offers an attractive, and sustainable, approach to the aforementioned economic and ecological concerns. In the same vein, cascade reactions are important tools to meet such challenges currently facing synthetic chemists and have received considerable attention as of

• late. Introduced by Tietze, cascade reactions are sequences of transformations where subsequent transformations occur only in virtue of functionality formed in previous steps [47]. This process repeats until a product stable under the reaction conditions is formed and the reaction terminates. Compared

• to the late TMs, iron can possess a wide array of oxidation states, ranging from 2− to 6+, allowing for iron catalysis to be utilized and perform several different types of reactions. As such, a closer look at Fe-catalyzed cascade reactions reveals several distinct features. One possible method for

Recent advances in organocatalytic asymmetric aza-Michael reactions of amines and amides

• Pratibha Sharma,
• Raakhi Gupta and
• Raj K. Bansal

Beilstein J. Org. Chem. 2021, 17, 2585–2610, doi:10.3762/bjoc.17.173

• -MRs, each highlighting a certain aspect of the reaction. While Sánchez-Roselló et al. [18] classified these reactions on the basis of the nature of the substrates, Nayak et al. [19] and Bhanja et al. [20] focused on the stereoselective synthesis of nitrogen heterocycles via Michael cascade reactions

• . Efforts are directed towards enhancing not only the yields of the products but also enantio- and diastereoselectivities of the aza-Michael reactions. New strategies have been adopted while making optimum utilization of the efficacies of the catalysts. Of these strategies, cascade reactions of the Michael

• enantioselectivity (47–98% ee). The observed results were rationalized with density functional theory calculations (Table 8) [42]. 1.3 Reactions catalyzed by chiral amines He and co-workers developed heterogeneous synergistic catalysis using chiral amines SBA-15 (cat. 44), which promote aza-Michael–Henry cascade

Recent advances in the tandem annulation of 1,3-enynes to functionalized pyridine and pyrrole derivatives

• Yi Liu,
• Puying Luo,
• Yang Fu,
• Tianxin Hao,
• Xuan Liu,
• Qiuping Ding and
• Yiyuan Peng

Beilstein J. Org. Chem. 2021, 17, 2462–2476, doi:10.3762/bjoc.17.163

• products 52 were obtained efficiently through the cascade reactions of enynals 51, primary amines, aliphatic isocyanides, and trimethylsilyl azide. The following reaction involves Ag-catalyzed intramolecular 5-endo-dig cyclization and base (DMAP)-promoted oxidative isomerization. The presence of DMAP is

Targeting active site residues and structural anchoring positions in terpene synthases

• Anwei Hou and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2021, 17, 2441–2449, doi:10.3762/bjoc.17.161

• attack of an olefinic double bond to the cationic centre Wagner–Meerwein rearrangements, and proton or hydride migrations [2]. These multistep cascade reactions ultimately result in terpene hydrocarbons that are often (poly)cyclic and contain several stereogenic centres [3][4]. In some cases, water is

Methodologies for the synthesis of quaternary carbon centers via hydroalkylation of unactivated olefins: twenty years of advances

• Thiago S. Silva and
• Fernando Coelho

Beilstein J. Org. Chem. 2021, 17, 1565–1590, doi:10.3762/bjoc.17.112

• potential of this strategy in total synthesis routes are the work by Liu [83] for the synthesis of hispidanin A (55, Scheme 23A) and the synthesis of (−)-nodulisporic acid C (58) described by Pronin [84] (Scheme 23B). In both studies, cascade reactions involving the putative enolate ion formed after the