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

Three-component reactions of conjugated dienes, CH acids and formaldehyde under diffusion mixing conditions

• Dmitry E. Shybanov,
• Maxim E. Kukushkin,
• Eugene V. Babaev,
• Nikolai V. Zyk and
• Elena K. Beloglazkina

Beilstein J. Org. Chem. 2025, 21, 262–269, doi:10.3762/bjoc.21.18

• main reaction products. Keywords: aldol condensation; [4 + 2]-cycloaddition; diffusion mixing; formaldehyde; Knoevenagel condensation; three-component reactions; Introduction Formaldehyde is a reactive electrophilic reagent widely used as a C1 building block in multicomponent reactions [1][2][3]. Its

• , which should significantly reduce undesirable polycondensations involving CH2O as well as polymerization of the intermediately formed methylidene derivatives. In this work, we generated methylidene adducts by formaldehyde condensation under diffusion mixing conditions in three-component reactions with

• various CH acid derivatives and conjugated dienes (cyclopentadiene, 1,3-cyclohexadiene, 2,3-dimethylbutadiene and isoprene), leading to [4 + 2]-cycloaddition adducts (Scheme 1). It should be noted that in previous works describing three-component reactions of carbonyl compounds, conjugated dienes and

Heteroannulations of cyanoacetamide-based MCR scaffolds utilizing formamide

• Marios Zingiridis,
• Danae Papachristodoulou,
• Despoina Menegaki,
• Konstantinos G. Froudas and
• Constantinos G. Neochoritis

Beilstein J. Org. Chem. 2025, 21, 217–225, doi:10.3762/bjoc.21.13

• Gewald three-component reactions. Our focus was to create a representative, diverse and structurally complex library of building blocks, covering a range of shapes and chemical spaces, to facilitate formamide-based heteroannulation for the synthesis of the desired adducts. Thus, we employed aliphatic and

Recent advances in electrochemical copper catalysis for modern organic synthesis

• Yemin Kim and
• Won Jun Jang

Beilstein J. Org. Chem. 2025, 21, 155–178, doi:10.3762/bjoc.21.9

• asymmetric electrocatalytic cyanophosphinoylation of vinylarenes (Figure 14) [69]. In the presence of a copper catalyst and the chiral ligand sBOX(iPr) (L8) in an electrochemical cell, these three component reactions using styrene derivatives 27, TMSCN (21), and diarylphosphine oxide 80 as starting materials

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

• type of reaction. Review Three-component reactions Several three-component procedures have been successfully carried out using Cu(OTf)2 as a catalyst. These processes have been exploited mainly to access nitrogen compounds endowed with various structures, in a faster and more sustainable way than

• counteranion. The use of a carbamate among the substrates instead of the amine allowed the synthesis of propargylcarbamates 11. This reaction, effective only for the aromatic aldehydes, did not require other co-catalysts or ligands (Scheme 8) [21]. Three-component reactions of alkynes, alkyltrifluoroborates

• as a catalyst in three-component processes was also demonstrated in three-component reactions involving alkynes, amines and α,β-unsaturated aldehydes to obtain 1,4-dihydropyridines 20 (Scheme 14) [31]. By using terminal alkynes, 2,6-unsubstituted products were achieved. Concerning the mechanism, it

Advances in radical peroxidation with hydroperoxides

• Oleg V. Bityukov,
• Pavel Yu. Serdyuchenko,
• Andrey S. Kirillov,
• Gennady I. Nikishin,
• Vera A. Vil’ and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2024, 20, 2959–3006, doi:10.3762/bjoc.20.249

• leads to the formation of the target product 139. Later, iron-catalyzed three-component reactions of α,β-unsaturated carbonyl compounds 140, aldehydes 141, and TBHP leading to α-ester-β-keto peroxides 142 have been developed (Scheme 45b) [106][107][108]. Radical coupling of arylaldehydes 144 with α,β

A facile three-component route to powerful 5-aryldeazaalloxazine photocatalysts

• Ivana Weisheitelová,
• Radek Cibulka,
• Marek Sikorski and
• Tetiana Pavlovska

Beilstein J. Org. Chem. 2024, 20, 1831–1838, doi:10.3762/bjoc.20.161

• have developed a facile, efficient and environmentally friendly method for the synthesis of 5-aryldeazaalloxazine (5-arylpyrimido[4,5-b]quinoline-2,4(1H,3H)-dione) derivatives via three-component reactions in DMSO, with the possibility of varying reaction conditions. Although the yields of the reaction

Generation of multimillion chemical space based on the parallel Groebke–Blackburn–Bienaymé reaction

• Evgen V. Govor,
• Vasyl Naumchyk,
• Ihor Nestorak,
• Dmytro S. Radchenko,
• Dmytro Dudenko,
• Yurii S. Moroz,
• Olexiy D. Kachkovsky and
• Oleksandr O. Grygorenko

Beilstein J. Org. Chem. 2024, 20, 1604–1613, doi:10.3762/bjoc.20.143

• -component reactions are very effective for the generation of synthetically tractable ultra-large chemical space [30][31][32]. Such virtual but readily accessible (REAL) compound libraries demonstrated excellent performance in early drug discovery programs when combined with modern computational tools such

• last two decades, the GBB reaction has been studied in more than 200 research papers [21] and a number of works (including the original publication by Blackburn and coauthors [20]) described its parallel synthesis version [24][25][26][27][28][29]. Recently, we have shown that other (pseudo-)three

Mechanistic investigations of polyaza[7]helicene in photoredox and energy transfer catalysis

• Johannes Rocker,
• Till J. B. Zähringer,
• Matthias Schmitz,
• Till Opatz and
• Christoph Kerzig

Beilstein J. Org. Chem. 2024, 20, 1236–1245, doi:10.3762/bjoc.20.106

• -component reactions (3-CRs) and it has been shown that substituting the helicene core with functional groups is a viable approach to fine-tune the photochemical properties [45][46], as has been demonstrated for other organic and metal-based chromophores. Our study focused on investigating the reaction

• rule [43]. However, helicenes have not been broadly considered as potential photocatalysts or sensitizers or their applications were unsuccessful [44]. Recently, one of our groups exploited the highly reducing polyaza[7]helicene (Aza-H, see Scheme 1 for its structure) for sulfonylation/arylation three

Palladium-catalyzed enantioselective three-component synthesis of α-arylglycine derivatives from glyoxylic acid, sulfonamides and aryltrifluoroborates

• Bastian Jakob,
• Nico Schneider,
• Luca Gengenbach and
• Georg Manolikakes

Beilstein J. Org. Chem. 2023, 19, 719–726, doi:10.3762/bjoc.19.52

• situ generation of reactive imine species, we have disclosed iron- and bismuth-catalyzed three-component reactions for the synthesis of α-arylglycines [14][15][16], in which the arylboronic acid could be replaced with an electron-rich (hetero)arene as nucleophile. In parallel, we have developed

• palladium-catalyzed three-component reactions between arylboronic or carboxylic acids, amides or sulfonamides and different aldehyde components as attractive and broadly applicable alternative to the classical Petasis borono-Mannich reaction (Scheme 1b) [17][18][19][20][21]. Recently, we were able to extend

• sterically hindered arylboronic acids. Herein, we report an improved version of this palladium-catalyzed enantioselective three-component reactions using aryltrifluoroborates as replacement of the arylboronic acid building block (Scheme 1d). The broader scope of this 2nd generation protocol is exploiting a

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

• PASE reactions of making spirooxindolepyrrolothiazoles are even more rare, which only involves three-component reactions with isatins and thioproline (Scheme 2A and 2B) [75][76]. Four-component double annulations through 2-substituted thioprolines formed in N,S-acetalation of aldehyde and cysteine was

Functionalization of imidazole N-oxide: a recent discovery in organic transformations

• Koustav Singha,
• Imran Habib and
• Mossaraf Hossain

Beilstein J. Org. Chem. 2022, 18, 1575–1588, doi:10.3762/bjoc.18.168

• the past years are discussed. This review contains cycloaddition reactions, nucleophilic halogenation reactions, metal-free coupling reactions, formation of N-heterocyclic carbenes, and multicomponent reactions, mainly three-component reactions. The mentioned methodologies have been performed by

• . Transition-metal-free three-component reactions, cycloaddition reaction methodology and nucleophilic addition reaction, mainly these three types of reaction methodologies can be found in the literature reports. The approaches were greener and the reaction conditions were milder or not harsh in most of the

Experimental and theoretical studies on the synthesis of 1,4,5-trisubstituted pyrrolidine-2,3-diones

• Nguyen Tran Nguyen,
• Vo Viet Dai,
• Nguyen Ngoc Tri,
• Luc Van Meervelt,
• Nguyen Tien Trung and
• Wim Dehaen

Beilstein J. Org. Chem. 2022, 18, 1140–1153, doi:10.3762/bjoc.18.118

• /bjoc.18.118 Abstract Substituted 4-acetyl-3-hydroxy-3-pyrroline-2-ones have been prepared via three-component reactions and the tautomerism of these 3-pyrroline-2-ones is due to the slight difference of energy, and the significantly large rate constant of transformation between two tautomers. 1,4,5

• ]. Acyl or aroyl groups can be introduced into the 4-position of 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones via three-component reactions of esters of acylpyruvic acid or of aroylpyruvic acid, respectively, with aromatic aldehydes, and amines. In addition, the resulting 2-pyrrolidinone derivatives also showed

Bifunctional thiourea-catalyzed asymmetric [3 + 2] annulation reactions of 2-isothiocyanato-1-indanones with barbiturate-based olefins

• Jiang-Song Zhai and
• Da-Ming Du

Beilstein J. Org. Chem. 2022, 18, 25–36, doi:10.3762/bjoc.18.3

• through a gram-scale synthesis, one-pot three-component reactions and further transformation experiments of the products. Keywords: asymmetric catalysis; cyclization reaction; Michael addition; one-pot three-component reaction; spirobarbiturates; Introduction Indane scaffolds exist in various

• yields and excellent diastereo- and enantioselectivities (up to >99% yield, >20:1 dr and >99% ee). In addition, a gram-scale synthesis, one-pot three-component reactions and further transformation experiments of the products were also demonstrated with excellent stereoselectivities. We believe that the

Silver-catalyzed synthesis of β-fluorovinylphosphonates by phosphonofluorination of aromatic alkynes

• Yajing Zhang,
• Qingshan Tian,
• Guozhu Zhang and
• Dayong Zhang

Beilstein J. Org. Chem. 2020, 16, 3086–3092, doi:10.3762/bjoc.16.258

• . Among the strategies for constructing diverse alkenes containing two-heteroatom bonds, such as disulfonylation [14][15][16], heterohalogenation [17][18][19][20], bis(trifluoromethyl)thiolation [21], and phosphorylation [22], the direct heterodifunctionalization of alkynes using three-component reactions

Three-component reactions of aromatic amines, 1,3-dicarbonyl compounds, and α-bromoacetaldehyde acetal to access N-(hetero)aryl-4,5-unsubstituted pyrroles

• Wenbo Huang,
• Kaimei Wang,
• Ping Liu,
• Minghao Li,
• Shaoyong Ke and
• Yanlong Gu

Beilstein J. Org. Chem. 2020, 16, 2920–2928, doi:10.3762/bjoc.16.241

A novel and robust heterogeneous Cu catalyst using modified lignosulfonate as support for the synthesis of nitrogen-containing heterocycles

• Bingbing Lai,
• Meng Ye,
• Ping Liu,
• Minghao Li,
• Rongxian Bai and
• Yanlong Gu

Beilstein J. Org. Chem. 2020, 16, 2888–2902, doi:10.3762/bjoc.16.238

• ). Recyclability of LS-FAS-Cu, LS-FM-Cu and Resin-Cu in the reaction between compounds 1a, 2a and 3a. Substrate scope of LS-FAS-Cu catalyzed three-component reactions of 4-aminoindoles, alkynes and aldehydes. Three-component reaction of 1a, 2a, and 3a to synthesis of 4aa. Optimizing the reaction condition of

One-pot synthesis of 1,3,5-triazine-2,4-dithione derivatives via three-component reactions

• Gui-Feng Kang and
• Gang Zhang

Beilstein J. Org. Chem. 2020, 16, 1447–1455, doi:10.3762/bjoc.16.120

• 100050, China 10.3762/bjoc.16.120 Abstract A catalyst-free one-pot synthetic methodology was developed for the preparation of 1,3,5-triazine-2,4-dithione derivatives through three-component reactions of arylaldehydes, thiourea, and orthoformates. The procedure tolerated a diverse range of arylaldehydes

Synthesis of pyrrolidinedione-fused hexahydropyrrolo[2,1-a]isoquinolines via three-component [3 + 2] cycloaddition followed by one-pot N-allylation and intramolecular Heck reactions

• Xiaoming Ma,
• Suzhi Meng,
• Xiaofeng Zhang,
• Qiang Zhang,
• Shenghu Yan,
• Yue Zhang and
• Wei Zhang

Beilstein J. Org. Chem. 2020, 16, 1225–1233, doi:10.3762/bjoc.16.106

• Two kinds of [3 + 2] cycloaddition intermediates generated from the three-component reactions of 2-bromobenzaldehydes and maleimides with amino esters or amino acids were used for a one-pot N-allylation and intramolecular Heck reactions to form pyrrolidinedione-fused hexahydropyrrolo[2,1-a

1,5-Phosphonium betaines from N-triflylpropiolamides, triphenylphosphane, and active methylene compounds

• Vito A. Fiore,
• Chiara Freisler and
• Gerhard Maas

Beilstein J. Org. Chem. 2019, 15, 2603–2611, doi:10.3762/bjoc.15.253

• achieved with 1,1,1,5,5,5-hexafluoropentane-2,4-dione as the active methylene component [12]. Some of these three-component reactions were even performed in aqueous media [13]. In mechanistic terms, the initially formed 1,3-betaine is C-protonated by the CH-acid, the anion of which then combines with the

• ]. We report now on three-component reactions of alkynes 1 with triphenylphosphane and active methylene compounds, leading to phosphonium betaines which are structurally different from those shown in Scheme 1. Results and Discussion Synthesis of betaines 3 The combination of equimolar amounts of

• the reaction course, because analogous three-component reactions using propiolic acid esters as Michael acceptors are known to furnish another type of betaines in which the ester group (COOR) is retained. Questions on some mechanistic details, in particular at which stage of the reaction sequence the

In water multicomponent synthesis of low-molecular-mass 4,7-dihydrotetrazolo[1,5-a]pyrimidines

• Irina G. Tkachenko,
• Sergey A. Komykhov,
• Vladimir I. Musatov,
• Svitlana V. Shishkina,
• Viktoriya V. Dyakonenko,
• Vladimir N. Shvets,
• Mikhail V. Diachkov,
• Valentyn A. Chebanov and
• Sergey M. Desenko

Beilstein J. Org. Chem. 2019, 15, 2390–2397, doi:10.3762/bjoc.15.231

• in this case. The three-component reactions of 5-aminotetrazole (1) with aldehydes 7a,b (paraformaldehyde, acetaldehyde) and a set of acetoacetic ester derivatives 8a–d in water under microwave irradiation at 100 °C led to the formation of the corresponding 5,6,7-trisubstituted 4,7-dihydrotetrazolo

Multicomponent reactions (MCRs): a useful access to the synthesis of benzo-fused γ-lactams

• Edorta Martínez de Marigorta,
• Jesús M. de Los Santos,
• Ana M. Ochoa de Retana,
• Javier Vicario and
• Francisco Palacios

Beilstein J. Org. Chem. 2019, 15, 1065–1085, doi:10.3762/bjoc.15.104

• -component reaction of formyl benzoate 29, amines 2 and alkynes 18. Copper-catalysed three-component reaction of formylbenzoate 29, amines 2 and ketones 31. Non-catalysed (A) and phase-transfer catalysed (B) three-component reactions of formylbenzoic acids 33, amines 2 and 1,3-dicarbonyl derivatives 34

Novel (2-amino-4-arylimidazolyl)propanoic acids and pyrrolo[1,2-c]imidazoles via the domino reactions of 2-amino-4-arylimidazoles with carbonyl and methylene active compounds

• Victoria V. Lipson,
• Tetiana L. Pavlovska,
• Nataliya V. Svetlichnaya,
• Anna A. Poryvai,
• Nikolay Yu. Gorobets,
• Erik V. Van der Eycken,
• Irina S. Konovalova,
• Svetlana V. Shiskina,
• Alexander V. Borisov,
• Vladimir I. Musatov and
• Alexander V. Mazepa

Beilstein J. Org. Chem. 2019, 15, 1032–1045, doi:10.3762/bjoc.15.101

• -bielectrophiles or their synthetic precursors in the case of three-component reactions between these amines, carbonyl compounds and CH acids. Previously, an unusual direction of the three-component reaction between 2-aminoimidazoles, aldehydes and 5,5-dimethyl-1,3-cyclohexanedione has led to the formation of the

• oxindole moiety, and the resulting structures can be considered as analogues of 3,3'-spiroxindole alkaloids, such as spirotryprostatin B (17, Figure 6) [37]. Indeed, the equimolar three-component reactions with the participation of 2-amino-4-arylimidazoles 1, isatins 18 and acyclic methylene active

• indicating their sp2 hybridization. Such a distribution of electron density allows discussing the zwitter-ionic form and considering the structure of 19a as superposition of two resonance structures similar to 16a (Scheme 6). Conclusion In the described three-component reactions with aldehydes or isatins and

The LANCA three-component reaction to highly substituted β-ketoenamides – versatile intermediates for the synthesis of functionalized pyridine, pyrimidine, oxazole and quinoxaline derivatives

• Tilman Lechel,
• Roopender Kumar,
• Mrinal K. Bera,
• Reinhold Zimmer and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2019, 15, 655–678, doi:10.3762/bjoc.15.61

• reactions in larger scale, e.g., the synthesis of β-ketoenamides KE35 that was prepared in 3.5 g quantity [34]. The scalability of the three-component reactions seems therefore no problem which is important for the multistep preparation of subsequent products (see below). Aromatic dinitriles such as 1,3

• adjacent 4-alkyl group. The scope of this method is again very broad as demonstrated by the 25 examples compiled in Table 5 and those of Scheme 17 and Scheme 18. This condensation method is compatible with all substituents that are available by the three-component reactions to β-ketoenamides KE, however

• in good yield [30]. The latter should be a suitable precursor for three-component reactions with alkoxyallenes and carboxylic acids to furnish new β-ketoenamides KE bearing a 6-adamantyl-2-cyclopropyl-5-methoxypyrimidin-4-yl substituent. This again stresses the flexibility and versatility of our

Catalyst-free assembly of giant tris(heteroaryl)methanes: synthesis of novel pharmacophoric triads and model sterically crowded tris(heteroaryl/aryl)methyl cation salts

• Rodrigo Abonia,
• Luisa F. Gutiérrez,
• Braulio Insuasty,
• Jairo Quiroga,
• Kenneth K. Laali,
• Chunqing Zhao,
• Gabriela L. Borosky,
• Samantha M. Horwitz and
• Scott D. Bunge

Beilstein J. Org. Chem. 2019, 15, 642–654, doi:10.3762/bjoc.15.60

• ][14][15][16][17][18][19][20][21][22]. Although, “Yonemitsu-type” three-component reactions have been employed for the synthesis of indole-based triarylmethanes [23][24][25][26] (Scheme 2), there still exists a need for the development of new approaches for easy access to libraries of triarylmethanes

• . [52] and by Mousavizadeh et al. [53] through the three-component reactions of indole and coumarin, but in all cases, ordinary aliphatic and aromatic aldehydes as the third partner, mediated by a catalyst or by a biphasic system as solvent, respectively, were used. The lack of structural diversity in