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

• compounds using dihalomethanes (Scheme 27) [79]. They developed a three-component reaction between amines (mainly tertiary amines), a dihalomethane, and a P(OH) species (like phosphonate, phosphinate, or secondary phosphine oxide) under catalyst-free conditions to afford α-amino phosphorus compounds 35. The

• multicomponent reactions where formaldehyde per se cannot react. For example, in the Groebke–Blackburn–Bienaymé (GBB) multicomponent reaction, a three-component reaction of heterocyclic amidines 39, aldehydes 40 and isocyanides 41 under acidic catalysis generates heterobicyclic products 42 through a [4 + 1

• and within shorter reaction times (Scheme 36). In recent years, several groups have applied these strategies to identify products with biological activity [94][95]. Representative examples are shown in Scheme 37. On the other hand, the van Leusen three-component reaction of an aryl-substituted tosyl

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

• generate crotonic condensation adducts of active methylene compounds and formaldehyde at room temperature in the absence of strong acids and bases. The formed adducts were highly reactive intermediates capable of reacting with dienes in a three-component reaction, leading to the formation of Diels–Alder

• adducts of the Diels–Alder (i.e., I) and the hetero-Diels–Alder reaction (i.e., II), or adducts resulting from the addition of a second equivalent of CH acid to the crotonic condensation product (i.e., III). Apparently ʟ-proline played an essential role as catalyst in this three-component reaction. Using

• was confirmed through the three-component reaction with acetylacetone, in which only the product 7 was formed (according to 1H NMR spectra of the reaction mixture). Stereoselective interactions between methylidene adducts and cyclopentadiene were confirmed for three-component reactions involving

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

• materials. The colored frames indicate the different scaffold types. Synthesis of N-substituted thienopyrimidones 5a–e by a Gewald three-component reaction employing 2-aminothiophenes 2a–e and formamide as C1 source. A characteristic fluorescence for compound 5a was reported (365 nm in DMSO). The reported

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

• Michael-type addition of 5-aminoindazole to afford the first coupling product XXXVIII. The subsequent intramolecular amination and dehydration then leads to the final product (Scheme 31) [50]. Polycyclic spiroindoline-3,4’-pyrano[3,2-b]pyran-4-ones 43 were synthesized exploiting the three-component

• reaction of isatin, 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (i.e. kojic acid) and malononitriles or cyanoacetates (Scheme 32) [51]. Compared to other Lewis acids, Cu(OTf)2 proved to be the best. Mechanistically, the process begins with a Knoevenagel-type condensation between isatin and the cyano

Tunable full-color dual-state (solution and solid) emission of push–pull molecules containing the 1-pyrindane moiety

• Anastasia I. Ershova,
• Sergey V. Fedoseev,
• Konstantin V. Lipin,
• Mikhail Yu. Ievlev,
• Oleg E. Nasakin and
• Oleg V. Ershov

Beilstein J. Org. Chem. 2024, 20, 3016–3025, doi:10.3762/bjoc.20.251

• [58] was prepared in the first step via three-component reaction between tetracyanoethylene, cyclopentanone, and hydrogen chloride. Then, multiacceptor compound 2 was involved in the condensation with aromatic aldehydes bearing electron-donor groups. As a result, a series of new push–pull molecules

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

• ) [105]. A three-component reaction of alkenes 137, aldehydes 138, and hydroperoxides catalyzed by FeCl2 to β-peroxy ketones 139 has been realized. The authors proposed the involvement both as acyl and tert-butylperoxy radicals into the reaction pathway. The tert-butoxy radical A and tert-butylperoxy

Synthesis of pyrrole-fused dibenzoxazepine/dibenzothiazepine/triazolobenzodiazepine derivatives via isocyanide-based multicomponent reactions

• Marzieh Norouzi,
• Mohammad Taghi Nazeri,
• Ahmad Shaabani and
• Behrouz Notash

Beilstein J. Org. Chem. 2024, 20, 2870–2882, doi:10.3762/bjoc.20.241

• -workers reported a one-pot three-component reaction (3-CR) of sulfamate‐derived cyclic imine, isocyanide, and acetylenedicarboxylate. In this reaction too, the pyrrole-fused sulfamate is synthesized through intermediacy of the in situ-formed zwitterion II and [1 + 2 + 2] annulation reaction (Scheme 1b

A review of recent advances in electrochemical and photoelectrochemical late-stage functionalization classified by anodic oxidation, cathodic reduction, and paired electrolysis

• Nian Li,
• Ruzal Sitdikov,
• Ajit Prabhakar Kale,
• Joost Steverlynck,
• Bo Li and
• Magnus Rueping

Beilstein J. Org. Chem. 2024, 20, 2500–2566, doi:10.3762/bjoc.20.214

Asymmetric organocatalytic synthesis of chiral homoallylic amines

• Nikolay S. Kondratyev and
• Andrei V. Malkov

Beilstein J. Org. Chem. 2024, 20, 2349–2377, doi:10.3762/bjoc.20.201

• [39] developed a direct, highly enantioselective three-component reaction between aromatic acetals, BocNH2, and various 2-monosubstituted or 2,3-disubstituted allyltrimethylsilanes in the presence of 10 mol % of triethylsilyl triflate (TESOTf) and 10 mol % of the chiral bifunctional thiourea catalyst

• stereospecific synthesis of γ- and γ,δ-substituted homoallylic amines by a three-component reaction between an aryl acetal, BocNH2 carbamate and a 2,3-disubstituted allylsilane, in presence of the triflate-assisted bifunctional HBD/πAr-Ar catalyst [39]. Catalytic cycle for the three-component allylation with HBD

Deuterated reagents in multicomponent reactions to afford deuterium-labeled products

• Kevin Schofield,
• Shayna Maddern,
• Yueteng Zhang,
• Grace E. Mastin,
• Rachel Knight,
• Wei Wang,
• James Galligan and
• Christopher Hulme

Beilstein J. Org. Chem. 2024, 20, 2270–2279, doi:10.3762/bjoc.20.195

• three-component reaction of α-amino-heterocycles, aldehydes, and isocyanides which affords various aza-bicyclic molecules [48][49][50][51][52]. The methodology has been widely used for file enhancement purposes. Three deuterated GBB products are presented, Scheme 9. Unlike the previous MCRs, labeling

Heterocycle-guided synthesis of m-hetarylanilines via three-component benzannulation

• Andrey R. Galeev,
• Maksim V. Dmitriev,
• Alexander S. Novikov and
• Andrey N. Maslivets

Beilstein J. Org. Chem. 2024, 20, 2208–2216, doi:10.3762/bjoc.20.188

• with heterocyclic substituents, acetone and various amines has been developed. The success of this three-component reaction is governed by the electron-withdrawing ability of the heterocyclic substituent in the 1,3-diketone, which can be evaluated with computational Hammett constants. As a rule-of

• -thumb, 1,3-diketones bearing substituents with σm or σp > 0.300 afford meta-anilines from alkylamines in good synthetic yields, and higher σm or σp are required for three-component condensation with less nucleophilic arylamines. The developed one-pot three-component reaction is efficient (yields up to

O,S,Se-containing Biginelli products based on cyclic β-ketosulfone and their postfunctionalization

• Kateryna V. Dil and
• Vitalii A. Palchykov

Beilstein J. Org. Chem. 2024, 20, 2143–2151, doi:10.3762/bjoc.20.184

• ) are the key methodology to access valuable heterocycles for medicinal chemistry projects. The classical Biginelli reaction (1893) is an acid-catalyzed, three-component reaction between an aldehyde, β-ketoester, and urea that produces 3,4-dihydropyrimidin-2(1H)-ones, also known as DHPMs (Scheme 1A

Multicomponent syntheses of pyrazoles via (3 + 2)-cyclocondensation and (3 + 2)-cycloaddition key steps

• Ignaz Betcke,
• Alissa C. Götzinger,
• Maryna M. Kornet and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2024, 20, 2024–2077, doi:10.3762/bjoc.20.178

• formed. Notably, this process is compatible with both aromatic and aliphatic aldehydes. Pyrazoles with fluorinated functionalities were synthesized via a three-component reaction utilizing trifluoroethanol both as a solvent and reactant. Gonçalves et al. developed a method whereby 1,1,1-trichloro-6

• vinyl ether enables the synthesis of 3-alkoxyalkenones 74, presenting an elegant route. Subsequently, these compounds undergo a three-component reaction with various hydrazines, forming 1,3-substituted pyrazoles 75 (Scheme 26) [104]. However, one limitation is the formation of 1,5-substituted pyrazoles

• β-ketoesters to form enaminones 85. The consecutive three-component reaction culminates in cyclization with substituted hydrazines, leading to the regioselective formation of 5-fluoroalkylpyrazoles 83 (Scheme 30) [111]. Following subsequent saponification, pyrazole-4-carboxylic acids can be obtained

The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162

• /bjoc.20.162 Abstract The Groebke–Blackburn–Bienaymé (GBB) three-component reaction, discovered in 1998, is a very efficient strategy to assemble imidazo[1,2-a]-heterocycles starting from amidines, aldehydes and isocyanides. This review aims to exhaustively describe innovative aspects of this reaction

• ; Introduction The Groebke-Blackburn-Bienaymé (GBB) three-component reaction has been discovered in 1998 and during the course of the first two decades has emerged as one of the most exploited isocyanide-based MCRs, with more than 200 original publications reported and exhaustively reviewed by Boltjes and

• generated, the intermediates 105 and isocyanides underwent formal [4 + 1] cycloaddition followed by tautomerization, affording benzothiazolpyrroles 106 (X = S) in moderate to good yields (52–82%). In addition, performing the three-component reaction using benzoxazole acetonitrile 104 (X = O) or 2-pyridyl

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 been successfully synthesised through a one-pot, three-component reaction involving N,N-dimethylbarbituric acid, an aromatic aldehyde and aniline. By utilizing readily available reagents, this approach opens up the opportunity for the efficient formation of a variety of 5-aryldeazaalloxazines

Rapid construction of tricyclic tetrahydrocyclopenta[4,5]pyrrolo[2,3-b]pyridine via isocyanide-based multicomponent reaction

• Xiu-Yu Chen,
• Ying Han,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2024, 20, 1436–1443, doi:10.3762/bjoc.20.126

• )-pentacarboxylates was developed by a three-component reaction. In the absence of any catalyst, the three-component reaction of alkyl isocyanides, dialkyl but-2-ynedioates and 5,6-unsubstituted 1,4-dihydropyridines in refluxing acetonitrile afforded polyfunctionalized tetrahydrocyclopenta[4,5]pyrrolo[2,3-b]pyridine

• -aza-1,3-butadienes [40][41][42][43][44]. Recently, we have found that the three-component reaction of isoquinolines, dialkyl but-2-ynediaotes and 5,6-unsubstituted 1,4-dihydropyridines afforded functionalized isoquinolino[1,2-f][1,6]naphthyridines in good yields and with high diastereoselectivity via

• ), dimethyl but-2-ynedioate (2a) and 5,6-unsubstituted dihydropyridine 3a as standard reaction. The main results are summarized in Table 1. The expected product was not observed when the three-component reaction was carried out in methanol, ethanol or tetrahydrofuran at room temperature (Table 1, entries 1–3

Challenge N- versus O-six-membered annulation: FeCl₃-catalyzed synthesis of heterocyclic N,O-aminals

• Giacomo Mari,
• Lucia De Crescentini,
• Gianfranco Favi,
• Fabio Mantellini,
• Diego Olivieri and
• Stefania Santeusanio

Beilstein J. Org. Chem. 2024, 20, 1412–1420, doi:10.3762/bjoc.20.123

• Abstract A new class of heterocyclic N,O-aminal and hemiaminal scaffolds was successfully obtained by means of a three-component reaction (3-CR) of 1,2-diaza-1,3-dienes (DDs), α-aminoacetals and iso(thio)cyanates. These stable imine surrogates are generated from key-substituted (thio)hydantoin

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

• cation was directly observed confirming the previously proposed mechanism of a three-component reaction. Several steps of the photoredox cycle were investigated separately, providing deep insights into the complex mechanism. The triplet-excited Aza-H, which was studied with quantitative LFP, is formed

• its photochemical reactivity. The main reaction class catalyzed by excited-state polyazahelicene Aza-H so far is the redox-neutral addition of sulfinates and cyanopyridines, under elimination of cyanide, to styrenes in a three-component reaction. The proposed mechanism was derived from the redox

Innovative synthesis of drug-like molecules using tetrazole as core building blocks

• Jingyao Li,
• Ajay L. Chandgude,
• Qiang Zheng and
• Alexander Dömling

Beilstein J. Org. Chem. 2024, 20, 950–958, doi:10.3762/bjoc.20.85

• reactions or other chemistries, aiding in the creation of a variety of complex, drug-like molecules. These innovative tetrazole building blocks are efficiently and directly synthesized using a Passerini three-component reaction (PT-3CR), employing cost-effective and readily available materials. We further

• step forward by employing novel 1H-protected tetrazole aldehydes as versatile building blocks, a strategy not previously explored. A key innovation of this research lies in the synthesis of these tetrazole building blocks. The use of the Passerini three-component reaction (PT-3CR) utilizing cost

SOMOphilic alkyne vs radical-polar crossover approaches: The full story of the azido-alkynylation of alkenes

• Julien Borrel and
• Jerome Waser

Beilstein J. Org. Chem. 2024, 20, 701–713, doi:10.3762/bjoc.20.64

• -component reaction, had surprisingly little influence on the transformation. At lower concentration only a slight decrease of yield was observed, whereas higher concentration led to a similar yield (Table 5, entries 10 and 11). The source of nucleophilic alkyne was evaluated, changing the counter ion from

• source such as green LEDs or a compact fluorescent lamp (CFL) were used only a small decrease in yield could be observed, although 4 hours of irradiation were needed to reach full conversion using CFL (Table 5, entries 8 and 9). The concentration, a factor expected to play an important role in a three

Palladium-catalyzed three-component radical-polar crossover carboamination of 1,3-dienes or allenes with diazo esters and amines

• Geng-Xin Liu,
• Xiao-Ting Jie,
• Ge-Jun Niu,
• Li-Sheng Yang,
• Xing-Lin Li,
• Jian Luo and
• Wen-Hao Hu

Beilstein J. Org. Chem. 2024, 20, 661–671, doi:10.3762/bjoc.20.59

• multicomponent reaction protocol. Keywords: carboamination; diazo chemistry; palladium catalysis; radical-polar crossover; three-component reaction; Introduction Since the discovery of the existence of non-canonical amino acids (AAs) in organisms, such structural motifs have attracted considerable attention

• diazoacetamide, affording the corresponding products 4ac, 4ad, and 4ae in high yields with Pd(PPh3)2Cl2 (69%, 71% and 65%, respectively). With a reliable set of conditions for the carboamination of 1,3-dienes with diazo esters and amines, we wondered whether this three-component reaction could be applied to

HPW-Catalyzed environmentally benign approach to imidazo[1,2-a]pyridines

• Luan A. Martinho and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2024, 20, 628–637, doi:10.3762/bjoc.20.55

• activities. The most direct way of obtaining this nucleus is the Groebke–Blackburn–Bienaymé three-component reaction (GBB-3CR) between aminopyridines, aldehydes, and isocyanides under both Lewis and Brønsted acid catalysis. However, several catalysts for this reaction have major drawbacks such as being

• conditions and the employment of relatively complex starting materials [19]. A more efficient way of obtaining this nucleus is through the Groebke–Blackburn–Bienaymé three-component reaction (GBB-3CR) between amidines (aminoazoles), aldehydes, and isocyanides under both Lewis and Brønsted acid catalysis [20

• ][21][22]. Multicomponent reactions (MCRs) provide one-pot reactions, simple synthetic procedures, less waste being produced, fewer purification steps, and a high atom economy [23]. The GBB three-component reaction is carried out in the presence of Lewis or Brønsted acid catalysis to increase the

Catalytic multi-step domino and one-pot reactions

• Svetlana B. Tsogoeva

Beilstein J. Org. Chem. 2024, 20, 254–256, doi:10.3762/bjoc.20.25

• through concerted or stepwise mechanisms. An enantioselective palladium-catalyzed three-component reaction of glyoxylic acid, sulfonamides, and aryltrifluoroborates toward synthetically useful α-arylglycine compounds is described by the Manolikakes group [11]. Moreover, Šebesta and co-workers report a

Copper-catalyzed multicomponent reaction of β-trifluoromethyl β-diazo esters enabling the synthesis of β-trifluoromethyl N,N-diacyl-β-amino esters

• Youlong Du,
• Haibo Mei,
• Ata Makarem,
• Ramin Javahershenas,
• Vadim A. Soloshonok and
• Jianlin Han

Beilstein J. Org. Chem. 2024, 20, 212–219, doi:10.3762/bjoc.20.21

• undergo a Mumm rearrangement to provide unsymmetrical β-trifluoromethyl diacyl-β-amino esters as products (Scheme 1c). Herein, we report our results on the design of β-trifluoromethyl β-diazo esters and their application in a three-component reaction with nitriles and carboxylic acids under mild

N-Sulfenylsuccinimide/phthalimide: an alternative sulfenylating reagent in organic transformations

• Fatemeh Doraghi,
• Seyedeh Pegah Aledavoud,
• Mehdi Ghanbarlou,
• Bagher Larijani and
• Mohammad Mahdavi

Beilstein J. Org. Chem. 2023, 19, 1471–1502, doi:10.3762/bjoc.19.106

• cyclization and sulfenylation promoted by AlCl3. Dialkyl disulfides 47 were also well tolerated in this Lewis acid-mediated sulfenylation reaction in solvent-free conditions at room temperature. In the same year, a three-component reaction between highly substituted cyclopropanes 49, sulfonamides 25 and N