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

• derivatives. Also, benzoisoindoles have been synthesized via the pseudo-four-component reaction of 3-phenylallylamines with maleic anhydride [35]. Finally, furfural was utilized in the Ugi reactions with unsaturated acids leading to the intramolecular Diels–Alder furan (IMDAF) reaction (Figure 1) [36]. In the

• these compounds were confirmed by NMR spectroscopy (see Supporting Information File 1). Conclusion In summary, we showed the practical usage of 3-(furan-2-yl)acrylaldehyde in the four-component Ugi reaction with the prospect of further intramolecular [4 + 2] cycloaddition of the Ugi reaction product. We

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

• , results in a spiro-cyclized intermediate XLI that affords the final product by deprotonation and loss of the copper species. Four-component reactions Two different four-component procedures catalyzed by Cu(OTf)2 are reported in the literature, both to access 1,2,3-triazole derivatives. The first one is a

Multicomponent reactions driving the discovery and optimization of agents targeting central nervous system pathologies

• Lucía Campos-Prieto,
• Aitor García-Rey,
• Eddy Sotelo and
• Ana Mallo-Abreu

Beilstein J. Org. Chem. 2024, 20, 3151–3173, doi:10.3762/bjoc.20.261

• single step. The oxazepine scaffold can be easily accessed using the Ugi four-component reaction. By modifying this scaffold, the researchers aimed to reduce the hydrogen-bond donating properties. The Passerini reaction, employing bifunctional salicylaldehydes and isocyanides successfully yielded

• /intramolecular Ullmann-type C–N coupling reactions. Azido-Ugi 4CR/cyclization (AU-4CR) strategy: The azido-Ugi four-component reaction (AU-4CR) is an elegant and atom economical approach for obtaining substituted tetrazoles, which are very relevant in medicinal chemistry [64]. When combined with suitable post

• active oxoindole-β-lactam compounds developed by Brãndao et al. [33]. The most promising hybrids synthesized via the Ugi-azide multicomponent reaction reported by Kushwaha et al. [34]. Most potent antioxidant compounds obtained through the Ugi four-component reaction developed by Pachón-Angona et al. [35

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

• , which transforms into alkyl radical D via CO elimination. Radical D adds to the double bond of alkene 130, to form the C-centered radical E, which recombines with radical B to yield the target product 132. Later, the same authors reported a four-component radical coupling of two different alkenes 133

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

• electrophilic sites simultaneously in their structure, these zwitterions are able to participate in various cyclization processes, especially for the synthesis of pyrroles [37][38][39][40]. For example, Li et al. developed a one-pot four-component reaction (4-CR) of malononitrile, aldehydes, and isocyanides

• , and benzoxazepine/triazolobenzodiazepine imine (Scheme 6). However, the yield of the products based on the four-component method was lower compared to those obtained via the three-component strategy. After the efficient and straightforward synthesis of the pyrrole-fused dibenzoxazepine

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

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

• tolerated in this consecutive four-component reaction, as the 1,3,4-thiadiazine synthesis competes with the thiazole synthesis. Salicylaldehydes 14 and 4-hydroxy-6-methyl-2H-pyran-2-one (16) can also be used to produce 1,3-dicarbonyl compounds 18 by Knoevenagel condensation and subsequent cyclization. This

• hydrolactite catalysts (C-Mg-Al HAT-3) [90]. With β-ketoesters, the method can be extended to a four-component synthesis. Initially, β-ketoesters react with hydrazine to form pyrazolones, while a Knoevenagel reaction between malononitrile and aldehyde simultaneously generates a Michael system. Both

• coordination of the magnesium ions and subsequent hydrazine inactivation. The diversity-oriented nature of this consecutive four-component synthesis was used to synthesize 17 different donor/acceptor-substituted pyrazoles 108 in moderate to good yields (Scheme 39) [136]. The synthesis of bispyrazoles was also

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

Ugi bisamides based on pyrrolyl-β-chlorovinylaldehyde and their unusual transformations

• Alexander V. Tsygankov,
• Vladyslav O. Vereshchak,
• Tetiana O. Savluk,
• Serhiy M. Desenko,
• Valeriia V. Ananieva,
• Oleksandr V. Buravov,
• Yana I. Sakhno,
• Svitlana V. Shishkina and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2024, 20, 1773–1784, doi:10.3762/bjoc.20.156

• compounds [1][2][3][4][5][6] to expand and systematically explore the chemical space within the concepts of molecular diversity chemistry (diversity oriented synthesis) [6] and biologically oriented synthesis [7]. Among the multicomponent processes, the four-component Ugi reaction (Ugi-4CR) [8][9][10][11

• presence of several alternative reaction centers in the structure of our substances, we sometimes encountered unexpected and intriguing results. Results and Discussion Synthesis of Ugi bisamides Four-component and three-component Ugi reactions The combination of pyrrole-containing α,β-unsaturated aldehyde

• 1, which contains a chlorine atom in the β-position, with convertible isocyanides 4a–d, para-substituted anilines 2a–e and monochloroacetic acid (3) as the smallest building blocks in a four-component reaction leads to the formation of the Ugi bisamides 5–8 (Table 1). Their structures offer several

Harnessing unprotected deactivated amines and arylglyoxals in the Ugi reaction for the synthesis of fused complex nitrogen heterocycles

• Javier Gómez-Ayuso,
• Pablo Pertejo,
• Tomás Hermosilla,
• Israel Carreira-Barral,
• Roberto Quesada and
• María García-Valverde

Beilstein J. Org. Chem. 2024, 20, 1758–1766, doi:10.3762/bjoc.20.154

• workup the only product observed was the corresponding benzodiazepinone 5, resulting from a spontaneous cyclization of the Ugi adduct, in a six-center four-component Ugi reaction (U-6C-4CR), which prevents the need of additional steps (Scheme 1, Table 1). Due to the interest of these results and

Syntheses and medicinal chemistry of spiro heterocyclic steroids

• Laura L. Romero-Hernández,
• Ana Isabel Ahuja-Casarín,
• Penélope Merino-Montiel,
• Sara Montiel-Smith,
• José Luis Vega-Báez and
• Jesús Sandoval-Ramírez

Beilstein J. Org. Chem. 2024, 20, 1713–1745, doi:10.3762/bjoc.20.152

• , such as a one-pot four-component synthesis and the use of ionic liquids as solvents [30]. Kanchithalaivan et al. [31] reported a library of 16-spiro pyrrolo[1,2-c][1,3]thiazoles of trans-androsterone and DHEA (49a and 49b, respectively). The syntheses were achieved through the 1,3-dipolar cycloaddition

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

• , 38200, La Laguna, Spain 10.3762/bjoc.20.104 Abstract Considering early-stage drug discovery programs, the Ugi four-component reaction is a valuable, flexible, and pivotal tool, facilitating the creation of two new amide bonds in a one-pot fashion to effectively yield the desired α-aminoacylamides. Here

• urgent need to find novel, effective and safe drugs for cancer therapy. Recently, focusing on the design of more potent anticancer drug candidates using more sustainable synthetic processes, we report a new Ugi four-component reaction approach for easy access to Ugi-derived isatin-peptoids in moderate to

• obtained using an Ugi four-component reaction (Ugi4CR). (B) The synthetic strategy reported in this work. Library of α-acetamide carboxamide oxindole hybrids 5 accessed via the Ugi4CR. Microwave-assisted CuAAC reaction to access α-acetamide carboxamide 1,2,3-triazole oxindole hybrid 7. Library of α

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

• developed building block approach, we decided to incorporate an oxo-tetrazole into an Ugi four-component reaction, the most studied and versatile MCR in organic synthesis and drug discovery [31][32]. Despite tremendous exploration, finding novel substrates or bioisosteres as a starting material in the Ugi

One-pot Ugi-azide and Heck reactions for the synthesis of heterocyclic systems containing tetrazole and 1,2,3,4-tetrahydroisoquinoline

• Jiawei Niu,
• Yuhui Wang,
• Shenghu Yan,
• Yue Zhang,
• Xiaoming Ma,
• Qiang Zhang and
• Wei Zhang

Beilstein J. Org. Chem. 2024, 20, 912–920, doi:10.3762/bjoc.20.81

• schistosomiasis [22][23][24][25]. The combination of the privileged heterocycles tetrazole and tetrahydroisoquinoline in one molecule generates new molecules which could have biological activities. A standard Ugi four-component reaction (Ugi-4CR) of an aldehyde, amine, isocyanide, and a carboxylic acid produces

• highly diverse peptidic structures A with up to four points of substitution (Scheme 1) [26][27]. By replacing the carboxylic acid with a nucleophilic azide reagent XN3 (generally TMSN3), the Ugi-azide four-component reaction (UA-4CR) of an aldehyde, amine, isocyanide, and azide gives 1,5-disubstituted 1H

• . The initial Ugi-azide four-component reaction constructs the tetrazole motif while the subsequent intramolecular Heck reaction assembles the tetrahydroisoquinoline. The one-pot reaction avoids the intermediate purification which has favorable PASE in the synthesis of heterocyclic compounds

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

• acetaldehyde dimethyl acetal as a masked form of acetaldehyde, which is hydrolyzed in situ, allowing for a higher product yield and fewer byproducts [15]. The group of Müller describes an elegant consecutive four-component reaction involving an alkynylation–cyclization–iodination–alkylation sequence toward

Decarboxylative 1,3-dipolar cycloaddition of amino acids for the synthesis of heterocyclic compounds

• Xiaofeng Zhang,
• Xiaoming Ma and
• Wei Zhang

Beilstein J. Org. Chem. 2023, 19, 1677–1693, doi:10.3762/bjoc.19.123

• pseudo-four-component reaction for the synthesis of tetrahydropyrrolothiazole derivatives. The reaction of cysteine with two equiv of arylaldehydes and one equiv of maleimides in EtOH at 90 °C for 12 h afforded tetrahydropyrrolothiazoles 29 in 66–79% yields with up to 7:1 dr (Scheme 17) [76]. Using

• ]isoquinolines. Pseudo-four-component reaction for the synthesis of tetrahydropyrrolothiazoles 29 and 30 (>4:1 dr). One-pot two-step synthesis of spirooxindole-pyrrolothiazoles 31 (>4:1 dr). Acknowledgements We would like to thank all our co-workers who worked on the research projects highlighted in this paper

Consecutive four-component synthesis of trisubstituted 3-iodoindoles by an alkynylation–cyclization–iodination–alkylation sequence

• Nadia Ledermann,
• Alae-Eddine Moubsit and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2023, 19, 1379–1385, doi:10.3762/bjoc.19.99

• generated by a consecutive four-component reaction starting from ortho-haloanilines, terminal alkynes, N-iodosuccinimide, and alkyl halides in yields of 11–69%. Initiated by a copper-free alkynylation, followed by a base-catalyzed cyclizive indole formation, electrophilic iodination, and finally

• prior to terminal alkylation could provide a straightforward entry to trisubstituted 3-iodoindoles, which are valuable building blocks for accessing highly decorated (aza)indoles (Scheme 1). Here, we report the concise consecutive four-component synthesis of trisubstituted 3-iodoindoles. Results and

• to directly employ these standard conditions to the sequence of ortho-haloanilines 1, terminal alkynes 2, N-iodosuccinimide (3), and alkyl halides 4 to screen the scope of the one-pot synthesis of trisubstituted 3-iodoindoles 5 in a consecutive four-component fashion (Scheme 2). The sequence

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

• multicomponent reactions have been successfully developed to construct multifunctionalized or polycyclic spirooxindoles. For example, Zhang successfully developed a recyclable bifunctional cinchona/thiourea-catalyzed four-component Michael/Mannich cyclization sequence for the asymmetric synthesis of

Unravelling a trichloroacetic acid-catalyzed cascade access to benzo[f]chromeno[2,3-h]quinoxalinoporphyrins

• Chandra Sekhar Tekuri,
• Pargat Singh and
• Mahendra Nath

Beilstein J. Org. Chem. 2023, 19, 1216–1224, doi:10.3762/bjoc.19.89

• Chandra Sekhar Tekuri Pargat Singh Mahendra Nath Department of Chemistry, Faculty of Science, University of Delhi, Delhi 110 007, India 10.3762/bjoc.19.89 Abstract A facile one-pot four-component synthetic methodology is evolved to construct novel copper(II) benzo[f]chromeno[2,3-h

• present study discloses an easy and first synthetic approach to build highly π-conjugated copper(II) benzo[f]chromeno[2,3-h]quinoxalinoporphyrins through a trichloroacetic acid-catalyzed one-pot four-component reaction of 2,3-diamino-5,10,15,20-tetraarylporphyrins, 2-hydroxynaphthalene-1,4-dione, aromatic

• ]chromeno[2,3-h]quinoxalinoporphyrins 3–8. For the optimization of the reaction conditions, a model four-component reaction of copper(II) 2,3-diamino-5,10,15,20-tetra(p-tolyl)porphyrin with 2-hydroxynaphthalene-1,4-dione (2), benzaldehyde and dimedone was carried out in the presence of 20 mol % p

Synthesis of imidazo[1,2-a]pyridine-containing peptidomimetics by tandem of Groebke–Blackburn–Bienaymé and Ugi reactions

• Oleksandr V. Kolomiiets,
• Alexander V. Tsygankov,
• Maryna N. Kornet,
• Aleksander A. Brazhko,
• Vladimir I. Musatov and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2023, 19, 727–735, doi:10.3762/bjoc.19.53

• 24 hours at room temperature in DMF with catalytic amounts of HClO4. The yield of compound 4a in this case was 76%. Then new heterocyclic acids were used as reagents for the Ugi four-component reaction. Due to the rather low solubility of the acids in methanol, it was necessary to increase the

• heterocyclic acid 8a was obtained by a three-component reaction of 2-amino-5-chloropyridine (1a), 4-formylbenzoic acid (5f), and tert-butyl isocyanide (3a) according to the procedure described above (Scheme 3). In another step, we attempted to introduce the acid 8a into the Ugi four-component reaction with 4

Enolates ambushed – asymmetric tandem conjugate addition and subsequent enolate trapping with conventional and less traditional electrophiles

• Péter Kisszékelyi and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 593–634, doi:10.3762/bjoc.19.44

• diastereomers were detected (Scheme 9A). Furthermore, the authors have also demonstrated a four-component coupling reaction: by simply increasing the amount of the organolithium reagent (2.05 equiv) used for the activation of the Zn enolate, β-hydroxyketones 40 were gained via 1,2-addition of the zincate

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

• 10.3762/bjoc.18.171 Abstract A novel four-component reaction in one pot as an atom- and step-economic process was developed to synthesize diastereoselectively spirooxindolepyrrolothiazoles through sequential N,S-acetalation of aldehydes with cysteine and decarboxylative [3 + 2] cycloaddition with olefinic

• 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

• results using ᴅ- and ʟ-cysteine to synthesize compound 5a (Scheme 5). We conferred green chemistry metrics to evaluate the process efficiency of four-component reaction via comprehensive and quantitative calculation. The metrics analysis is carried out for the two-step synthesis with intermediate

Molecular diversity of the base-promoted reaction of phenacylmalononitriles with dialkyl but-2-ynedioates

• Hui Zheng,
• Ying Han,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2022, 18, 991–998, doi:10.3762/bjoc.18.99

• dialkyl but-2-ynedioate. Thus, a quasi-four-component reaction led to the final product. There are two chiral carbon atoms in the molecules, thus two diastereoisomers would be formed in the reaction. However, the 1H and 13C NMR spectra gave only one set of resonances for the characteristic groups, which

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

• Shao-Cong Zhan Ren-Jie Fang Jing Sun Chao-Guo Yan College of Chemistry & Chemical Engineering, Yangzhou University, Yangzhou 225002, China 10.3762/bjoc.18.80 Abstract In the presence of copper sulfate, three- or four-component reactions of 2-methylindole, aromatic aldehydes and various cyclic

• dienophiles, 5-arylidene-1,3-dimethylbarbituric acids, could be in situ generated by aromatic aldehydes and 1,3-dimethylbarbituric acid under the standard conditions. Therefore, the four-component reaction was carried out by using two molecular aromatic aldehydes, 1,3- dimethylbarbituric acid and 2

• '-indolines] 2a–h, in which the two phenyl groups exist in cis-position. This result clearly indicated that this reaction has a similar outcome of stereochemistry. Based on the success of the four-component reaction through in situ generation of dienes and dienophiles, we further considered whether more

Heteroleptic metallosupramolecular aggregates/complexation for supramolecular catalysis

• Prodip Howlader and
• Michael Schmittel

Beilstein J. Org. Chem. 2022, 18, 597–630, doi:10.3762/bjoc.18.62

• = 24 kHz (at 298 K). A similar exchange process was observed in the four-component rotors [90] developed along two orthogonal self-sorting motifs (HETPYP = Npy → [Cu(phenAr2)]+ and NDABCO → ZnPor interactions). Again, the synthetic approach is a straightforward multicomponent self-sorting assembly

• , thermodynamic stabilization quantitatively drives the reaction to the hetero-assembly 59, simply by mixing the components in the correct stoichiometric ratio (Figure 13). Various nanorotor assemblies are possible by this approach. The dynamics of the four-component rotor 59 = [Cu2(55)(57)(60)]2+ cannot be

• ) through nanomechanical motion. Recently, the suitability of the four-component rotors to act as catalysts in various click reactions was investigated having a look at nanorotors [Cu2(55)(60)(X)]2+ (with X = 62, 63 or 64), revealing an unexpected correlation between their rotational speed and catalytic