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

• environmentally friendly synthetic strategies, especially one-pot multicomponent and tandem reactions, are key to modern organic and medicinal chemistry [1][2][3][4][5][6][7] and have proven to be successful in generating diverse heterocyclic scaffolds, as highlighted in a recent book [8]. Multicomponent

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

• [4][5][6] and polymerization processes of unstable methylidene adducts [7][8][9], instead of the desired formation of a monocrotonic product. Therefore, heating [6][10][11][12][13][14] or Lewis acid activation [15][16][17][18] have often been used in the literature for successful multicomponent

• reactions that proceed through the formation of formaldehyde condensation products (Scheme 1). Previously, we have proposed a convenient diffusion mixing technique for multicomponent reactions based on the absorption of volatile reagent vapors by a mixture containing the remaining reaction components. This

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

• molecules, contributing significantly to sustainability, innovation and economic growth across various sectors. In this study, we present an efficient and rapid method for synthesizing a variety of heteroannulated pyrimidones using cyanoacetamide-based multicomponent reaction (MCR) chemistry. By utilizing

• structure was obtained, revealing certain geometrical features. Keywords: 2-amino-substituted heterocycles; cyanoacetamide; Gewald reaction; multicomponent reaction (MCR); pyrimidine; Introduction The term “net-zero carbon” is becoming increasingly common as we consider a future marked by a rising global

• is mostly due to their presence in greenhouse emissions [5][6]. Although abundant and inexpensive, their valorization still remains problematic due to their thermodynamic stability and chemical inertness [7][8][9][10][11][12][13][14][15]. Multicomponent reaction (MCR) chemistry is a type of

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

• Venezian 21, 20133, Milano, Italy 10.3762/bjoc.21.7 Abstract This review reports the achievements in copper(II) triflate-catalyzed processes concerning the multicomponent reactions, applied to the synthesis of acyclic and cyclic compounds. In particular, for the heteropolycyclic systems mechanistic

• ; heteropolycycles; multicomponent reactions; one-pot reaction; Introduction Copper has gained a relevant role in organic synthesis as an alternative to precious metals due to its low toxicity, ease of handling, high catalytic activity, and cost-effectiveness [1][2]. In recent years, Cu(OTf)2 has significantly

• toxicity [3][4][5][6][7]. Multicomponent reactions are one of the most effective methods to assemble multiple reagents, thus facilitating access to the target molecules more quickly, due to atom/step economy, short reaction times, and eco-friendly benefits. Combining multicomponent reactions with

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

• . Diagonal 643, E-08028 Barcelona, Spain 10.3762/bjoc.20.261 Abstract The ongoing quest to discover effective treatments for diseases remains a significant challenge for the scientific community. Multicomponent reactions (MCRs) have emerged as powerful tools in accelerating drug discovery, enabling the

• to the authors whose important contributions may not be included. By concentrating on these pivotal studies, we strive to offer a clear and concise perspective on current research trends and breakthroughs in this field. Keywords: Alzheimer; depression; epilepsy; multicomponent reactions; Parkinson

• ; schizophrenia; Introduction Multicomponent reactions Due to efforts to develop new drug arsenals faster to overcome the difficulties of medicinal chemistry (multistage and highly wasteful processes), multicomponent reactions (MCRs) have emerged as a plausible solution. MCRs are convergent reactions in which

Synthesis of the 1,5-disubstituted tetrazole-methanesulfonylindole hybrid system via high-order multicomponent reaction

• Cesia M. Aguilar-Morales,
• América A. Frías-López,
• Nadia V. Emilio-Velázquez,
• Alejandro Islas-Jácome,
• Angelica Judith Granados-López,
• Jorge Gustavo Araujo-Huitrado,
• Yamilé López-Hernández,
• Hiram Hernández-López,
• Luis Chacón-García,
• Jesús Adrián López and
• Carlos J. Cortés-García

Beilstein J. Org. Chem. 2024, 20, 3077–3084, doi:10.3762/bjoc.20.256

• , 98160, México 10.3762/bjoc.20.256 Abstract A series of 1,5-disubstituted tetrazole-indole hybrids were synthesized via a high-order multicomponent reaction consisting of an Ugi-azide/Pd/Cu-catalyzed hetero-annulation cascade sequence. This operationally simple one-pot protocol allowed high bond-forming

• efficiency and creating six new bonds (two C–C, three C–N, and one N–N). Additionally, the products were evaluated against breast cancer MCF-7 cells, finding moderate activity in the compounds substituted with fluorine and chlorine. Keywords: 1,5-disubstituted tetrazoles; high-order multicomponent reaction

• affinity compared to their drug parents and by using powerful synthetic tools such as multicomponent reactions (MCRs) [11][12][13]. Among these, isocyanide-based multicomponent reactions (I-MCRs), such as the Ugi-azide reaction, have demonstrated the highest biological-synthetic relevance [1][14][15][16

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

• .20.241 Abstract An efficient and facile synthesis of pyrrole-fused dibenzoxazepine/dibenzothiazepine/triazolobenzodiazepine derivatives was developed through the isocyanide-based multicomponent reaction of isocyanides, gem-diactivated olefins, and cyclic imines such as dibenzoxazepine, dibenzothiazepine

• great attention in biomedical applications, clinical diagnostics, and conjugate materials. Keywords: cyclic imines; dibenzothiazepine; dibenzoxazepine; isocyanides; multicomponent reactions; pyrrole; triazolobenzodiazepine; Introduction Pyrroles and their derivatives are important N-heterocyclic

• /benzoxazepine/benzothiazepine is very important. Due to the wide applications of pyrrole-fused heterocycles, very diverse approaches have been developed for their synthesis [28][29][30][31][32]. In recent years, multicomponent reactions (MCRs) have emerged as one of the most efficient and powerful methods to

Multicomponent synthesis of α-branched amines using organozinc reagents generated from alkyl bromides

• Baptiste Leroux,
• Alexis Beaufils,
• Federico Banchini,
• Olivier Jackowski,
• Alejandro Perez-Luna,
• Fabrice Chemla,
• Marc Presset and
• Erwan Le Gall

Beilstein J. Org. Chem. 2024, 20, 2834–2839, doi:10.3762/bjoc.20.239

• Paris, France 10.3762/bjoc.20.239 Abstract The use of alkylzinc bromides in the multicomponent Mannich reaction is described. Heteroleptic organozinc compounds were obtained in THF or 2-MeTHF by direct insertion of zinc dust into the C–Br bond of alkyl bromides. It was found that the presence of a

• primary organozinc reagents. Keywords: alkyl bromides; branched amines; Mannich reaction; multicomponent reaction; zinc; Introduction The multicomponent Mannich reaction is one of the most powerful tools available in organic synthesis for the straightforward generation of α-branched amines [1][2][3

• through the direct insertion of zinc dust into the C–I bond in acetonitrile at 50 °C [23]. Secondary as well as tertiary organozinc iodides were found to be more reactive than primary ones. Recently, Gaunt and co-workers confirmed this tendency in a related reductive multicomponent procedure involving

Copper-catalyzed yne-allylic substitutions: concept and recent developments

• Shuang Yang and
• Xinqiang Fang

Beilstein J. Org. Chem. 2024, 20, 2739–2775, doi:10.3762/bjoc.20.232

• shuttling (Scheme 53, 51a–k). Furthermore, they established a Cu-catalyzed asymmetric multicomponent reaction for yne-allylic substitution, seamlessly integrating 13C-labeled CO2 into enantiomerically pure products (Scheme 54, 51a, 51c, 51f, 51g). This methodology enabled the synthesis of diverse, high

Synthesis of spiroindolenines through a one-pot multistep process mediated by visible light

• Francesco Gambuti,
• Jacopo Pizzorno,
• Chiara Lambruschini,
• Renata Riva and
• Lisa Moni

Beilstein J. Org. Chem. 2024, 20, 2722–2731, doi:10.3762/bjoc.20.230

• : isocyanide; multicomponent reactions; one-pot reaction; oxidation; spiroindolenine; Ugi reaction; visible light; Introduction Diversity-oriented synthesis (DOS) is a successful approach to biologically active scaffolds directed to create an enormous exploratory space in pharmaceutical hit discovery [1][2

• spiro-heterocyclic indolenines from readily available starting materials under mild conditions and in a diversity-oriented fashion remains desirable. In this contest, oxidative isocyanide-based multicomponent reactions (oxidative IMCRs) can be considered as a convenient tool [15]. Actually, the use of

• an external oxidant in combination with a multicomponent process allows to improve the scope of known MCRs by broadening the diversity and availability of starting materials, or by transforming unstable multicomponent adducts into stable compounds. Following our research interest in developing new

Applications of microscopy and small angle scattering techniques for the characterisation of supramolecular gels

• Connor R. M. MacDonald and
• Emily R. Draper

Beilstein J. Org. Chem. 2024, 20, 2608–2634, doi:10.3762/bjoc.20.220

• is the possibility of using different probes in a multicomponent network. Onogi et al. reported one of the first examples of direct imaging, in situ, of self-sorted supramolecular nanofibres [17]. TEM was able to show that the mixture of gelators gave rise to nanofibres with a morphology similar to

• fluorescent derivatives to visualise a multicomponent system consisting of neutral and charged gelators (NG and CG, respectively), the self-assembly of neutral and charged fibres (NF and CF, respectively) could be visualised over time. CSLM shows the self-assembly proceeds by the initial self-sorting of NGs

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

• [D2]-isonitriles across 8 multicomponent reactions (MCRs) to give diverse arrays of deuterated products. A highlight is the synthesis of several FDA-approved calcium channel blockers, selectively deuterated at a t1/2 limiting metabolic soft-spot via use of [D1]-aldehydes. Surrogate pharmacokinetic

• significantly enhanced metabolic stability, a key parameter for property-based design efforts. Keywords: deuterated aldehydes; deuterated formamides; deuterated isocyanides; DHPs; kinetic isotope effect; Leuckart–Wallach; microsomal stability; multicomponent reactions; Introduction Multicomponent reactions

• isocyanides with a goal to apply them to the field of isocyanide multicomponent reaction (IMCR) chemistry which enables rapid access to arrays of biologically relevant chemotypes or secondary reactions thereafter [14][15]. Many of these chemotypes have populated corporate collections through in-house

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

• gossypii, Tripomastigote Chagas, Tcruzi amastigota, Tcruzi epimastigota, Leishmania amazonensis, and Dengue larvicida. Keywords: dihydropyrimidinone/thione/selenone; green chemistry; in silico biological profile; multicomponent reaction (MCR); thiopyrandioxide; Introduction Multicomponent reactions (MCRs

• of other sulfones of both synthetic and biological importance can be obtained by using the in this work reported efficient, multicomponent and green protocol. We postfunctionalized the typical Biginelli product using Hantzsch-type thiazole chemistry and desulfurization. Assessing drug-likeness, we

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

• reaction of carbon radicals with isocyanides generates imidoyl radicals as key active species [12], and addition and cyclization reactions using these radical species are useful in synthetic organic chemistry, especially multicomponent synthesis. If various functional groups can be appropriately attached

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

• numerous other applications. The search for new and efficient syntheses of these heterocycles is therefore highly relevant. The modular concept of multicomponent reactions (MCR) has paved a broad alley to heteroaromatics. The advantages over traditional methods are the broader scope and increased

• cross-coupling and radical chemistry, as well as providing versatile synthetic approaches to pyrazoles. This overview summarizes the most important MCR syntheses of pyrazoles based on ring-forming sequences in a flashlight fashion. Keywords: cycloaddition; cyclocondensation; multicomponent reaction

• the ecological and economic requirements. This “ideal” synthesis would commence with simple starting materials, progress through safe, catalytic, and quantitative conversions, and culminate in streamlined processes, all conducted within a single reaction vessel. Multicomponent reactions (MCR) closely

Diastereoselective synthesis of highly substituted cyclohexanones and tetrahydrochromene-4-ones via conjugate addition of curcumins to arylidenemalonates

• Deepa Nair,
• Abhishek Tiwari,
• Banamali Laha and
• Irishi N. N. Namboothiri

Beilstein J. Org. Chem. 2024, 20, 2016–2023, doi:10.3762/bjoc.20.177

• , curcumin showcases its Michael donor–acceptor ability in different ways, such as simple Michael addition, [4 + 2] annulation, Michael addition followed by cyclization or one-pot multicomponent reactions (MCR), etc. (Scheme 1) [25]. In 2011, our group reported the reactivity of curcumin as a Michael donor

• cascade triple-Michael (Michael/Michael/oxa-Michael) reaction between curcumins and isatylidene malononitriles, giving spiro-oxindoles in excellent yields and diastereoselectivities [36]. Sahu et al. introduced a one-pot multicomponent reaction of curcumin, arylaldehyde and 2-aminobenzothiazole to

Harnessing the versatility of hydrazones through electrosynthetic oxidative transformations

• Aurélie Claraz

Beilstein J. Org. Chem. 2024, 20, 1988–2004, doi:10.3762/bjoc.20.175

• 2018, Yuan and Yang developed a multicomponent synthesis of 1-aryl and 1,5-disubstitued 1,2,4-triazoles using tetrabutylammonium iodide as electromeditor [49]. 1-Methylene-2-arylhydrazine 52 was in situ generated through the condensation of paraformaldehyde 51 with arylhydrazines 50, while the

Novel oxidative routes to N-arylpyridoindazolium salts

• Oleg A. Levitskiy,
• Yuri K. Grishin and
• Tatiana V. Magdesieva

Beilstein J. Org. Chem. 2024, 20, 1906–1913, doi:10.3762/bjoc.20.166

• was formed. When TEMPO was used as a mediator, S3 was isolated in 10% yield, along with the starting amine (18%) and the tetraarylhydrazine as the main product (50%). In the case of the diarylnitroxide, a complicated multicomponent reaction mixture was formed. Besides the products mentioned above, it

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

• achieved during the last five years, and classifies them into five categories: synthetic methods, building blocks, scaffolds, biological activities and physical properties. Keywords: Groebke–Blackburn–Bienaymé reaction; multicomponent reactions; heterocycles; imidazo[1,2-a]pyridines; isocyanides

• considered old enough to be a key-holder to his family's home, and thus hold a symbolic 'senior' position in the family. Similarly, we can think of the GBB reaction in 2019 as having received the key-holder from the multicomponent reaction family, occupying now a senior position within it. The success

• encountered by the reaction until 2019 was far from being at its peak, in fact during the last 5 years about 70 new original works have been published, and it is therefore worth analyzing what are the new features of this, now, mature reaction. Among isocyanide [2] based multicomponent reactions, the GBB

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

• purification. Thus, it significantly improves existing approaches. Keywords: catalysis; deazaalloxazine; flavin; multicomponent approach; one-pot reaction; Introduction Heterocyclic compounds containing pyrimidine and quinoline motifs in their structure, both of natural and synthetic origin, find a wide set

• 2, as demonstrated in our previous studies with 5-aryldeazaflavins 1 [14][15][16][17][18]. Multicomponent reactions (MCRs) remain a powerful strategy in synthetic organic chemistry due to their widespread applications in drug discovery. By offering significant advantages over conventional, linear

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

• heterylidenepyruvic acid. An optimized synthetic protocol for this transformation was elaborated and a plausible sequence involving the elimination of the 2-chloroacetamide moiety and the conversion of the β-chlorovinyl fragment into a vinyl one is provided. Keywords: convertible isocyanides; multicomponent reaction

• 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

• used as acid components in tandem combinations of various multicomponent processes such as Ugi and Ugi, azido-Ugi and Ugi, Ugi and Passerini, Groebke–Blackburn–Bienaymé and Ugi, etc. [15][17][37][38]. The creation of hybrid molecules by using primary and post-modified Ugi products in combination with

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

• drugs highlighting their importance in the discovery of novel bioactive compounds. However, their synthesis often faces challenges, including complex functionalization and lengthy reaction sequences. Multicomponent reactions, notably the Ugi reaction, have emerged as powerful tools to address these

• kinase inhibitor tinengotinib [8] (Figure 1). Despite the interest of these structures, several drawbacks are typically found during their syntheses, for instance the difficulty in obtaining certain functionalizations or the need of long, elaborated reaction sequences. In recent years, multicomponent

• Ugi reaction. The reduced nucleophilic character of the amino group of the anthranilic acid, indole-2-carboxylic acid, pyrrole-2-carboxylic acid or N-phenylglycine allowed the use of these compounds in this multicomponent reaction without triggering competitive reactions. The presence of an additional

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

• through a one-pot multicomponent reaction (MCR) involving the reaction of substituted 2-aminopyridines, isocyanides, and the cholestanone derivatives 56 [36]. The reactions were conducted in dimethyl sulfoxide at 70 °C, and catalysed by propylphosphonic anhydride (T3P®), providing high yields in all cases

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

• showed biological activity according to the ChEMBL database. Keywords: fused rings; heterocycles; imidazoles; isonitrile; multicomponent reactions; Introduction Multicomponent reactions are widely recognized as a powerful source of biologically active compounds, in particular, for drug discovery

• purposes [1][2][3][4][5][6]. Isonitrile-based multicomponent reactions, such as the Groebke–Blackburn–Bienaymé (GBB) reaction, is an important tool in chemical synthesis providing easy access to a huge compound diversity and complexity [7][8][9][10][11][12][13][14][15][16][17]. Essentially, the GBB

Synthesis of 2-benzyl N-substituted anilines via imine condensation–isoaromatization of (E)-2-arylidene-3-cyclohexenones and primary amines

• Lu Li,
• Na Li,
• Xiao-Tian Mo,
• Ming-Wei Yuan,
• Lin Jiang and
• Ming-Long Yuan

Beilstein J. Org. Chem. 2024, 20, 1468–1475, doi:10.3762/bjoc.20.130

• of anilines through Brønsted acid or transition-metal-promoted conversion of 2-cyclohexanone oximes [15][16][17][18] (Scheme 1, (2)). Moreover, Strauss and co-workers described a green, multicomponent reaction of aromatic aldehydes, 2-cyclohexenone and amines to afford 2-arylmethyl N-substituted