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

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

• been known as indispensable building blocks in modern organic chemistry. Many isocyanide-based carbon–carbon and carbon–heteroatom bond forming reactions have been developed in fascinating ways over the past decades [4][5][6]. The famous multicomponent reactions such as Passerini reaction, Ugi reaction

• generated by addition reaction of isocyanides to electron-deficient alkynes, which were sequentially trapped by various electrophiles and nucleophiles to give versatile acyclic and heterocyclic compounds [15][16][17][18][19][20][21][22][23][24][25][26]. In recent years, many multicomponent reactions based

• synthetic protocols and in continuation of our aim to develop isocyanide-based multicomponent reactions for construction of diverse nitrogen-containing heterocyclic compounds [47][48][49][50][51][52][53][54][55][56][57][58], herein we wish to report the mutlicomponent reaction of alkyl isocyanides, dialkyl

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

• intermediates through selective FeCl3-catalyzed intramolecular N-annulation. Keywords: α-aminoacetals; fused-ring systems; heterocyclic hemiaminals; heterocyclic N,O-aminals; multicomponent reactions; Introduction N-Fused heterocycles are ubiquitous within crucial molecules, including biologically active

• of diversity-oriented synthesis of N-heterocycles via sequential multicomponent approaches, we envisioned that α-aminoacetals could act as bifunctional building blocks along with 1,2-diaza-1,3-diene (DD) coupling partners [22][23], in obtaining functionalized N-aminohydrazones as key intermediates

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

• /H2O (9:1). The low reduction potential of singlet-excited Aza-H (PC•+/PC* = –1.87 V vs SCE) led us to propose that the singlet-excited photocatalyst is oxidized by 4-cyanopyridine (4CP) (4CP/4CP•− = −1.81 V vs SCE) as the first step in this multicomponent reaction (Scheme 1, left). The oxidized

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

• aspects. Multicomponent reactions (MCRs) are remarkable tools which demonstrated great potential for more sustainable production of active pharmaceutical ingredients (API’s). These flexible and versatile one-pot transformations in which three or more reagents are combined to access a new complex scaffold

Manganese-catalyzed C–C and C–N bond formation with alcohols via borrowing hydrogen or hydrogen auto-transfer

• Mohd Farhan Ansari,
• Atul Kumar Maurya,
• Abhishek Kumar and
• Saravanakumar Elangovan

Beilstein J. Org. Chem. 2024, 20, 1111–1166, doi:10.3762/bjoc.20.98

• the corresponding indole (98% yield) at 100 °C for 48 h [34]. One year later, Kempe and co-workers showed the multicomponent synthesis of pyrimidines from amidines and alcohols using Mn4 via C–C and C–N bond formations [94]. Various amidines were selectively coupled with different alcohols using 2 mol

• pyrrole synthesis under the same reaction conditions. In 2019, Rueping, El-Sepelgy and co-workers achieved the sustainable multicomponent synthesis of pyrroles from readily available substrates catalyzed by manganese-pincer complex Mn12 [96]. The use of 2 mol % of Mn12 in combination with a catalytic

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

• introduced from their nitrile precursors through late-stage functionalization. In this work, we propose a novel strategy involving the use of diversely protected, unprecedented tetrazole aldehydes as building blocks. This approach facilitates the incorporation of the tetrazole group into multicomponent

• showcase the versatility of these new tetrazole building blocks by integrating the tetrazole moiety into various multicomponent reactions (MCRs), which are already significantly employed in drug discovery. This technique represents a unique and complementary method to existing tetrazole synthesis processes

• . It aims to meet the growing demand for tetrazole-based compound libraries and novel scaffolds, which are challenging to synthesize through other methods. Keywords: building blocks; green chemistry; multicomponent reaction; Passerini tetrazole reaction; tetrazole; Ugi reaction; Introduction The

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

• and Heck cyclization reactions. The integration of the multicomponent and post-condensation reactions in one-pot maximizes the pot-, atom-, and step-economy (PASE). Keywords: Heck reaction; one-pot; tetrahydroisoquinoline; tetrazolo-pyrazino[2,1-a]isoquinolin-6(5H)-ones; tetrazole; Ugi-azide reaction

• to use 1 mmol of 5a with 10 mol % Pd(OAc)2 and 20 mol % PPh3, 2 equiv of K2CO3 in 3 mL CH3CN at 105 °C for 3 h under N2 atmosphere which afforded product 6a in 70% yield (Table 1, entry 3). The combination of an initial multicomponent reaction with post-condensation reactions in one-pot is a good

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

• . Multicomponent reactions (MCRs) by virtue of high efficiency for the construction of complex chemicals, have shown the superiority in high step and atom economy in organic synthesis [25][26][27]. Over the past two decades, our group and others have developed a transition-metal-catalyzed MCR strategy involving

• diverse derivatizations further highlight the practical utility of this MCR protocol. Background (a and b) and proposed carboamination MCR with diazo esters (c). a) Selected bioactive γ- and ε-amino acid derivatives. b) Multicomponent reaction strategies with diazo compounds. c) Our design: a radical MCR

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

• ][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

• formation, essential for the GBB-3CR mechanism. Moderate yields were obtained with the use of 2-aminothiazole derivatives (4yy–aaa). These lower yields did not change using MeOH as a solvent or increasing the amount of HPW used. The use of aliphatic aldehydes in the GBB multicomponent reaction for the

• synthesis of imidazo[1,2-a]pyridines is not as usual, given that Schiff bases from aliphatic aldehydes are found to be less stable and readily polymerize in comparison to stable Schiff bases of aromatic aldehydes. Nonetheless, our protocol for the HPW-catalyzed GBB multicomponent reaction proved to be very

Entry to new spiroheterocycles via tandem Rh(II)-catalyzed O–H insertion/base-promoted cyclization involving diazoarylidene succinimides

• Alexander Yanovich,
• Anastasia Vepreva,
• Ksenia Malkova,
• Grigory Kantin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2024, 20, 561–569, doi:10.3762/bjoc.20.48

• acid (17), the formation of a complex mixture was observed, the main component of which turned out to be phthalide (19). The use of 2-bromoethanol (20) gave a similar result – compound 21 was transformed under the action of DBU into a multicomponent mixture of unidentifiable compounds. Judging from the

• consequence, the significantly greater nucleophilicity of the nearest α-carbon atom. When an attempt was made to generate an anion from compound 25 under the action of a stronger base (t-BuOK/THF, 0 °C) in order to effect spirocyclization, only the formation of a complex multicomponent mixture was observed

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

• ; multi-step reactions; multicomponent reactions; one-pot synthesis; organocatalysis; tandem reactions; transition-metal-catalysis; The synthesis of pharmaceutical ingredients, natural products, agrochemicals, ligand systems, and building blocks for materials science has reached a high level of

• . Zhang, Ma, and W. Zhang reflects the state of the art in the α-amino acid-based [3 + 2] cycloaddition reactions of N–H-type azomethine ylides in multicomponent, one-pot, and stepwise reactions for the synthesis of diverse bioactive heterocyclic compounds and natural products [9]. Computational studies

Photochromic derivatives of indigo: historical overview of development, challenges and applications

• Gökhan Kaplan,
• Zeynel Seferoğlu and
• Daria V. Berdnikova

Beilstein J. Org. Chem. 2024, 20, 228–242, doi:10.3762/bjoc.20.23

• using heme-containing oxygenases (cytochrome P450 monooxygenases, styrene/indole monooxygenases, flavin-containing monooxygenases, Baeyer–Villiger monooxygenases, etc.) or non-heme iron oxygenases (naphthalene dioxygenases, multicomponent phenol hydroxylases) [5][6][7][8]. The synthetic approaches

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

• IKERBASQUE, Basque Foundation for Science, Alameda Urquijo 36-5, Plaza Bizkaia, 48011 Bilbao, Spain 10.3762/bjoc.20.21 Abstract An efficient multicomponent reaction of newly designed β-trifluoromethyl β-diazo esters, acetonitrile, and carboxylic acids via an interrupted esterification process under copper

• General procedure for copper-catalyzed multicomponent reaction of β-amino esters Into a flask were added amines 1 (0.4 mmol), acids 3 (0.1 mmol), CuI (20 mol %), and CH3CN (2 mL). Then, the mixture was stirred at room temperature under a nitrogen atmosphere and t-BuONO (0.4 mmol) was added dropwise

Metal-catalyzed coupling/carbonylative cyclizations for accessing dibenzodiazepinones: an expedient route to clozapine and other drugs

• Amina Moutayakine and
• Anthony J. Burke

Beilstein J. Org. Chem. 2024, 20, 193–204, doi:10.3762/bjoc.20.19

• been used in a multitude of reactions [16][17]. The present approach enables the formation of two C–N bonds along with a C–C bond and provides a good alternative to previously reported strategies, as it enables the formation of these structures in a multicomponent fashion in the presence of a CO

Perspectives on push–pull chromophores derived from click-type [2 + 2] cycloaddition–retroelectrocyclization reactions of electron-rich alkynes and electron-deficient alkenes

• Michio Yamada

Beilstein J. Org. Chem. 2024, 20, 125–154, doi:10.3762/bjoc.20.13

• CS-state formation for 60 depending on the solvent, was also observed for excitation at 458 nm corresponding to the ICT band. A series of multicomponent systems consisting of anilino-substituted TCBD or PCBD coupled with zinc porphyrins (ZnPs) were synthesized, and their photophysical properties were

Effects of the aldehyde-derived ring substituent on the properties of two new bioinspired trimethoxybenzoylhydrazones: methyl vs nitro groups

• Dayanne Martins,
• Roberta Lamosa,
• Talis Uelisson da Silva,
• Carolina B. P. Ligiero,
• Sérgio de Paula Machado,
• Daphne S. Cukierman and
• Nicolás A. Rey

Beilstein J. Org. Chem. 2023, 19, 1713–1727, doi:10.3762/bjoc.19.125

• stability in aqueous medium. Thus, the electronic absorption spectra of hdz-CH3 and hdz-NO2 were recorded in a 10% DMSO/buffer solution (pH 7.4) immediately after preparation and at regular time intervals. The UV–vis spectrum of hdz-CH3 between 250 and 450 nm (Figure 6A) shows two multicomponent absorptions

• observed for hdz-CH3, with a multicomponent band and a shoulder centered, correspondingly, at 300 and 343 nm (Figure 7B). We propose that the latter is exclusively related to a broad gaussian component calculated at 331 nm, which was assigned to a protonated NBA transition through comparison with the

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

• -type AMYs in multicomponent, one-pot, and stepwise reactions for the synthesis of diverse heterocycles related to some bioactive compounds and natural products. Keywords: [3 + 2] cycloaddition; decarboxylation; 1,3-dipolar; double cycloaddition; one-pot synthesis; multicomponent reaction; semi

• aldehydes and alkenes. The first cycloaddition products 3c or 3d can also be used as intermediates for other transformations to synthesize novel heterocyclic rings via multicomponent, one-pot, and stepwise synthesis [63][64]. Presented in the following sections is our work on the development of amino acid

• minor diastereomeric product through an exo-cycloaddition. One-pot synthesis of triazolobenzodiazepines Other than the multicomponent double cycloaddition reactions shown in the last section, we also utilized the first cycloaddition products for post-condensation reactions to generate new heterocyclic

Morpholine-mediated defluorinative cycloaddition of gem-difluoroalkenes and organic azides

• Tzu-Yu Huang,
• Mario Djugovski,
• Sweta Adhikari,
• Destinee L. Manning and
• Sudeshna Roy

Beilstein J. Org. Chem. 2023, 19, 1545–1554, doi:10.3762/bjoc.19.111

• generated via an azide–alkyne cycloaddition or a multicomponent reaction between carbonyls and azides [17]. α-Trifluoromethyl (α-CF3) carbonyls were recently utilized to generate NH-1,2,3-triazoles and fully substituted 1,2,3-triazoles [28][29]. However, there are no reports of a formal [3 + 2

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

• HCl-promoted 1,2-thiofunctionalization of aromatic alkenes. Coupling reaction of diazo compounds with N-sulfenylsuccinimides. Multicomponent reactions of disulfides with isocyanides and other nucleophiles. α-Sulfenylation and β-sulfenylation of α,β-unsaturated carbonyl compounds.

α-(Aminomethyl)acrylates as acceptors in radical–polar crossover 1,4-additions of dialkylzincs: insights into enolate formation and trapping

• Angel Palillero-Cisneros,
• Paola G. Gordillo-Guerra,
• Fernando García-Alvarez,
• Olivier Jackowski,
• Franck Ferreira,
• Fabrice Chemla,
• Joel L. Terán and
• Alejandro Perez-Luna

Beilstein J. Org. Chem. 2023, 19, 1443–1451, doi:10.3762/bjoc.19.103

• enolate with electrophiles in protocols wherein all the reactive partners can be introduced from the start, given that dialkylzinc reagents offer a large functional group tolerance; and 3) the radical character of the process allows for the use of alkyl iodides as alkyl source in multicomponent reactions