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

• state, in good yield. Keywords: alkynylation; catalysis; cyclization; indoles; iodination; multicomponent reactions; Introduction Indoles and their derived substitution patterns are omnipresent heterocyclic structural motifs in nature [1], many natural products [2][3], drugs [4][5][6][7][8], and dyes

• increasingly interesting [26][27]. In addition, as one-pot processes with a huge exploratory potential and diversity-oriented character, syntheses of indoles by multicomponent reactions have aroused considerable interest [28][29][30]. As part of our program to develop heterocycle syntheses based upon

Acetaldehyde in the Enders triple cascade reaction via acetaldehyde dimethyl acetal

• Alessandro Brusa,
• Debora Iapadre,
• Maria Edith Casacchia,
• Alessio Carioscia,
• Giuliana Giorgianni,
• Giandomenico Magagnano,
• Fabio Pesciaioli and
• Armando Carlone

Beilstein J. Org. Chem. 2023, 19, 1243–1250, doi:10.3762/bjoc.19.92

• Superiore di Pavia, Palazzo del Broletto, Piazza della Vittoria, 15, 27100, Pavia, Italy INSTM, Consorzio Nazionale per la Scienza e Tecnologia dei Materiali, RU L’Aquila, Italy 10.3762/bjoc.19.92 Abstract Asymmetric organocatalyzed multicomponent reactions represent an important toolbox in the field of

• enantioselectivity. Keywords: acetaldehyde; acetaldehyde dimethyl acetal; cascade reaction; multicomponent reaction; organocatalysis; Introduction Multicomponent reactions (MCRs) are chemical processes that involve three or more compounds, in which the product contains all the atoms of the reagents, except for

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

• substituent. A plausible reaction mechanism is proposed to explain the formation of the different spirooxindoles. Keywords: cascade reaction; dimedone; isatin; 3-methyleneoxindole; multicomponent reaction; spirooxindole; Introduction Spirooxindole is one important privileged structural skeleton and is found

• as Michael acceptors, 1,3-dipolarophiles, 1,4-dienophiles and other multiple substrates. They have been widely employed as key component to finish many multicomponent and domino reactions [26][27][28][29][30][31][32][33][34][35]. Recently, the Michael adduct of 3-methyleneoxindoles with various

• 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

• ; multicomponent synthesis; one-pot reaction; trichloroacetic acid; Introduction π-Conjugated porphyrin macrocycles are known for their applications in numerous areas ranging from oxygen transport, photosynthesis, catalysis and medicine [1][2][3]. In the past several years, diverse organic scaffolds have been

• contruction of periphery-modified porphyrinoids [30][31][32][33][34][35][36][37][38][39][40][41], we thought to assemble benzo[f]chromeno[2,3-h]quinoxalinoporphyrins by incorporating porphyrin, quinoxaline and xanthene scaffolds in a single molecular framework using a multicomponent synthetic strategy. The

The unique reactivity of 5,6-unsubstituted 1,4-dihydropyridine in the Huisgen 1,4-diploar cycloaddition and formal [2 + 2] cycloaddition

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

Beilstein J. Org. Chem. 2023, 19, 982–990, doi:10.3762/bjoc.19.73

• as one of the most valuable synthons to construct diverse carbocyclic and heterocyclic systems as well as many open-chain compounds [9][10][11][12][13][14][15]. In recent years, in situ generated Huisgen 1,4-dipoles were also widely employed to design highly efficient multicomponent and domino

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

• –Bienaymé reaction; imidazo[1,2-a]pyridine; isocyanide; multicomponent reaction; peptidomimetic; Ugi reaction; Introduction The use of isocyanide multicomponent reactions (IMCR) to prepare biologically active compounds is one of the most promising tools in modern organic and medicinal chemistry. Therefore

• , isocyanide multicomponent reactions are the way to prepare the necessary drugs "of tomorrow", and the possibility to combine such reactions gives a powerful method to rapidly and qualitatively expand the molecular diversity of biologically active compounds. The following possible combinations of IMCR have

• been described till today: Ugi and Ugi, azido-Ugi and Ugi, Ugi and Passerini, Groebke–Blackburn–Bienaymé (GBB-3CR) and Ugi, GBB-3CR and GBB-3CR, GBB-3CR and Passerini, Orru and Ugi, Orru and Passerini [1] (Scheme 1). However, the issue of whether certain isocyanide multicomponent reactions can be

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

• products. Keywords: amino acids; asymmetric catalysis; multicomponent reaction; palladium catalysis; Petasis reaction; sulfonamides; Introduction α-Amino acids play a crucial role in every aspect of our human life [1]. They are important synthetic intermediates in the chemical industry and used for the

• , e.g., the antiplatelet drug clopidogrel [7] or the β-lactam antibiotic amoxicillin [8] (Figure 1). Therefore, the chemical synthesis of α-aryglycines has received considerable attention. Among the different methods introduced over time, multicomponent reactions utilizing an in situ generated reactive

• imine species provide a very flexible approach to the arylglycine scaffold [2][9]. The Petasis borono-Mannich reaction constitutes a prominent example for such an imine-based multicomponent reaction (Scheme 1a). The reaction of glyoxylic acid, an amine component and an arylboronic acid offers a highly

Strategies in the synthesis of dibenzo[b,f]heteropines

• David I. H. Maier,
• Barend C. B. Bezuidenhoudt and
• Charlene Marais

Beilstein J. Org. Chem. 2023, 19, 700–718, doi:10.3762/bjoc.19.51

• . through a multicomponent reaction system [57]. The authors provided a series of substituted derivatives through Pd/Rh-catalysed domino coupling. The reaction proceeded via a Suzuki coupling, followed by an in situ Buchwald–Hartwig amination. The authors reported moderate to good yields in a series with

• electron-donating and electron-withdrawing groups, as well as N-aryl and N-alkylamines (Scheme 15). Lam et al. [58] expanded on the multicomponent method to form substituted dihydropyridobenzazepines 80–82 wherein vinylpyridines 77 are coupled with boronate ester anilines 78 in a Suzuki reaction

Nucleophile-induced ring contraction in pyrrolo[2,1-c][1,4]benzothiazines: access to pyrrolo[2,1-b][1,3]benzothiazoles

• Ekaterina A. Lystsova,
• Maksim V. Dmitriev,
• Andrey N. Maslivets and
• Ekaterina E. Khramtsova

Beilstein J. Org. Chem. 2023, 19, 646–657, doi:10.3762/bjoc.19.46

• -benzothiazol-2-yl(diazo)acetates (Scheme 1, entry 3) [12], dearomative [3 + 2] cycloaddition reactions of benzothiazoles with cyclopropanes (Scheme 1, entry 4) [13][14][15], multicomponent reactions (MCRs) of benzothiazoles, isocyanides and 2-methylidenemalonates (Scheme 1, entry 5) [16], 1,3-dipolar

Transition-metal-catalyzed domino reactions of strained bicyclic alkenes

• Austin Pounder,
• Eric Neufeld,
• Peter Myler and
• William Tam

Beilstein J. Org. Chem. 2023, 19, 487–540, doi:10.3762/bjoc.19.38

Discrimination of β-cyclodextrin/hazelnut (Corylus avellana L.) oil/flavonoid glycoside and flavonolignan ternary complexes by Fourier-transform infrared spectroscopy coupled with principal component analysis

• Nicoleta G. Hădărugă,
• Gabriela Popescu,
• Dina Gligor (Pane),
• Cristina L. Mitroi,
• Sorin M. Stanciu and
• Daniel Ioan Hădărugă

Beilstein J. Org. Chem. 2023, 19, 380–398, doi:10.3762/bjoc.19.30

• a ternary complex, considering the vegetable oil as a single component, an on-site antioxidant can protect labile FA glycerides by co-nanoencapsulation into a CD cavity. However, it is very difficult to evaluate the way of interaction in such multicomponent systems. There are some studies on the CD

• discrimination of such ternary complexes on the basis of FTIR. The evaluation of the encapsulation competitiveness of such multicomponent mixtures is very challenging (highly hydrophobic FA triglycerides, mono- and diglycerides, free FAs, as well as more hydrophilic flavonoid glycoside, namely hesperidin

An efficient metal-free and catalyst-free C–S/C–O bond-formation strategy: synthesis of pyrazole-conjugated thioamides and amides

• Shubham Sharma,
• Dharmender Singh,
• Sunit Kumar,
• Vaishali,
• Rahul Jamra,
• Naveen Banyal,
• Deepika,
• Chandi C. Malakar and
• Virender Singh

Beilstein J. Org. Chem. 2023, 19, 231–244, doi:10.3762/bjoc.19.22

• ]. Substituted pyrazoles are also of considerable interest because of their synthetic utility as chiral auxiliaries [32], synthetic reagents in multicomponent reactions [33][34], and guanylating agents [35]. The installation of a thioamide functionality has attracted an immense attention in medicinal chemistry

• elemental sulfur under metal and catalyst-free conditions. The salient features of the current protocol may be attributed to the broad substrate scope, commercially available secondary amines, operational simplicity, multicomponent character of the reaction, easy isolation of products, short reaction time

Inclusion complexes of the steroid hormones 17β-estradiol and progesterone with β- and γ-cyclodextrin hosts: syntheses, X-ray structures, thermal analyses and API solubility enhancements

• Alexios I. Vicatos,
• Zakiena Hoossen and
• Mino R. Caira

Beilstein J. Org. Chem. 2022, 18, 1749–1762, doi:10.3762/bjoc.18.184

• of a wide variety of analytical and confirmatory techniques [22][23][24][25][26][27][28] as well as solubility analyses [29][30][31][32][33][34][35][36][37][38] to investigate the physicochemical properties of CD inclusion complexes and multicomponent CD inclusion systems based on numerous

A novel bis-triazole scaffold accessed via two tandem [3 + 2] cycloaddition events including an uncatalyzed, room temperature azide–alkyne click reaction

• Ksenia Malkova,
• Andrey Bubyrev,
• Vasilisa Krivovicheva,
• Dmitry Dar’in,
• Alexander Bunev and
• Mikhail Krasavin

Beilstein J. Org. Chem. 2022, 18, 1636–1641, doi:10.3762/bjoc.18.175

• ] which underwent aromatization with the loss of sulfur dioxide and N-Boc-aniline. The multicomponent character and the fairly large scope of this reaction allows to place pairwise reactive groups in the aldehyde and the amine components, which would set a scene for further elaboration of the product’s

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

• nitrogen-based heterocycles, such as multicomponent reactions (MCRs) [18][19][20][21][22][23], one-pot cascade reactions [24][25][26][27][28][29][30][31][32] as good examples of PASE synthesis. We have reported a series of multicomponent reactions, like Groebke–Blackburn–Bienayme for making BET inhibitors

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

• summarized so that the chemists, researchers, and pharmaceutical industries find its effectiveness in near future for the synthesis of potent, novel, and non-toxic drug molecules. Keywords: functionalization; imidazole N-oxide; mechanistic insights; multicomponent reaction; nucleophilic substitution

• , like cycloaddition, metal-free coupling reactions, three-component or multicomponent reactions etc., which use N-oxide chemistry. In 2021 Timofey D. Moseev and co-workers unfolded an attractive procedure of the coupling reaction between 2H-imidazole 1-oxides and polyphenols under metal-free conditions

• 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

On drug discovery against infectious diseases and academic medicinal chemistry contributions

• Yves L. Janin

Beilstein J. Org. Chem. 2022, 18, 1355–1378, doi:10.3762/bjoc.18.141

• , parallel/combinatorial synthesis, multicomponent chemistry, metal-catalyzed coupling reactions as well as NMR, preparative/analytical liquid chromatography and mass spectrometry). – An improved understanding of molecular pharmacology along with in vitro or in vivo assays to detect various aspects of drug

• stories [238]. To illustrate the long term benefits of the constitution of chemical libraries and as depicted in Figure 2, it is a 2013 screening on SARS-CoV-1 main protease [79][80] of compounds produced by multicomponent chemistry [239][240][241][242], which provided hits such as compounds 4 and 5

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

• a 3-pyrroline-2-one skeleton could be promising drug candidates. Therefore, these nitrogen-containing heterocycles have attracted attention and they have been investigated most intensively via multicomponent reactions (MCRs). This kind of reaction has been proven to be an efficient synthetic pathway

• to obtain structurally complicated and biologically active products containing substantial portions of all starting materials [27]. Recently, polysubstituted 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones have been synthesized via eco-friendly multicomponent reactions of aromatic aldehydes, amines, and

• -acetyl-3-hydroxy-3-pyrroline-2-ones via multicomponent reactions of ethyl 2,4-dioxovalerate with aromatic aldehydes, and aniline in glacial acetic acid. These 2-pyrrolidinone derivatives were then reacted with aliphatic amines in ethanol to obtain a library of 1,4,5-trisubstituted pyrrolidine-2,3-dione

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

• prolonging the reaction time could not increase the yield of the product 3a. Therefore, the functionalized 5-hydroxy-cyclopent-1-ene derivatives can be conveniently prepared in satisfactory yield in very simple reaction conditions. It should be pointed that a similar triethylamine-promoted multicomponent

Morita–Baylis–Hillman reaction of 3-formyl-9H-pyrido[3,4-b]indoles and fluorescence studies of the products

• Nisha Devi and
• Virender Singh

Beilstein J. Org. Chem. 2022, 18, 926–934, doi:10.3762/bjoc.18.92

• -3 position. Our group has previously explored 1-formyl-β-carbolines and 3-formyl-β-carbolines for the generation of β-carboline-imidazo[1,2-a]azine conjugates at C-1 as well as C-3 position by the application of the Groebke–Blackburn–Bienaymé (GBB) multicomponent approach [46][47]. Our research

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

• underwent a [4 + 2] cycloaddition reaction (reaction 1 in Scheme 1) [69][70][71][72][73][74]. This metal-catalyzed one-pot reaction not only combined the advantages of a traditional Diels–Alder reaction and the recently developed multicomponent reactions, but also meets the goal of green and sustainable

• -acetate for the efficient synthesis of diverse spiro tetrahydrocarbazoles. In the presence of CuSO4, the multicomponent reactions of aromatic aldehydes, 2-methylindole and various cyclic dieneophiles such as 3-phenacylideneoxindoles, isatylidene malononitriles and the in situ generated 5-arylidene-1,3

• -known 3,3'-(arylmethylene)bis(2-methylindoles) 6. Conclusion In summary, we have developed a copper-catalyzed multicomponent Diels–Alder reaction of 2-methylindole, aromatic aldehydes and cyclic 1,3-diones through in situ generated dienes and dienophiles under the same conditions. These strategies are

Synthesis of bis-spirocyclic derivatives of 3-azabicyclo[3.1.0]hexane via cyclopropene cycloadditions to the stable azomethine ylide derived from Ruhemann's purple

• Alexander S. Filatov,
• Olesya V. Khoroshilova,
• Anna G. Larina,
• Vitali M. Boitsov and
• Alexander V. Stepakov

Beilstein J. Org. Chem. 2022, 18, 769–780, doi:10.3762/bjoc.18.77

• azomethine ylides generated from primary or secondary α-amino acids and carbonyl compounds such as alloxan, isatin, tryptanthrin, and 11H-indeno[1,2-b]quinoxalin-11-one were performed in a multicomponent fashion [19][20][21][24]. In these reactions, the azomethine ylides generated in situ are highly reactive

• cyclopropenes with azomethine ylides from ninhydrin were also successfully carried out in a multicomponent fashion [23]. Mention should also be made of the recent advances in developing enantioselective approaches to the synthesis of 3-azabicyclo[3.1.0]hexane derivatives. Deng and co-workers reported the first

A trustworthy mechanochemical route to isocyanides

• Francesco Basoccu,
• Federico Cuccu,
• Federico Casti,
• Rita Mocci,
• Claudia Fattuoni and
• Andrea Porcheddu

Beilstein J. Org. Chem. 2022, 18, 732–737, doi:10.3762/bjoc.18.73

• , they are often used in heterocycles formation [8][9], multicomponent strategies [10][11], polymers production [12][13], and metal complexation [14][15]. The molecular structure is composed of an N–C planar triple bond where the nitrogen atom assumes a positive charge due to the fourth bond with a

Inductive heating and flow chemistry – a perfect synergy of emerging enabling technologies

• Conrad Kuhwald,
• Sibel Türkhan and
• Andreas Kirschning

Beilstein J. Org. Chem. 2022, 18, 688–706, doi:10.3762/bjoc.18.70

• electromagnetic field. Other comparisons include the Pd-mediated transfer hydrogenations using ethanol in cyclohexene (Scheme 9, case A), multicomponent reactions (Scheme 9, case B), pericyclic reactions (Scheme 10, case A) and Pd-catalyzed reactions (Scheme 10, case B) [53]. Noteworthy, packed bed fillings used

• for the transfer hydrogenations (Pd) are reusable for several reductions without the need to adjust the overall reaction conditions (flow rate and residence time, temperature etc.). Multicomponent reactions (MCRs) are of particular interest in the field of flow chemistry because this enabling

• consisting of O-allylation and Claisen rearrangement for the continuous synthesis of 2-allyl-4,6-difluorophenol (SiC = silicon carbide) [52]. Continuous flow reactions and comparison with batch reaction (oil bath). A. Pd-catalyzed transfer hydrogenations using ethanol in cyclohexene [53], B. multicomponent

DDQ in mechanochemical C–N coupling reactions

• Shyamal Kanti Bera,
• Rosalin Bhanja and
• Prasenjit Mal

Beilstein J. Org. Chem. 2022, 18, 639–646, doi:10.3762/bjoc.18.64

• ten innovative technologies that IUPAC recognized [7]. To perform organic transformations in a greener way, the mechanochemical methods can also be considered as one of the alternative approaches [8][9][10]. The one-pot multicomponent synthesis of important heterocycles can be the state of art