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 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

• limitation of the photoinduced palladium-catalyzed carboamination reactions and the radical-mediated difunctionalization of alkenes with diazo compounds. We envisioned an interesting MCR strategy with mild conditions to access unsaturated γ- and ε-AA derivatives via a π-allyl Pd radical-polar crossover

• started our studies with the palladium-catalyzed MCR of ethyl diazoacetate (1a), 1,3-butadiene (2a), and 1-phenylpiperazine (3a) in the presence of 5 mol % Pd(OAc)2 and 10 mol % Xantphos as ligand. To our delight, after irradiation with blue LED light in dimethylformamide (DMF) for 12 h at room

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

• a given reaction makes it possible to very quickly not only to insert important pharmacophoric fragments, but also to create a wide chemical space for the search for lead structures to solve problems of medicinal chemistry. Examples of drugs synthesized by MCR clearly demonstrate the immense

• the MCR repertoire. Therefore, an urgent problem is to synthesize structurally complex compounds, molecular hybrids containing pharmacophoric and peptidomimetic fragments, to explore their biological activity. The possibility of inserting an unsubstituted imidazo[1,2-a]pyridine fragment into the

Mechanochemical halogenation of unsymmetrically substituted azobenzenes

• Dajana Barišić,
• Mario Pajić,
• Ivan Halasz,
• Darko Babić and
• Manda Ćurić

Beilstein J. Org. Chem. 2022, 18, 680–687, doi:10.3762/bjoc.18.69

• -dimensional (2D) plot of the time-resolved Raman monitoring of NG of L2 (0.50 mmol) with NBS (0.60 mmol) and SiO2 (250 mg). b) Reaction profile derived from multivariate curve analysis - alternating least squares fitting (MCR-ALS analysis). c) Extracted Raman spectra of species observed during Raman

In-depth characterization of self-healing polymers based on π–π interactions

• Josefine Meurer,
• Julian Hniopek,
• Johannes Ahner,
• Michael Schmitt,
• Jürgen Popp,
• Stefan Zechel,
• Kalina Peneva and
• Martin D. Hager

Beilstein J. Org. Chem. 2021, 17, 2496–2504, doi:10.3762/bjoc.17.166

• polymers. All dynamic mechanical analysis (DMA) experiments were performed on a MCR 301 rheometer (SN80386674) from Anton Paar (Graz, Austria) using a convection temperature device CTD 450 which covers a broad temperature range of −100 to 450 °C. For measurements and the export of data the Rheocompas

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

Microwave-assisted multicomponent reactions in heterocyclic chemistry and mechanistic aspects

• Shivani Gulati,
• Stephy Elza John and
• Nagula Shankaraiah

Beilstein J. Org. Chem. 2021, 17, 819–865, doi:10.3762/bjoc.17.71

• economic perspective due to increased amounts of waste generation, toxic solvents, and no real-time control of pollution generated, etc. [4]. Therefore, in this connection, the multicomponent reaction (MCR) is one such approach where three or more reactants combine to form a single product retaining the

• atorvastatin, a potent HMG-CoA reductase inhibitor. Dömling and co-workers efficiently demonstrated an Ugi-based MCR approach towards the synthesis of atorvastatin in four steps ruling out the lengthy seven step protocol, and paving a rapid entry to the drug discovery market [12]. Alternatively, microwave

• [29][30], focusing on the synthetic aspect of five, six, seven and dicyclic structures. Later in 2013, Gupta et al. compiled reports of microwave-assisted cross-coupling, MCR with few cycloaddition reactions [31]. During the course of writing this review, we realized the very presence of two reviews

Dirhamnolipid ester – formation of reverse wormlike micelles in a binary (primerless) system

• David Liese,
• Hans Henning Wenk,
• Xin Lu,
• Jochen Kleinen and
• Gebhard Haberhauer

Beilstein J. Org. Chem. 2020, 16, 2820–2830, doi:10.3762/bjoc.16.232

• freshly cleaned mica surface (Plano) and waiting for 12 h. The AFM data were analyzed using the Gwyddion-2.53 software. Rheological measurements The rheological data were obtained using an Anton Paar MCR 301 rheometer equipped with a cylindrical geometry (CC27 – measuring unit). The temperature was

Controlling the stereochemistry in 2-oxo-aldehyde-derived Ugi adducts through the cinchona alkaloid-promoted electrophilic fluorination

• Yuqing Wang,
• Gaigai Wang,
• Anatoly A. Peshkov,
• Ruwei Yao,
• Muhammad Hasan,
• Manzoor Zaman,
• Chao Liu,
• Stepan Kashtanov,
• Olga P. Pereshivko and
• Vsevolod A. Peshkov

Beilstein J. Org. Chem. 2020, 16, 1963–1973, doi:10.3762/bjoc.16.163

• -component Passerini [19][20][21][22] and four-component Ugi [23][24] reactions that rely on the ability of organic isocyanides to participate in the nucleophilic attack onto the carbonyl or imine group are among the most studied MCRs. Accordingly, a wide range of post-MCR transformations have been

Natural dolomitic limestone-catalyzed synthesis of benzimidazoles, dihydropyrimidinones, and highly substituted pyridines under ultrasound irradiation

• Kumar Godugu,
• Venkata Divya Sri Yadala,
• Mohammad Khaja Mohinuddin Pinjari,
• Trivikram Reddy Gundala,
• Lakshmi Reddy Sanapareddy and
• Chinna Gangi Reddy Nallagondu

Beilstein J. Org. Chem. 2020, 16, 1881–1900, doi:10.3762/bjoc.16.156

• Biginelli reaction is a renowned and tunable MCR to synthesize the pharmacologically active 3,4-dihydropyrimidin-2-(1H)-ones (DHPMs, Biginelli products) [31]. These compounds occupy an important position in the fields of natural products and synthetic organic chemistry owing to their potential

Synthesis of pyrrolidinedione-fused hexahydropyrrolo[2,1-a]isoquinolines via three-component [3 + 2] cycloaddition followed by one-pot N-allylation and intramolecular Heck reactions

• Xiaoming Ma,
• Suzhi Meng,
• Xiaofeng Zhang,
• Qiang Zhang,
• Shenghu Yan,
• Yue Zhang and
• Wei Zhang

Beilstein J. Org. Chem. 2020, 16, 1225–1233, doi:10.3762/bjoc.16.106

• , triazolobenzodiazepines and tetrahydrochromeno[3,4-b]pyrrolizine (Scheme 2) [30][31][32][33][34][35][36][37][38][39]. Many of these scaffolds were synthesized through the combination of MCR and one-pot synthesis. A literature search indicated that a [3 + 2] cycloaddition-initiated method has also been used for the

Ultrasonic-assisted unusual four-component synthesis of 7-azolylamino-4,5,6,7-tetrahydroazolo[1,5-a]pyrimidines

• Yana I. Sakhno,
• Maryna V. Murlykina,
• Oleksandr I. Zbruyev,
• Anton V. Kozyryev,
• Svetlana V. Shishkina,
• Dmytro Sysoiev,
• Vladimir I. Musatov,
• Sergey M. Desenko and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2020, 16, 281–289, doi:10.3762/bjoc.16.27

• heterocycles of the types V–X (Scheme 2). It should be noted that such a type of MCR, giving previously undescribed 7-azolylamino-substituted tetrahydroazolopyrimidines, is reported for the first time herein. Thus, using 2 equivalents of 5-aminopyrazole-4-carbonitrile 1a/b in MCRs with aromatic aldehydes 2a–c

Multicomponent reactions III

• Thomas J. J. Müller

Beilstein J. Org. Chem. 2019, 15, 1974–1975, doi:10.3762/bjoc.15.192

• Thomas J. J. Muller Heinrich-Heine Universität Düsseldorf, Institut für Organische Chemie und Makromolekulare Chemie, Universitätsstraße 1, D-40225 Düsseldorf, Germany 10.3762/bjoc.15.192 Keywords: MCR; multicomponent reactions; In times of steadily increasing relevance of sustainability and

• of synthetic efficiency. Biologically and pharmaceutically relevant scaffolds are likewise tackled as chromophores, methodology development and conceptual design of macro(hetero)cycles go hand in hand with MCR-based heterocyclic chemistry. As in the previous thematic issues also this issue opens the

• actual field of MCR chemistry to a broader interested community by five reviews on MCR based concepts. As the guest editor of this thematic issue in the Beilstein Journal of Organic Chemistry I cordially thank all authors, dedicated and excellent scientists, for sharing their exciting findings and, in

Recent advances on the transition-metal-catalyzed synthesis of imidazopyridines: an updated coverage

• Gagandeep Kour Reen,
• Ashok Kumar and
• Pratibha Sharma

Beilstein J. Org. Chem. 2019, 15, 1612–1704, doi:10.3762/bjoc.15.165

• well exploited by Wen and Lu for a one-pot MCR for the synthesis of cyanoimidazo[1,2-a]pyridines 129 [128]. A variety of copper salts including CuI, CuBr, CuCl, Cu(OAc)2 and Cu2O were tried but only CuI gave some appreciable results. The product yield was improved by using N-methyl-2-pyrrolidone (NMP

Efficiency Eff_syn of complex syntheses as multicomponent reactions, its algorithm and calculations based on concrete criteria

• Heiner Eckert

Beilstein J. Org. Chem. 2019, 15, 1425–1433, doi:10.3762/bjoc.15.142

• synthesis steps yn (Equation 1). An extreme example for the impact of the overall yield is the tropinone synthesis by Willstätter (yoa = 0.75%) [7][8] compared to the Robinson–Schöpf synthesis (yoa = 90%) [9][10]) using a double Mannich reaction, a multicomponent reaction (MCR) [11][12][13]. The Mannich-3CR

• = 0.75%, N = 20, Effsyn = 0.038% [7][8]), compared with the Robinson–Schöpf synthesis (yoa = 90%, N = 1, Effsyn = 90% [9][10]). The latter MCR is therefore 2368 times (!) more efficient than the original Willstätter synthesis. Further examples, including the comprehensive synthesis of complex natural

• serious issue, for example, if one simply assumes that 4 reactions with 97% yield each are better than a 4CR with 90% yield. The fact that the outlay (fixed costs) during MCR drop by a massive 75% – compared to the 4 separate reactions – is often ignored. And those 4 separate reactions actually have an

Doebner-type pyrazolopyridine carboxylic acids in an Ugi four-component reaction

• Maryna V. Murlykina,
• Oleksandr V. Kolomiets,
• Maryna M. Kornet,
• Yana I. Sakhno,
• Sergey M. Desenko,
• Victoriya V. Dyakonenko,
• Svetlana V. Shishkina,
• Oleksandr A. Brazhko,
• Vladimir I. Musatov,
• Alexander V. Tsygankov,
• Erik V. Van der Eycken and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2019, 15, 1281–1288, doi:10.3762/bjoc.15.126

• skeleton can be achieved by MCR. Several publications illustrated this principle: synthesis of heterocyclic acids [26][43] or enols [44] in a first multicomponent step, followed by subjecting them to a subsequent Ugi process, thus, applying the MCR2 approach (group IV, Scheme 1). Actually, there was no

• diversity-oriented synthetic (DOS) approaches. First, by using CBD and MCR strategies in a Doebner-type reaction we synthesized pyrazolopyridine carboxylic acids which were subsequently applied in the Ugi reaction, thus, combining two multicomponent procedures. Results and Discussion As mentioned above, the

Steroid diversification by multicomponent reactions

• Leslie Reguera,
• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Daniel G. Rivera

Beilstein J. Org. Chem. 2019, 15, 1236–1256, doi:10.3762/bjoc.15.121

• as the conjugation of steroids to amino acids, peptides and carbohydrates. We demonstrate that steroids are available with almost all types of MCR reactive functionalities, e.g., carbonyl, carboxylic acid, alkyne, amine, isocyanide, boronic acid, etc., and that steroids are suitable starting

• steroid biological functions. Such oxygenated and alkene groups represent the entrance door for subsequent synthetic modifications, including the incorporation of MCR reactive functionalities. In the last two decades, MCRs have emerged as effective tools for the rapid derivatization of steroidal skeletons

• MCR is due to the ring contraction of the 7-membered ring cyclic intermediate by transannular acyl transfer, which leads to the β-lactam derivative. Despite the chiral nature of the steroidal substrate, no significant stereoselective induction was observed, probably because the 7-membered ring

Unexpected polymorphism during a catalyzed mechanochemical Knoevenagel condensation

• Sebastian Haferkamp,
• Andrea Paul,
• Adam A. L. Michalchuk and
• Franziska Emmerling

Beilstein J. Org. Chem. 2019, 15, 1141–1148, doi:10.3762/bjoc.15.110

• clearly separated compounds, the Raman spectra suggest the parallel presence of 1a, m3a and t3a. Multivariate curve resolution (MCR) aims to extract information on the pure compounds [27]. In our case, the time series of Raman spectra may be considered as a superposition of all compounds present at a

• certain time of the reaction. In contrast to PCA, where only the variance of data is evaluated, in MCR chemical knowledge on the number of involved compounds, some constraints such as non-negativity are included. As a result, relative component concentrations as a function of time and the corresponding

• spectra can be evaluated. In this case, four spectral compounds were used in form of an initial guess for MCR, namely fluorinated benzaldehyde, PMMA (background from the milling jar), monoclinic and triclinic fluorobenzylidene malonodinitrile. MCR analysis without an initial guess resulted in models with

Synthesis of (macro)heterocycles by consecutive/repetitive isocyanide-based multicomponent reactions

• Angélica de Fátima S. Barreto and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2019, 15, 906–930, doi:10.3762/bjoc.15.88

• -amino cyanides, reported in 1850, is considered to be the first example of an MCR [13]. Since then, several different MCRs have been reported, including the well documented isocyanide-based MCRs (IMCRs). These particular MCRs take advantage of the unique properties of the isocyanide functional group

• a fast and reproducible synthesis of more complex products. It can be foreseen that this useful strategy will continue to be applied to the synthesis of molecules with even more structural diversity. Comparison between a normal sequential reaction and an MCR. Synthesis of tetrazoles and

Catalyst-free assembly of giant tris(heteroaryl)methanes: synthesis of novel pharmacophoric triads and model sterically crowded tris(heteroaryl/aryl)methyl cation salts

• Rodrigo Abonia,
• Luisa F. Gutiérrez,
• Braulio Insuasty,
• Jairo Quiroga,
• Kenneth K. Laali,
• Chunqing Zhao,
• Gabriela L. Borosky,
• Samantha M. Horwitz and
• Scott D. Bunge

Beilstein J. Org. Chem. 2019, 15, 642–654, doi:10.3762/bjoc.15.60

• of hydroxycoumarins 7{1–4} (Scheme 5) was chosen as the second source of nucleophilic partners for elaboration in our MCR experiments. With these building blocks at hand, an initial three-component assay was performed starting with indole 1{1} (1.0 equiv), quinoline aldehyde 6{1} (1.0 equiv) and

• in the MCR experiments. Exploratory reaction leading to isolation of products 8{1,1,1} and 9{1,1,1}. Chemset of further aldehydes 6{8–10} for elaboration in the MCR experiments. Synthesis of crowed (Het12Het2/Ar2)C+PF6− salts 10. Optimization of the reaction conditions for the three-component

Selectivity in multiple multicomponent reactions: types and synthetic applications

• Ouldouz Ghashghaei,
• Francesca Seghetti and
• Rodolfo Lavilla

Beilstein J. Org. Chem. 2019, 15, 521–534, doi:10.3762/bjoc.15.46

• reactants of a kind, displaying different reactivities, are used, their relative nucleophilicities/electrophilicities [7] may lead, in principle, to biased mixtures. At the same time, this innate selectivity is not straightforward, as the most reactive combination would promote a fast first MCR, and likely

• the following MCR processes may also involve this same set [8]. Experimental findings showing complex mixtures, although far from statistical product ratios, are the usual outcome of MMCRs involving several reactants of one kind. There are, however, cases where this indiscriminate reactivity is

• synthetically useful: MCR polymerizations, typically involving two doubly functionalized reactants, which yield macromolecular adducts [9][10][11]. In these processes, the reactivity of the equivalent FGs is nearly identical in the reactants and in the oligo/polymeric intermediates, as they are usually

Design of indole- and MCR-based macrocycles as p53-MDM2 antagonists

• Constantinos G. Neochoritis,
• Maryam Kazemi Miraki,
• Eman M. M. Abdelraheem,
• Ewa Surmiak,
• Tryfon Zarganes-Tzitzikas,
• Beata Łabuzek,
• Tad A. Holak and
• Alexander Dömling

Beilstein J. Org. Chem. 2019, 15, 513–520, doi:10.3762/bjoc.15.45

• perturbations plotted onto the structure of MDM2 (wheat); orange (despairing – indicating stronger binding), light orange (>0.1 ppm), yellow (0.05–0.1 ppm). Residues which disappear upon titration experiment are labeled on the Mdm2 surface. MCR approach to indole-based macrocycles; a more effective strategy is

Thiol-free chemoenzymatic synthesis of β-ketosulfides

• Adrián A. Heredia,
• Martín G. López-Vidal,
• Marcela Kurina-Sanz,
• Fabricio R. Bisogno and
• Alicia B. Peñéñory

Beilstein J. Org. Chem. 2019, 15, 378–387, doi:10.3762/bjoc.15.34

• benign conditions is highly desirable. Based on our previously developed MCR [43] for the synthesis of enol esters with sulfur-containing substituents, we envisaged a two-step methodology starting from an α-haloketone, a thiocarboxylate and an alkyl (pseudo)halide (Scheme 2). Thus, once the enolester is

• hydrolysis and the MCR reaction were optimised, we investigated the robustness of this protocol for the one-pot two-step preparation of different β-ketosulfide departing from the corresponding α-haloacetophenone at higher scale, as shown in Scheme 3, and isolated the products in good yields. As depicted in

• . The combination of the MCR and the lipase-catalysed hydrolysis can be carried out a in one-pot two-step fashion and afford the desired products in high isolated yield and high selectivity. A gram-scale experiment exemplifies the robustness of this methodology that can efficiently be employed in the

Thermophilic phosphoribosyltransferases Thermus thermophilus HB27 in nucleotide synthesis

• Ilja V. Fateev,
• Ekaterina V. Sinitsina,
• Aiguzel U. Bikanasova,
• Maria A. Kostromina,
• Elena S. Tuzova,
• Larisa V. Esipova,
• Tatiana I. Muravyova,
• Alexei L. Kayushin,
• Irina D. Konstantinova and
• Roman S. Esipov

Beilstein J. Org. Chem. 2018, 14, 3098–3105, doi:10.3762/bjoc.14.289

• (CamR) / fhuA2 lacZ::T7 gene1 [lon] ompT ahpC gal λatt::pNEB3-r1-cDsbC (SpecR, lacIq) ΔtrxB sulA11 R(mcr-73::miniTn10--TetS)2 [dcm] R(zgb-210::Tn10 --TetS) endA1 Δgor ∆(mcrC-mrr)114::IS10] New England Biolabs (USA, MA), b) E.coli BL21(DE3) fhuA2 [lon] ompT gal (λ DE3) [dcm] ΔhsdS λ DE3 = λ sBamHIo

Mn-mediated sequential three-component domino Knoevenagel/cyclization/Michael addition/oxidative cyclization reaction towards annulated imidazo[1,2-a]pyridines

• Olga A. Storozhenko,
• Alexey A. Festa,
• Delphine R. Bella Ndoutoume,
• Alexander V. Aksenov,
• Alexey V. Varlamov and
• Leonid G. Voskressensky

Beilstein J. Org. Chem. 2018, 14, 3078–3087, doi:10.3762/bjoc.14.287

• , complicated by the need of an oxidant to fulfil the final aromatization. Following our interest in domino [42][43] and MCR chemistry [44][45] and taking an advantage of 2-iminochromene reactivity, herein we report a sequential three-component domino reaction of salicylaldehydes 2 and N-(cyanomethyl)pyridinium

One-pot syntheses of blue-luminescent 4-aryl-1H-benzo[f]isoindole-1,3(2H)-diones by T3P^® activation of 3-arylpropiolic acids

• Melanie Denißen,
• Alexander Kraus,
• Guido J. Reiss and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2017, 13, 2340–2351, doi:10.3762/bjoc.13.231

• ] where fundamental organic reactions are combined in one-pot sequences [25][26][27][28][29]. Multicomponent reactions (MCR) take advantage of creating and transforming reactive functionalities in the same reaction vessel without intermediary work-up [30]. Syntheses of functional chromophores by MCR [31

• ][32] have indeed become a powerful tool in synthetic chemistry for convergently approaching substance libraries of luminescent molecules. In particular, blue-emissive heterocyclic chromophores, intensively requested in illumination research, are equally accessible by MCR strategies [33]. Cyclic imides