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

β-Cyclodextrin- and adamantyl-substituted poly(acrylate) self-assembling aqueous networks designed for controlled complexation and release of small molecules

• Liang Yan,
• Duc-Truc Pham,
• Philip Clements,
• Stephen F. Lincoln,
• Jie Wang,
• Xuhong Guo and
• Christopher J. Easton

Beilstein J. Org. Chem. 2017, 13, 1879–1892, doi:10.3762/bjoc.13.183

• for dye complexation, K11, and the corresponding ΔH and TΔS were derived from the UV–vis data as described in the Results and Discussion section. Rheology Rheological measurements were carried out with a Physica MCR 501 (Anton Parr GmbH) stress-controlled rheometer with a 25 mm cone and plate geometry

A practical and efficient approach to imidazo[1,2-a]pyridine-fused isoquinolines through the post-GBB transformation strategy

• Taofeng Shao,
• Zhiming Gong,
• Tianyi Su,
• Wei Hao and
• Chao Che

Beilstein J. Org. Chem. 2017, 13, 817–824, doi:10.3762/bjoc.13.82

• attracted broad attention in the field of organic synthesis [40][41][42]. In order to expand the structural diversity of GBB products, further investigation of GBB-based synthetic strategies remains highly desirable. In continuation of our research on the development of MCR strategies for the rapid library

• isoquinoline-containing derivatives. GBB-based MCR strategy for the imidazo[1,2-a]pyridine-fused isoquinoline derivatives. Optimization of the cyclization reaction conditions.a Substrate scope for the syntheses of compounds 4 and 6.a Supporting Information Supporting Information File 174: Characterization

Highly reactive, liquid diacrylamides via synergistic combination of spatially arranged curing moieties

• Maximilian Maier,
• Magnus S. Schmidt,
• Markus Ringwald and
• Christoph P. Fik

Beilstein J. Org. Chem. 2017, 13, 372–383, doi:10.3762/bjoc.13.40

• -dimethylaminobenzoate. FTIR spectra were measured using an iS10 FTIR spectrometer (Thermo Scientific). Viscosity was measured on an Anton Paar Physica MCR 300 equipped with CP 50-1 plate–plate geometry at a shear stress τ of 5 Pa and 25 data points from 0.72 to 1450 rad were taken and averaged. Refractive indices (RI

The synthesis of α-aryl-α-aminophosphonates and α-aryl-α-aminophosphine oxides by the microwave-assisted Pudovik reaction

• Erika Bálint,
• Ádám Tajti,
• Anna Ádám,
• István Csontos,
• Konstantin Karaghiosoff,
• Mátyás Czugler,
• Péter Ábrányi-Balogh and
• György Keglevich

Beilstein J. Org. Chem. 2017, 13, 76–86, doi:10.3762/bjoc.13.10

• scale. This calculation (MCR-ALS, multivariate curve resolution – alternating least squares) gives the concentration profiles of the components and also the spectra of pure components. From Figure 3, it can be seen that the addition reaction was complete after 3.5 h. Finally, the characteristic IR

Multicomponent synthesis of spiropyrrolidine analogues derived from vinylindole/indazole by a 1,3-dipolar cycloaddition reaction

• Manjunatha Narayanarao,
• Lokesh Koodlur,
• Vijayakumar G. Revanasiddappa,
• Subramanya Gopal and
• Susmita Kamila

Beilstein J. Org. Chem. 2016, 12, 2893–2897, doi:10.3762/bjoc.12.288

• in the construction of functionalized spiro compounds. We report herein the facile synthesis of novel spiropyrrolidine compounds through a one-pot three-component reaction involving N-substituted vinylindole/indazole, ninhydrin and sarcosine/L-proline. The present multicomponent reaction (MCR) leads

Synthesis of acylhydrazino-peptomers, a new class of peptidomimetics, by consecutive Ugi and hydrazino-Ugi reactions

• Angélica de Fátima S. Barreto,
• Veronica Alves dos Santos and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2016, 12, 2865–2872, doi:10.3762/bjoc.12.285

• hydrazino-Ugi reaction (or a classical Ugi reaction). The hydrazides 3a–c used in the first MCR were prepared by the reaction of glycine-derived esters 2, 5 and 7 with hydrazine monohydrate (hydrazinolysis), following a known procedure [63][64] (Scheme 2). The obtained hydrazides were then reacted with

A new paradigm for designing ring construction strategies for green organic synthesis: implications for the discovery of multicomponent reactions to build molecules containing a single ring

• John Andraos

Beilstein J. Org. Chem. 2016, 12, 2420–2442, doi:10.3762/bjoc.12.236

• integer partitioning algorithm to monocyclic rings. Supporting Information File 367: Excel file of an MCR database of literature routes to various heterocycles. Supporting Information File 368: Excel file of statistics AE(min) and probability of intrinsic greenness for heterocyclic MCRs. Acknowledgements

Stereoselective synthesis of fused tetrahydroquinazolines through one-pot double [3 + 2] dipolar cycloadditions followed by [5 + 1] annulation

• Xiaofeng Zhang,
• Kenny Pham,
• Shuai Liu,
• Marc Legris,
• Alex Muthengi,
• Jerry P. Jasinski and
• Wei Zhang

Beilstein J. Org. Chem. 2016, 12, 2204–2210, doi:10.3762/bjoc.12.211

• ; tetrahydroquinazoline; Introduction The synthesis of new molecules with potential biological activity through pot, atom and step-economic (PASE) reactions is an attractive green organic technique [1][2][3][4][5]. By the combination of multicomponent reactions (MCR) [6][7][8][9][10][11] with stepwise one-pot reactions

One-pot synthesis of tetracyclic fused imidazo[1,2-a]pyridines via a three-component reaction

• Bo Yang,
• Chuanye Tao,
• Taofeng Shao,
• Jianxian Gong and
• Chao Che

Beilstein J. Org. Chem. 2016, 12, 1487–1492, doi:10.3762/bjoc.12.145

• scaffolds can be constructed in great diversity by a multicomponent reaction of amidines, aldehydes and isocyanides. This MCR, a variant of the Ugi reaction [24][25], was discovered independently by three groups and is known as the Groebke–Blackburn–Bienaymé (GBB) reaction [26][27][28][29]. The reaction

• development of new GBB-based methods for the efficient synthesis of novel polycyclic fused imidazo[1,2-a]pyridines is highly desirable. In an earlier study, we have developed a GBB/lactamization MCR strategy, which provided the rapid access to isoquinolinone-fused imidazo[1,2-a]pyridines with potent and

• selective CDK2 inhibition properties [34][35]. As a continuing effort, we report herein our recent efforts in the development of a GBB-based MCR method for the one-pot synthesis of diverse quinazolin-2-one fused imidazo[1,2-a]pyridines (Scheme 1). Parts of the work have been disclosed in a previous patent