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

• macroheterocycles in a reduced number of steps. Keywords: consecutive/repetitive multicomponent reactions; isocyanide; isocyanide-based multicomponent reactions; (macro)heterocycles; Passerini reaction; Ugi reaction; Introduction Isocyanide (isonitrile) chemistry was first described by Lieke in 1859 [1] and forms

• , which is able to undergo both electrophilic and nucleophilic reactions at the carbon atom. The Ugi reaction, firstly reported by Ugi et al. in 1959 [14], involves an amine, a ketone or aldehyde, an isocyanide, and a carboxylic acid to form a dipeptide product. It is undoubtedly one of the most important

• IMCRs known and has found many applications in synthetic organic chemistry [2][3][9][10]. Among the IMCRs the Ugi reaction has been the most used in the repetitive/consecutive strategy for the synthesis of (macro)heterocycles. The union of different types of MCRs for the synthesis of more complex

Synthesis of a novel category of pseudo-peptides using an Ugi three-component reaction of levulinic acid as bifunctional substrate, amines, and amino acid-based isocyanides

• Maryam Khalesi,
• Azim Ziyaei Halimehjani and
• Jürgen Martens

Beilstein J. Org. Chem. 2019, 15, 852–857, doi:10.3762/bjoc.15.82

• synthesis of a novel category of pseudo-peptides via intramolecular Ugi reaction of levulinic acid (4-oxopentanoic acid), aromatic and aliphatic amines, and amino acid-based isocyanides is reported. Levulinic acid was applied as a bifunctional substrate containing both carbonyl and acid moieties suitable

• for the Ugi reaction. This article provides a facile and convenient one-pot procedure for the synthesis of peptide-like heterocyclic molecules containing 2-pyrrolidone (γ-lactam), amide and ester functional groups with good to excellent yields. Keywords: amino acid-based isocyanides; levulinic acid

• ; multicomponent; pseudo-peptides; Ugi reaction; Introduction The multistep synthesis of complex molecules normally requires a large number of repetitive synthetic operations, such as extraction, separation, chromatography and other purification steps. These disadvantages encouraged chemists to synthesize complex

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

• for p53-MDM2 inhibition by fluorescence polarization and 1H,15N HSQC NMR measurements confirm MDM2 binding. Keywords: 1H,15N HSQC NMR; indole; macrocycles; multicomponent; p53-MDM2; Ugi reaction; Introduction Macrocycles are the chemical entities that are consisting of a 12-membered or even bigger

Synthesis of a tubugi-1-toxin conjugate by a modulizable disulfide linker system with a neuropeptide Y analogue showing selectivity for hY1R-overexpressing tumor cells

• Rainer Kufka,
• Robert Rennert,
• Goran N. Kaluđerović,
• Lutz Weber,
• Wolfgang Richter and
• Ludger A. Wessjohann

Beilstein J. Org. Chem. 2019, 15, 96–105, doi:10.3762/bjoc.15.11

• triple-negative breast cancer MDA-MB-468 cells. Keywords: drug targeting; neuropeptide Y; PDC; peptide–drug conjugate; targeted tumor therapy; tubugi; tubulysin A; Ugi reaction; Introduction Until recently, the medication of tumor diseases was primarily based on more or less unspecific

• three cell lines was determined as proof for targeted delivery. Results and Discussion Synthesis of tubugi-1 building blocks We established the Ugi reaction as a powerful tool for peptide synthesis and ligation, including the first syntheses of tubulysine derivatives by us and later also others [44][53

• ][55][56]. In a single step, the Ugi reaction permits the introduction of different functionalities which may be followed with additional modifications on the side chain (e.g., via ring-closing metathesis or Click reaction) [53]. For tubugi conjugates we learned that alkyl amide bonds and several types

Gold-catalyzed post-Ugi alkyne hydroarylation for the synthesis of 2-quinolones

• Xiaochen Du,
• Jianjun Huang,
• Anton A. Nechaev,
• Ruwei Yao,
• Jing Gong,
• Erik V. Van der Eycken,
• Olga P. Pereshivko and
• Vsevolod A. Peshkov

Beilstein J. Org. Chem. 2018, 14, 2572–2579, doi:10.3762/bjoc.14.234

• University, 53 Kabanbay Batyr Ave, Block 7, Astana, 010000, Republic of Kazakhstan 10.3762/bjoc.14.234 Abstract A series of propargylamides containing an electron-rich benzene ring was prepared through the Ugi reaction of 3,5-dimethoxyaniline with various propiolic acids, aldehydes and isocyanides

• . Subjecting these adducts to a gold-catalyzed intramolecular alkyne hydroarylation process allowed to efficiently construct the 2-quinolone core bearing a branched substituent on the nitrogen atom. Keywords: gold catalysis; hydroarylation; 2-quinolones; Ugi reaction; Introduction Quinoline and its oxidized

• address this issue by employing propargylamides 7 obtained by a four-component Ugi reaction of propiolic acids 3, aldehydes 4, isocyanides 5 and 3,5-dimethoxyaniline (6a) (Scheme 2). We anticipated that the resulting adducts 7 would readily produce 2-quinolones 8 bearing a branched substituent on the

Applications of organocatalysed visible-light photoredox reactions for medicinal chemistry

• Michael K. Bogdos,
• Emmanuel Pinard and
• John A. Murphy

Beilstein J. Org. Chem. 2018, 14, 2035–2064, doi:10.3762/bjoc.14.179

• an organophotocatalytic version of the Ugi reaction. These procedures were undertaken in a flow chemistry set-up, using irradiation by green LEDs and Rose Bengal as the photocatalyst (Scheme 13) [56]. The scope of the reaction is fairly broad, especially considering the method was developed in a flow

Sequential Ugi reaction/base-induced ring closing/IAAC protocol toward triazolobenzodiazepine-fused diketopiperazines and hydantoins

• Robby Vroemans,
• Fante Bamba,
• Jonas Winters,
• Joice Thomas,
• Jeroen Jacobs,
• Luc Van Meervelt,
• Jubi John and
• Wim Dehaen

Beilstein J. Org. Chem. 2018, 14, 626–633, doi:10.3762/bjoc.14.49

• (CSIR-NIIST), Thiruvananthapuram-19, India 10.3762/bjoc.14.49 Abstract A practical three-step protocol for the assembly of triazolobenzodiazepine-fused diketopiperazines and hydantoins has been developed. The synthesis of these tetracyclic ring systems was initiated by an Ugi reaction, which brought

• ; hydantoin; intramolecular azide–alkyne cycloaddition; Ugi reaction; Introduction The versatile bioactivities of multiring-fused heterocyclic scaffolds continue to attract significant attention in developing new methods for their synthesis. A plethora of functionalized fused heterocycles can be easily

• multiring-fused derivatives incorporating all these heterocyclic moieties. We hypothesized that 2,5-diketopiperazine-fused triazolobenzodiazepine could be obtained by proper functionalization of building blocks starting with an Ugi reaction; followed by two ring-closing steps, one being a base-induced

Consecutive hydrazino-Ugi-azide reactions: synthesis of acylhydrazines bearing 1,5-disubstituted tetrazoles

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

Beilstein J. Org. Chem. 2017, 13, 2596–2602, doi:10.3762/bjoc.13.256

• 1,5-disubstituted tetrazoles due to the intrinsic generation of molecular diversity [11][12][13][14][15]. As the Ugi reaction also requires an amine component, we envisaged that reactions of hydrazino compounds (RNHNH2) with TMSN3 could furnish useful compounds bearing both the hydrazino and the

Mechanochemical synthesis of small organic molecules

• Tapas Kumar Achar,
• Anima Bose and
• Prasenjit Mal

Beilstein J. Org. Chem. 2017, 13, 1907–1931, doi:10.3762/bjoc.13.186

• reaction of electron-rich arenes [88][98]. Mechanochemical aryl halogenation reaction using trihaloisocyanuric acids [100]. Mechanochemical fluorination reaction by LAG method [102]. Mechanochemical Ugi reaction [116]. Mechanochemical Passerine reaction [116]. Mechanochemical synthesis of α-aminonitriles

Development of a method for the synthesis of 2,4,5-trisubstituted oxazoles composed of carboxylic acid, amino acid, and boronic acid

• Kohei Yamada,
• Naoto Kamimura and
• Munetaka Kunishima

Beilstein J. Org. Chem. 2017, 13, 1478–1485, doi:10.3762/bjoc.13.146

• prehalogenation [16]. iii) The multicomponent method: only two strategies have been reported to the best of our knowledge. One is a combination of the Ugi reaction, which uses 2,4-dimethoxybenzylamine, arylglyoxal, carboxylic acid, and isonitrile as components, and a subsequent Robinson–Gabriel reaction [17]. The

A speedy route to sterically encumbered, benzene-fused derivatives of privileged, naturally occurring hexahydropyrrolo[1,2-b]isoquinoline

• Olga Bakulina,
• Alexander Ivanov,
• Vitalii Suslonov,
• Dmitry Dar’in and
• Mikhail Krasavin

Beilstein J. Org. Chem. 2017, 13, 1413–1424, doi:10.3762/bjoc.13.138

• non-classical inputs for the Joullié–Ugi reaction and for subsequent preparation [28] of sterically encumbered, constrained peptidomimetic frameworks. Diversely substituted indolenines 9 are easy to prepare via the Fischer indole synthesis [26] and their use in the CCR can be expected to result in

New tricks of well-known aminoazoles in isocyanide-based multicomponent reactions and antibacterial activity of the compounds synthesized

• Maryna V. Murlykina,
• Maryna N. Kornet,
• Sergey M. Desenko,
• Svetlana V. Shishkina,
• Oleg V. Shishkin,
• Aleksander A. Brazhko,
• Vladimir I. Musatov,
• Erik V. Van der Eycken and
• Valentin A. Chebanov

Beilstein J. Org. Chem. 2017, 13, 1050–1063, doi:10.3762/bjoc.13.104

• -aryl-1H-pyrazole-4-carboxamides; antibacterial activity; Groebke–Blackburn–Bienaymé reaction; isocyanide Ugi reaction; Introduction An intensive progress in pharmaceutical and medicinal chemistry, as well as in the generation and improvement of medicinal technologies has led to defeating a wide scope

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

• conditions and a broad substrate scope, allowing for the rapid construction of structurally complex and diverse heterocycles in moderate to good yields. Keywords: Groebke–Blackburn–Bienaymé reaction; imidazo[1,2-a]pyridines; isoquinolines; multicomponent reaction; Ugi reaction; Introduction Imidazo[1,2-a

• discovery [22][23][24][25][26][27]. The Ugi reaction [28], an elegant pioneer of a multicomponent reaction, represents a powerful synthetic tool to assemble versatile peptide-like compounds. It has found many applications in the facile synthesis of natural products and biologically interesting molecules [29

• combination of the Ugi reaction with other transformations proved to be powerful strategies for the efficient synthesis of novel heterocycles. In 1998, the Groebke–Blackburn–Bienaymé (GBB) reaction, an Ugi-3CR variant was discovered by three groups independently [36][37][38]. The GBB reaction of an amidine

Synthesis of structurally diverse 3,4-dihydropyrimidin-2(1H)-ones via sequential Biginelli and Passerini reactions

• Andreas C. Boukis,
• Baptiste Monney and
• Michael A. R. Meier

Beilstein J. Org. Chem. 2017, 13, 54–62, doi:10.3762/bjoc.13.7

• Passerini or Ugi reactions in a sequential one-pot procedure [32]. Furthermore, up to eight components were reacted by the combination of three multicomponent reactions [33]. In 2010, the Ugi reaction and the Ugi–Smiles reaction were combined by Westermann et al. [34]. In addition, the Ugi reaction was used

• in combination with the Biginelli reaction by Brodsky et al. [35]. In this work, five Biginelli acids were synthesized in 33–83% yields and utilized in a Ugi reaction for the synthesis of six DHMP amides with 21–63% yields. In a similar reaction strategy, Wipf et al. synthesized a library of twelve

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

• for the synthesis of acylhydrazino-peptomers, a new class of peptidomimetics. The key idea in this approach is based on a simple route using a one-pot hydrazino-Ugi four-component reaction followed by a hydrazinolysis or hydrolysis reaction and subsequent hydrazino-Ugi reaction or classical Ugi

• acylhydrazino portion. The use of a consecutive Ugi reaction to access peptidomimetics has proven very useful [56][57][58][59][60][61][62]. It is important to point out that these molecules cannot be obtained directly via the “submonomer approach”. Results and Discussion Our approach involves the use of two

• multicomponent reactions (Scheme 1): the hydrazino-Ugi four-component reaction (HU-4CR) and the classical Ugi reaction (U-4CR). The strategy was based on the formation of an acylhydrazino-peptomer via an initial hydrazino-Ugi reaction followed by a hydrazinolysis reaction (or ester hydrolysis) and a subsequent

Application of heterocyclic aldehydes as components in Ugi–Smiles couplings

• Katelynn M. Mason,
• Michael S. Meyers,
• Abbie M. Fox and
• Sarah B. Luesse

Beilstein J. Org. Chem. 2016, 12, 2032–2037, doi:10.3762/bjoc.12.191

• . In 2005, El Kaïm and co-workers extended the utility of the Ugi reaction with the development of an Ugi–Smiles reaction, replacing the carboxylic acid component with an electron-deficient phenol [4][5][6][7]. Recent efforts to assemble biologically-relevant heterocycles have used multicomponent

• has generally found success in cascade processes [17][18][19], the intolerance of heterocyclic aldehyde components has prevented use with common IMDA strategies. Although heterocyclic aldehyde components are competent partners for the classic Ugi reaction [20], they have been inefficient carbonyl

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

Diastereoselective Ugi reaction of chiral 1,3-aminoalcohols derived from an organocatalytic Mannich reaction

• Samantha Caputo,
• Andrea Basso,
• Lisa Moni,
• Renata Riva,
• Valeria Rocca and
• Luca Banfi

Beilstein J. Org. Chem. 2016, 12, 139–143, doi:10.3762/bjoc.12.15

• , allowing the introduction of five diversity inputs. Keywords: aminoalcohols; isocyanides; multicomponent reactions; peptidomimetics; Ugi reaction; Findings Isocyanide-based multicomponent reactions [1][2][3], such as the Ugi reaction, were demonstrated to be very useful in the rapid assembly of complex

• drug candidates [4], introducing three to four diversity inputs. Furthermore, a nearly limitless variety of heterocycles can be accessed through post-condensation transformations [5][6][7], adding only one to two steps to the synthetic sequence. However, the main drawback of the Ugi reaction is the

• poor stereochemical control that is typically achieved [8][9], which hampers its utilization in the diversity-oriented or target-oriented synthesis of complex chiral peptidomimetics. No efficient asymmetric catalytic classic Ugi reaction has been reported to date (whereas some success was obtained on

Synthesis of antibacterial 1,3-diyne-linked peptoids from an Ugi-4CR/Glaser coupling approach

• Martin C. N. Brauer,
• Ricardo A. W. Neves Filho,
• Bernhard Westermann,
• Ramona Heinke and
• Ludger A. Wessjohann

Beilstein J. Org. Chem. 2015, 11, 25–30, doi:10.3762/bjoc.11.4

• -libraries of homo- and heterodimers verified by ESI-MS and HPLC. In a preliminary evaluation, some compounds display moderate activity against the Gram-positive bacterium Bacillus subtilis. Keywords: antibacterial; combinatorial; diynes; homodimerization; multicomponent reactions; peptoids; Ugi reaction

Synthesis of α-amino amidines through molecular iodine-catalyzed three-component coupling of isocyanides, aldehydes and amines

• Praveen Reddy Adiyala,
• D. Chandrasekhar,
• Jeevak Sopanrao Kapure,
• Chada Narsimha Reddy and
• Ram Awatar Maurya

Beilstein J. Org. Chem. 2014, 10, 2065–2070, doi:10.3762/bjoc.10.214

• economy, wide substrate scope and high yields. Keywords: α-amino amidines; iodine; isocyanide; multicomponent reaction; Ugi reaction; Introduction Amidines are a class of organic compounds exhibiting a variety of biological activity that makes them potential candidates for drug development and discovery

• strategies for the synthesis of amidines. The Ugi reaction is probably one of the best multicomponent reactions to provide huge structural diversification of the products [12]. Thus, several modifications of the Ugi reaction were explored recently. As depicted in Figure 1, diamides, α-amino amides, and α

• part of our ongoing interest towards the synthesis of new molecular libraries [21][22][23][24], we were interested in developing a one-pot MCR strategy for the synthesis of amidines. Results and Discussion To check the feasibility of the iodine-catalyzed amidine synthesis through the modified Ugi

Multicomponent reactions in nucleoside chemistry

• Mariola Koszytkowska-Stawińska and
• Włodzimierz Buchowicz

Beilstein J. Org. Chem. 2014, 10, 1706–1732, doi:10.3762/bjoc.10.179

• . Activity of hybrid compounds 28 and 29 against VZV and CMV viruses, as well as against Leishmania donovani promastigotes, was evaluated. Unfortunately, none of them showed any activity up to 250 μM. 3. The Ugi reaction The Ugi reaction allows for a facile synthesis of a bisamide from a ketone (or an

• aldehyde), an amine, an isocyanide, and a carboxylic acid (Scheme 13) [77][78]. The Ugi MCRs involving a nucleoside as the substrate bearing the formyl, amino, or isocyano group have been reported. The four-component Ugi reaction employing 3',5'-di-O-acetyl-5-formyl-2'-deoxyuridine (14) as the key

• Kingsbury reported a facile synthesis of N-methylated di- and tri-peptide polyoxins by the Ugi reaction (Scheme 16) [81]. The aldehyde 36, aq methylamine, racemic isonitrile 37, and (S)-N-(benzyloxycarbonyl)phenylalanine were combined in MeOH to produce 38 as a mixture of four possible diastereoisomers in a

Asymmetric Ugi 3CR on isatin-derived ketimine: synthesis of chiral 3,3-disubstituted 3-aminooxindole derivatives

• Giordano Lesma,
• Fiorella Meneghetti,
• Alessandro Sacchetti,
• Mattia Stucchi and
• Alessandra Silvani

Beilstein J. Org. Chem. 2014, 10, 1383–1389, doi:10.3762/bjoc.10.141

• methodologies to access chiral 3,3-disubstituted 3-aminooxindoles [16][17][18][19], we looked at isocyanide-based multicomponent reactions as a possible efficient tool to quickly prepare oxindole-based peptidomimetic compounds [20][21][22]. Despite the synthetic efficiency of the Ugi reaction and its wide

• created, the stereoselectivity remains a difficult task. Waiting for enantioselective versions of the Ugi reaction [29][30][31], the diastereoselective approach by using chiral material is a possible solution. In particular, amines have shown to be promising as chiral auxiliaries, even though only a few

• reduction of both the yield and the reaction rate. The application of sonication to shorten the reaction times was also useful, since compound 4 was obtained after 6 hours with the same dr, although in a lower yield (Table 1, entry 14). To exploit the potential of the Ugi reaction to introduce molecular

Consecutive isocyanide-based multicomponent reactions: synthesis of cyclic pentadepsipeptoids

• Angélica de Fátima S. Barreto,
• Otilie E. Vercillo,
• Ludger A. Wessjohann and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2014, 10, 1017–1022, doi:10.3762/bjoc.10.101

• reactions; Passerini reaction; sansalvamide A; Ugi reaction; Introduction Peptoids are an interesting class of non-natural compounds that have recently received much attention due to their wide range of biological activities, which makes them attractive candidates for drug discovery [1][2][3][4][5][6][7

• compounds can be achieved using a strategy based on: (a) formation of a peptoid via Ugi reaction; (b) ester hydrolysis; (c) formation of an acyclic depsipeptoid scaffold through a Passerini reaction; (d) deprotection of the amine/acid groups and (e) a macrocyclization step via an intramolecular Ugi reaction

• can be obtained by changes in the amine component in the first Ugi reaction, in the carbonyl component in the Passerini reaction or in the isocyanide and carbonyl components in the macrocyclization step. The general route and procedure developed allows an easy access to complex molecules with a

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

• (PADAM) strategy was reported for the first time by Banfi and co-workers in 2003 [23]. In addition, subsequent oxidation of 7 gives access to α-keto amides 8 that show important protease inhibitory activities. The Ugi reaction One of the most important MCRs that generates peptide-like structures was

• 3-CR, the Ugi 4-CR is favoured in polar protic solvents like low-molecular weight alcohols such as methanol, ethanol or trifluoroethanol. However, many examples in polar aprotic solvents are also reported. The generally accepted mechanism for the Ugi reaction proceeds via in situ imine formation of

• -formation of the imine or the use of bifunctional inputs (e.g. amino acids) can reduce this Ugi-4CR to an Ugi-3CR. In particular, the Ugi reaction with bifunctional inputs is called an Ugi-four-center-three-component reaction (U-4C-3CR) and has been extensively applied in peptidomimetic synthesis [21][22

Diversity-oriented synthesis of dihydrobenzoxazepinones by coupling the Ugi multicomponent reaction with a Mitsunobu cyclization

• Lisa Moni,
• Luca Banfi,
• Andrea Basso,
• Alice Brambilla and
• Renata Riva

Beilstein J. Org. Chem. 2014, 10, 209–212, doi:10.3762/bjoc.10.16

• derivatives. Keywords: benzoxazepines; diversity-oriented synthesis; multicomponent reactions; Mitsunobu reaction; Ugi reaction; Introduction Although the classical Ugi 4-component reaction (U-4CR) leads to acyclic peptide-like compounds, post-condensation cyclizations can afford a huge variety of drug-like

• triphenylphosphine oxide. We eventually found that the easiest and most efficient protocol involved reduction with Me3P, followed by evaporation of the solvent and by subsequent Ugi reaction on the crude. With Me3P, phosphazene hydrolysis was much faster and the phosphine oxide was much more easily separated by

• operationally simple protocol opens a straightforward route to 2,3-dihydrobenzo[f][1,4]oxazepin-3-ones 10 starting from 2-(benzyloxy)benzyl azides, in turn accessible from variously substituted salicylic aldehydes or acids. We were able to use directly the azides as input in the Ugi reaction without the need to