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

Synthesis and biological activity of N-substituted-tetrahydro-γ-carbolines containing peptide residues

• Nadezhda V. Sokolova,
• Valentine G. Nenajdenko,
• Vladimir B. Sokolov,
• Daria V. Vinogradova,
• Elena F. Shevtsova,
• Ludmila G. Dubova and
• Sergey O. Bachurin

Beilstein J. Org. Chem. 2014, 10, 155–162, doi:10.3762/bjoc.10.13

• chiral centre of the isocyanoazide does not occur under the conditions of the Ugi reaction [20]. This approach permits to prepare a broad variety of azidopeptides using multicomponent methodology. The modification of N-substituted tetrahydro-γ-carbolines 3a–d by peptide fragments was performed using Cu(I

• added to the residue. After evaporation of the solvent the corresponding dihydrochlorides 7a–g were obtained. Structures of dimebon and SS peptides. Synthesis of starting N-substituted tetrahydro-γ-carbolines 3a–d. Synthesis of peptides 5 through the Ugi reaction. Synthesis of N-substituted tetrahydro-γ

The multicomponent approach to N-methyl peptides: total synthesis of antibacterial (–)-viridic acid and analogues

• Ricardo A. W. Neves Filho,
• Sebastian Stark,
• Bernhard Westermann and
• Ludger A. Wessjohann

Beilstein J. Org. Chem. 2012, 8, 2085–2090, doi:10.3762/bjoc.8.234

• ; toxin; Ugi reaction; Introduction Viridic acid (1) is a tetrapeptide produced by several fungi of the genus Penicillium, including P. viridicatum, P. nordicum, and P. aurantiogriseum among others [1][2][3][4]. It was first isolated from the basic fraction of the chloroform/methanol extract of P

• substance (Scheme 2) [5]. In order to more rapidly access derivatives for biological activity screens, we decided to investigate the suitability of a MCR approach utilizing the Ugi reaction. Due to the character of the Ugi-4CR, the racemate of viridic acid and congeners is easily available, and assaying

Synthetic studies towards bottromycin

• Stefanie Ackermann,
• Hans-Georg Lerchen,
• Dieter Häbich,
• Angelika Ullrich and
• Uli Kazmaier

Beilstein J. Org. Chem. 2012, 8, 1652–1656, doi:10.3762/bjoc.8.189

• thiopeptide 3 [37], easily obtained by thio-Ugi reaction in excellent yield. The reaction was very fast and was finished already after 15 min, and peptide 3 crystallized directly from the reaction mixture. Because our first attempts to couple 3 directly with amines to the corresponding amidine 5 failed [43

• subjected to a thio-Ugi reaction as described before, and the expected sterically highly demanding endothiopeptide 8 was obtained in high yield as a 1:1 diastereomeric mixture. In this case, the diastereomers could not be separated. Elongation of the peptide chain under standard peptide coupling conditions

• intramolecular fashion. The intramolecular approach allows the synthesis of the bottromycin ring system in a straightforward manner. The synthesis of the bottromycins and derivatives thereof is currently under investigation. Bottromycins. Syntheses of endothiopeptides by thio-Ugi reaction. Synthesis of amidine 5

Parallel and four-step synthesis of natural-product-inspired scaffolds through modular assembly and divergent cyclization

• Hiroki Oguri,
• Haruki Mizoguchi,
• Hideaki Oikawa,
• Aki Ishiyama,
• Masato Iwatsuki,
• Kazuhiko Otoguro and
• Satoshi Ōmura

Beilstein J. Org. Chem. 2012, 8, 930–940, doi:10.3762/bjoc.8.105

• (Scheme 3). According to the previously reported protocol [22], Ugi reaction employing allylamine (31) and stepwise installation of a diazoimide group provided 35 in good yield. Upon treatment of 35 with Rh2(OAc)4 in benzene under reflux, 1,3-dipolar cycloaddition of the ylide intermediate with the

Synthesis of (−)-julocrotine and a diversity oriented Ugi-approach to analogues and probes

• Ricardo A. W. Neves Filho,
• Bernhard Westermann and
• Ludger A. Wessjohann

Beilstein J. Org. Chem. 2011, 7, 1504–1507, doi:10.3762/bjoc.7.175

• heterocyclic precursor as an amino input in Ugi four-component reactions (Ugi-4CR) [1]. Keywords: diversity oriented synthesis; julocrotine; leishmania; Mitsunobu reaction; Ugi reaction; Introduction Julocrotine (1) is a natural glutarimide alkaloid isolated from several plants of the genus Croton [2][3][4

Ugi post-condensation copper-triggered oxidative cascade towards pyrazoles

• Aurélie Dos Santos,
• Laurent El Kaim,
• Laurence Grimaud and
• Caroline Ronsseray

Beilstein J. Org. Chem. 2011, 7, 1310–1314, doi:10.3762/bjoc.7.153

• ; isocyanide; pyrazolidinone; Introduction In the last twenty years, the Ugi reaction coupled with its various post-condensations towards heterocyclic libraries has established the success of isocyanide-based multicomponent reactions [1][2][3][4][5][6][7]. Chemists in both academia and industry have taken

• these optimized conditions. Results are reported in Table 1. Surprisingly, the reaction appears to be only efficient with Ugi adducts prepared with formaldehyde as the carbonyl component (Table 1, entries 1–5). With other aldehydes and ketones, even if the Ugi reaction was performed easily, the

• following cyclization failed to give the expected pyrazolidinones and resulted in complex mixture formation. Intermediate Ugi adduct 3g (Table 1, entry 6) only resulted in a small amount of ring-opened product 4g. The reaction is also limited to N-aryl hydrazones due to the lower efficiency of the Ugi

A straightforward approach towards combined α-amino and α-hydroxy acids based on Passerini reactions

• Ameer F. Zahoor,
• Sarah Thies and
• Uli Kazmaier

Beilstein J. Org. Chem. 2011, 7, 1299–1303, doi:10.3762/bjoc.7.151

• powerful tool for the synthesis of acylated α-hydroxyacid amides [10]. Later on, in 1961, Ugi and Steinbrückner reported the extension of this protocol by incorporating also a primary amine as a fourth component [11]. Therefore, the Ugi reaction is even more flexible than the Passerini approach, but both

• reactions together have made the IMCR highly popular in combinatorial chemistry [7][8]. Our group has been involved in amino acid and peptide synthesis for nearly two decades [12][13], and multicomponent reactions are known to play a dominant role [14][15]. In particular, the Ugi reaction has so far been

• peptide-derived drugs. Attempts to improve the yields and to evaluate the scope and limitations are currently underway. Passerini reactions of α,β-unsaturated aldehyde 5. Passerini and Ugi reaction of saturated aldehyde 7. Synthesis of γ-oxo-amino acids. Passerini reactions of γ-oxo-amino acids

Multicomponent synthesis of artificial nucleases and their RNase and DNase activity

• Anton V. Gulevich,
• Lyudmila S. Koroleva,
• Olga V. Morozova,
• Valentina N. Bakhvalova,
• Vladimir N. Silnikov and
• Valentine G. Nenajdenko

Beilstein J. Org. Chem. 2011, 7, 1135–1140, doi:10.3762/bjoc.7.131

• Abstract The synthesis of new, artificial ribonucleases containing two amino acid residues connected by an aliphatic linker has been developed. Target molecules were synthesized via a catalytic three-component Ugi reaction from aliphatic diisocyanides. Preliminary investigations proved unspecific nuclease

• , containing two amide bonds and variable substituents, can be synthesized by the Ugi reaction with subsequent removal of diamine residue (Scheme 1). Original substrates for the synthesis could be aliphatic diisocyanides 3, amines (with an easily removable protective group) and aldehydes. We used an

• organocatalytic three-component modification of the Ugi reaction, recently developed by List et al. [25]. The reaction results in diamines 4, thus avoiding the acid residue removal stage. The starting diisocyanides 3 were obtained in good overall yields from commercially available diamines containing 6, 7, 8, 10

Novel synthesis of pseudopeptides bearing a difluoromethyl group by Ugi reaction and desulfanylation

• Jingjing Wu,
• Hui Li and
• Song Cao

Beilstein J. Org. Chem. 2011, 7, 1070–1074, doi:10.3762/bjoc.7.123

• Jingjing Wu Hui Li Song Cao Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China 10.3762/bjoc.7.123 Abstract Thirteen difluoromethyl-containing pseudopeptides were synthesized by Ugi reaction using the novel

• cleavage; Ugi reaction; Introduction Fluorinated amino acids and pseudopeptides have increasingly attracted attention in recent years [1][2][3][4][5]. The selective incorporation of fluorine-containing groups, such as trifluoromethyl, difluoromethyl and difluoromethylene, into peptides or peptidomimetics

• continuation of our interest in the synthesis of diverse difluoromethyl-containing pseudopeptides, we herein report a novel and efficient synthesis of difluoromethyl-containing pseudopeptides through Ugi reaction, with gem-difluoromethylene-containing acid as a key component, followed by reductive cleavage of

Long-range diastereoselectivity in Ugi reactions of 2-substituted dihydrobenzoxazepines

• Luca Banfi,
• Andrea Basso,
• Valentina Cerulli,
• Valeria Rocca and
• Renata Riva

Beilstein J. Org. Chem. 2011, 7, 976–979, doi:10.3762/bjoc.7.109

• Luca Banfi Andrea Basso Valentina Cerulli Valeria Rocca Renata Riva Department of Chemistry and Industrial Chemistry, University of Genova, I-16146 Genova, Italy 10.3762/bjoc.7.109 Abstract The Ugi reaction of 2-substituted dihydrobenzoxazepines was found to proceed with unexpectedly good

• diastereoselectivitiy (diastereoisomeric ratios up to 9:1), despite the large distance between the pre-existing stereogenic centre and the newly generated one. This result represents the first good 1,4 asymmetric induction in an Ugi reaction as well as the first example of diastereoselective Ugi reaction of seven

• membered cyclic imines. It allows the diversity-oriented synthesis of various tetrahydro[f][1,4]benzoxazepines. Keywords: benzoxazepines; cyclic imines; long range stereoinduction; multicomponent reactions; Ugi reaction; Introduction The Ugi reaction is probably the most renowned and widely used

Synthesis of dihydrophenanthridines by a sequence of Ugi-4CR and palladium- catalyzed intramolecular C-H functionalization

• Florence Bonnaterre,
• Michèle Bois-Choussy and
• Jieping Zhu

Beilstein J. Org. Chem. 2008, 4, No. 10, doi:10.3762/bjoc.4.10

• -functionalization reaction has proven to be an efficient strategy to increase the skeleton diversity. Results The Ugi reaction of an o-iodobenzaldehyde (2), an aniline (3), an isocyanide (4), and a carboxylic acid (5) afforded α-acetamido-α-phenylacetamide (6) in good to excellent yields. The palladium-catalyzed

• summarized in Table 2. 4-Nitroaniline (3c) is known to be inactive in Ugi reaction due to the reduced nucleophilicity of the nitrogen and the low basicity of the resulting imine leading consequently to a low concentration of the iminium ion. However, by performing the reaction in trifluoroethanol (TFE) [35