Microwave-assisted efficient and facile synthesis of tetramic acid derivatives via a one-pot post-Ugi cascade reaction

• Yong Li,
• Zheng Huang,
• Jia Xu,
• Yong Ding,
• Dian-Yong Tang,
• Jie Lei,
• Hong-yu Li,
• Zhong-Zhu Chen and
• Zhi-Gang Xu

Beilstein J. Org. Chem. 2020, 16, 663–669, doi:10.3762/bjoc.16.63

• 10 min. The acid (0.50 mmol) and the isocyanide (0.50 mmol) were then added separately. The mixture was stirred at room temperature overnight, and the progress of the reaction was monitored by TLC. The solvent was removed under a stream of nitrogen, and the residue was dissolved in DMF (3.0 mL), and

The reaction of arylmethyl isocyanides and arylmethylamines with xanthate esters: a facile and unexpected synthesis of carbamothioates

• Narasimhamurthy Rajeev,
• Toreshettahally R. Swaroop,
• Ahmad I. Alrawashdeh,
• Shofiur Rahman,
• Abdullah Alodhayb,
• Seegehalli M. Anil,
• Kuppalli R. Kiran,
• Chandra,
• Paris E. Georghiou,
• Kanchugarakoppal S. Rangappa and
• Maralinganadoddi P. Sadashiva

Beilstein J. Org. Chem. 2020, 16, 159–167, doi:10.3762/bjoc.16.18

• theory (DFT) analysis is also presented in this article. Results and Discussion Synthesis At the onset of our study, the reaction between O-benzyl S-methyl dithiocarbonate (1a) and benzyl isocyanide was conducted in the presence of sodium hydride in DMF. The product, obtained in 85% yield after 10 min

• 1a with 4-methylbenzyl isocyanide (2b) and 4-fluorobenzyl isocyanide (2c) gave the corresponding products 4b and 4c in 84% and 87% yield, respectively (Figure 1). S-Methyl O-(2-methylbenzyl) dithiocarbonate (1b) reacted with benzyl isocyanide (2a) to give O-(2-methylbenzyl) benzylcarbamothioate (4d

• ) in 81% yield. O-(3-Methoxybenzyl) S-methyl dithiocarbonate (1c) reacted with 4-fluorobenzyl isocyanide (2c) or 4-chlorobenzyl isocyanide (2d) to give the corresponding carbamothioates 4e and 4f in 83% and 79% yield, respectively. The generality of the reaction was further probed by reacting O-(4

Combining the Ugi-azide multicomponent reaction and rhodium(III)-catalyzed annulation for the synthesis of tetrazole-isoquinolone/pyridone hybrids

• Gerardo M. Ojeda,
• Prabhat Ranjan,
• Pavel Fedoseev,
• Lisandra Amable,
• Upendra K. Sharma,
• Daniel G. Rivera and
• Erik V. Van der Eycken

Beilstein J. Org. Chem. 2019, 15, 2447–2457, doi:10.3762/bjoc.15.237

• moiety. The effect of the R1 substituent at the tetrazole ring and the aryl substituents of the alkyne (Ar, Scheme 1) on the efficiency of the annulation reaction were also evaluated. As shown in Scheme 4, the system is tolerant to a variety of substituents R1 (originating from the isocyanide component

• tetrazole ring takes part in the catalytic reaction mechanism by chelating Rh(III) upon activation of the amide ortho-position. This work illustrates the synthetic potential of combining isocyanide-based multicomponent reactions with metal-catalyzed transformations to generate structural diversity and

• equiv) components were mixed in EtOH (2.0 mL) in a sealed vial provided with a magnetic stirring bar. The reaction was heated at 100 °C under MW irradiation for 15 minutes. Then, the isocyanide (2.2 mmol, 1.1 equiv) component and azidotrimethylsilane (2.2 mmol, 1.1 equiv, 292 μL) were added into the

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

A novel three-component reaction between isocyanides, alcohols or thiols and elemental sulfur: a mild, catalyst-free approach towards O-thiocarbamates and dithiocarbamates

• András György Németh,
• György Miklós Keserű and
• Péter Ábrányi-Balogh

Beilstein J. Org. Chem. 2019, 15, 1523–1533, doi:10.3762/bjoc.15.155

• -stable, environmentally benign, cheap and nontoxic elemental sulfur offers an alternative starting material to integrate sulfur into the product [69]. For a single molecule, Tan and co-workers showed isothiocyanate might be formed from an isocyanide by elemental sulfur in the presence of a base in low

• and improved a catalyst-free method for the preparation of isothiocyanates. Results and Discussion The model reaction of 2,6-dimethylphenyl isocyanide (1a), elemental sulfur (S8) and methanol (2a) was employed to screen for the optimal reaction conditions (Table 1). The reactions were followed by TLC

• isocyanide component under air. In the case of using other bases, such as caesium carbonate (Cs2CO3), diisopropylethylamine (DIPEA) or sodium ethoxide (NaOEt), only the isothiocyanate intermediate of the reaction was isolated (Table 1, entries 17, 18, and 20). However, using diazabicycloundecene (DBU) as the

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

• -type condensation of aminopyrazoles, aldehydes and pyruvic acid [45][46] with the isocyanide-based four-component Ugi reaction. As we have shown before [47][48] the application of the CBD strategy to multicomponent Doebner-type condensations involving aminoazoles allowed the synthesis of several

• optimal acidity to the reaction medium needed for successful protonation of the intermediate azomethine, formed between the aromatic aldehyde 8 and aniline 9, to the corresponding iminium cation and its further transformation involving carboxylic acid 4 and isocyanide 10. As a result, we developed an

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

• materials for relevant MCRs such as those based on imine and isocyanide. The focus is mainly posed on proving the amenability of MCRs for the diversity-oriented derivatization of naturally occurring steroids and the construction of complex steroid-based platforms for drug discovery, chemical biology and

• the steroidal nucleus, the assembly of nitrogen-heterocycles fused to the steroid-ring system, the steroid conjugation and macrocyclization, all relying on MCRs. 2 Modification of the steroidal nucleus and the side chain 2.1 Isocyanide-based MCRs 2.1.1 Steroids as carbonyl component: One of the first

Ugi reaction-derived prolyl peptide catalysts grafted on the renewable polymer polyfurfuryl alcohol for applications in heterogeneous enamine catalysis

• Alexander F. de la Torre,
• Gabriel S. Scatena,
• Oscar Valdés,
• Daniel G. Rivera and
• Márcio W. Paixão

Beilstein J. Org. Chem. 2019, 15, 1210–1216, doi:10.3762/bjoc.15.118

• incorporate proline [15] and the furan functionality into pseudo-peptide catalysts. As shown in Scheme 2, Boc-L-proline and acetone were employed as acid and oxo components, respectively, in combination either with furfurylamine and cyclohexyl isocyanide or with (S)-α-methylbenzylamine and furfuryl isocyanide

• amine and the enantio- and diastereoselectivity of the catalytic process. In this case, furfuryl derivatives – used either as amine or isocyanide component – were ligated [16] to the peptide skeleton aimed at assessing whether the position of the polymerizable handle was important for the

• . 241, (wavelength: 589 nm). Melting points were obtained in a MQAPF-301 apparatus. General procedure A. A suspension of the amine (1.0 mmol) and acetone (1.0 mmol) in MeOH (5 mL) was stirred for 1 h at room temperature. The carboxylic acid (1.0 mmol) and the isocyanide (1.0 mmol) were then added and

Multicomponent reactions (MCRs): a useful access to the synthesis of benzo-fused γ-lactams

• Edorta Martínez de Marigorta,
• Jesús M. de Los Santos,
• Ana M. Ochoa de Retana,
• Javier Vicario and
• Francisco Palacios

Beilstein J. Org. Chem. 2019, 15, 1065–1085, doi:10.3762/bjoc.15.104

• rearrangement that would lead to isoindolinone 46 through the bridged intermediate 51. Therefore, this mechanistic path shows that the enantioselectivity of the reaction is a consequence of a dynamic kinetic resolution of enamine 50. Cyanide can also be used, instead of isocyanide, in an analogous three

• of the reactive aryne 80 which is first trapped with the nucleophilic isocyanide to form 81 and then with the electrophilic CO2 (78), to furnish an intermediate benzoic acid derivative 82. Intramolecular cyclization would produce the corresponding isobenzofurane 83, which alternatively, could also be

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

• Angelica de Fatima S. Barreto Carlos Kleber Z. Andrade Universidade de Brasília, Instituto de Química, Laboratório de Química Metodológica e Orgânica Sintética (LaQMOS), 70910-970 Brasília-DF, Brazil 10.3762/bjoc.15.88 Abstract Isocyanide-based multicomponent reactions are a versatile tool in the

• synthesis of heterocycles. This review describes recently developed approaches based on the combination of consecutive or repetitive isocyanide-based multicomponent reactions for the synthesis of structurally diverse heterocycles. These strategies have also allowed the synthesis of a plethora of

• 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

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

• prominent and studied MCRs is the Ugi reaction. The Ugi four-component condensation reaction (U-4CC) between an aldehyde, an amine, a carboxylic acid and an isocyanide provides a rapid preparation of α-aminoacyl amide or pseudo-peptide derivatives. These biologically active peptide-like molecules can be

• acid, aromatic and aliphatic amines and amino acid-based isocyanides. First of all, racemic α-amino acids such as DL-tryptophan, DL-phenylalanine and DL-leucine were used as amine source for the synthesis of isocyanide esters 3 through three sequential reactions [30][31]. The first reaction is

• esterification of the α-amino acid using thionyl chloride in methanol as reagent and solvent. The second reaction is the formylation of the corresponding amino acid ester salt with ethyl formate in the presence of NaHCO3. Finally, the formamide group was transformed to the corresponding isocyanide 3 using POCl3

The LANCA three-component reaction to highly substituted β-ketoenamides – versatile intermediates for the synthesis of functionalized pyridine, pyrimidine, oxazole and quinoxaline derivatives

• Tilman Lechel,
• Roopender Kumar,
• Mrinal K. Bera,
• Reinhold Zimmer and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2019, 15, 655–678, doi:10.3762/bjoc.15.61

• ]. Alternatively, the conversion of PM44 into oxime PM46 or a van Leusen oxazole synthesis [51] of PM48 with tosylmethyl isocyanide giving PM49 were possible. The synthesis of pyrimidine derivative PM49 with three heterocyclic substituents is remarkable and stresses the flexibility of the methods presented here

• of pyrimidine derivatives PM through selenium dioxide oxidations of PM5, PM9, PM15 and PM19 leading to 4-formyl-substituted pyrimidines PM41, PM42, PM44 and PM48 and selected subsequent transformations (TosMIC = tosylmethyl isocyanide). Conversion of 2-vinyl-substituted pyrimidine PM7 into aldehyde

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

• Biginelli/Ugi-azide sequential reactions were reported by Shahrisa [29]. Similarly, Sharma and co-workers disclosed a related approach [30]. Moreover, 2,4-diaminopyrimidine underwent selective GBB processes leading to a single monoadduct, which reacted again with another isocyanide/aldehyde pair to yield a

• [32], exploiting a non-symmetrical diisocyanide A (Scheme 8). The designed sequence requires the α-acidic isocyanide to undergo the 3CR leading to a 2-imidazoline in the first step, the aliphatic isocyanide remaining intact (without protection) and being later incorporated in a variety of isocyanide

• -based MCRs. In this way, the selective formation of intermediate B, leads to the following MCR processes based in different isocyanide MCRs. This approach made possible a remarkable 8-CR process for the one-pot synthesis of compounds with up to 11 diversity points. A conceptually distinct approach for

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

• . Then, tert-butyl isocyanide was added, diluted with more MeOH and irradiated again the reaction mixture at 120 °C for an additional 1 h in a final concentration of 0.1 M (Scheme 3). By this way, a rapid, one-pot access to macrocycles 2a–p was achieved otherwise very difficult to synthesize in

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

• synthesis of 2-quinolones using either intramolecular Heck reaction [60] or Knoevenagel condensation [61][62]. Results and Discussion We began our study with the preparation of the model substrate 7a through the Ugi reaction of tetrolic acid (3a), benzaldehyde (4a), tert-butyl isocyanide (5a) and 3,5

Methyl isocyanide as a convertible functional group for the synthesis of spirocyclic oxindole γ-lactams via post-Ugi-4CR/transamidation/cyclization in a one-pot, three-step sequence

• Amarendar Reddy Maddirala and
• Peter R. Andreana

Beilstein J. Org. Chem. 2018, 14, 875–883, doi:10.3762/bjoc.14.74

• -substituted 2-indolinones through a three-step post-Ugi-4CR/Bechamp type-reduction followed by a transamidation sequence strategy [40], we came across interesting observations. We noted that when methyl isocyanide [41][42] was used for the Ugi-4CR and the subsequent post-intramolecular transamidation was

• performed under acidic conditions, particularly in the presence of TFA, the reaction led to 3-substituted 2-indolinones in a three-step process [40]. In this work, we discovered that methyl isocyanide [43] operates under a mechanism of convertible isocyanides (CICs) [44][45][46][47][48][49], and could be

• thought of as a synthetic equivalent to ‘CO’ for insertion into the 2-indolinone backbone (shown in Scheme 1). To further elaborate on this observation and for understanding the role of methyl isocyanide as a CIC, we designed an efficient synthetic strategy for spiro[indoline-3,2'-pyrrole]-2,5'(1'H

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

• -azidobenzaldehyde (1a), propargylamine (2a), 2-chloroacetic acid (3a) and benzyl isocyanide (4a, Scheme 2). Initially, the condensation of the aldehyde and the amine was effected in MeOH in the presence of 4 Å MS. This was followed by the sequential addition of chloroacetic acid and the isocyanide which, after 24

• one-pot; which involved neutralization after base-induced diketopiperazine synthesis and dilution with EtOH before the IAAC step. Our first attempt was to study the effect of different substituents on the isocyanide (4a–d) moiety; from which we observed a slight decrease in the yield of the final

• inseparable mixture of diastereomers. Various attempts were made with other azidobenzaldehydes (5-azido-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde, 2-azidoquinoline-3-carbaldehyde and 2-azido-5-nitrobenzaldehyde) and isocyanides (2-morpholinoethyl isocyanide) towards the synthesis of diketopiperazine-fused

Vinylphosphonium and 2-aminovinylphosphonium salts – preparation and applications in organic synthesis

• Anna Kuźnik,
• Roman Mazurkiewicz and
• Beata Fryczkowska

Beilstein J. Org. Chem. 2017, 13, 2710–2738, doi:10.3762/bjoc.13.269

• of triphenylphosphine oxide and the formation of a new C–C bond between the carbon atom at the α-position of the phosphonium salt and the carbon atom of the carbonyl group of the carboxylate anion. The obtained enone 123 was then trapped by reaction with alkyl isocyanide, which finally led to ring

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

• Angelica de Fatima S. Barreto Veronica Alves dos Santos Carlos Kleber Z. Andrade Laboratório de Química Metodológica e Orgânica Sintética, Instituto de Química, Universidade de Brasília, 70910-970, Brasília-DF, Brazil 10.3762/bjoc.13.256 Abstract Isocyanide-based multicomponent reactions (IMCRs

• . The products synthesized herein contain functional groups within their structures that can be easily modified to obtain new acylhydrazino 1,5-disubstituted tetrazoles. Keywords: acylhydrazines; consecutive Ugi reactions; 1,5-disubstituted tetrazoles; isocyanide-based multicomponent reactions (IMCRs

• tetrazoles are intermolecular cycloaddition reactions and isocyanide-based multicomponent reactions (IMCRs). Indeed, the Ugi-multicomponent reaction using TMSN3 (trimethylsilyl azide) as acid component, originally reported by Ugi in 1961 [10], is one of the best and most general methods for the synthesis of

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

• ]. Mechanochemical methods of the Mannich reaction, Paal–Knorr synthesis, Bigineli reaction, Hantzsch reaction, and syntheses of substituted pyran, thiophene, isoquinoline derivatives, etc. are also reported [104][107][112][113]. Isocyanide-based multi-component reactions are also well known [114][115]. Recently, in

• 2016 Juaristi and co-workers have reported Ugi 4-component reactions (4-CR) by liquid-assisted grinding (LAG) using MeOH. Equimolar amounts of benzaldehyde, chloroacetic acid, tert-butyl isocyanide, and propargylamine in the presence of 2 mol % InCl3, under ball-mill yielded the desired Ugi product in

• 74% yield (Scheme 28) [116]. Juaristi and co-workers have also reported a mechanochemical Passerine 3-component reaction (3-CR). tert-Butyl isocyanide, benzaldehyde and benzoic acid in equimolar proportion under milling conditions for 90 min led to 73% of Passerine product (Scheme 29). Both electron

Direct catalytic arylation of heteroarenes with meso-bromophenyl-substituted porphyrins

• Alexei N. Kiselev,
• Olga K. Grigorova,
• Alexei D. Averin,
• Sergei A. Syrbu,
• Oskar I. Koifman and
• Irina P. Beletskaya

Beilstein J. Org. Chem. 2017, 13, 1524–1532, doi:10.3762/bjoc.13.152

• isocyanide Pd complex followed by the ring closure [32]; on the other hand, the arylation of benzothiophene in the presence of Pd(OAc)2/PCy3*HBF4/PivOH proceeds in accordance with the concerted metalation–deprotonation mechanism [33][34]. We also investigated the reaction of zinc meso-(3-bromophenyl

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

• chemical space with the aim of finding new biologically active structures. Modern chemistry offers several approaches, for instance, diversity oriented synthesis (DOS) for the generation of diverse compound libraries [6][7][8]. From this point of view, multicomponent reactions (MCRs), including isocyanide

• -carboxylate are described in GBB-3CR [29][71][83][84][94][95][96]. To the best of our knowledge, there is no information about the reactivity of aminoazoles as an amine component in Ugi-4CR. Taking into account the above-mentioned facts, several aminoazoles, whose reactivity in isocyanide-based reactions had

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

• , an aldehyde and an isocyanide proceeds through the isocyanide-involving formal [4 + 1] cycloaddition [39] affording the biologically important imidazo[1,2-a]pyridine scaffold. Due to the atom and step economy, high efficiency and intriguing biological profiles of the products, the GBB reaction has

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

• 9 and an isocyanide 11 [21]. The Passerini reaction works best in non-polar solvents like dichloromethane. The mechanism of the Passerini reaction (Scheme 1b) is proposed to proceed via the formation of a hydrogen bond (H-bond) adduct between carboxylic acid 8 and carbonyl component 9, resulting in

• a six-membered cyclic H-bond adduct 10. Subsequently, isocyanide 11 reacts with 10, thereby showing a simultaneous nucleophilic and electrophilic reactivity (α-addition). The herein formed seven-membered intermediate has not been isolated, because it immediately undergoes a rearrangement, affording

• Figure 1 carry an isocyanide functionality, which could hydrolyze under the acidic conditions for the Biginelli reaction [38]. Components A2, B2 and C2 carry an aldehyde functional group for the Passerini reaction, but this could react on both sides in the Biginelli reaction. Therefore, A2, B2, C2 as

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

• and have inspired the development of new multicomponent coupling reactions. Isocyanide-based multicomponent couplings [1], led by the foundational Ugi four-component coupling [2][3], have been used extensively for the synthesis of natural products and the preparation of diverse heterocyclic scaffolds

• reactants for the four-component Ugi–Smiles coupling [21]. A notable exception is one reported example of 2-furaldehyde participating in a Ti(O-iPr)4-catalyzed modified Ugi–Smiles reaction that used an isocyanide as an amine equivalent [22]. We recently reported a successful tandem Ugi–Smiles intramolecular

• components to determine the substrate scope that would be tolerated in this tandem process (Table 2). Amines were combined with 2-nitrophenol, cyclohexyl or tert-butyl isocyanide, and 2-furaldehyde in methanol (50 °C, 30 h). As no lone Ugi–Smiles reactions had been reported with furyl-substituted aldehydes