New efficient synthesis of polysubstituted 3,4-dihydroquinazolines and 4H-3,1-benzothiazines through a Passerini/Staudinger/aza-Wittig/addition/nucleophilic substitution sequence

• Long Zhao,
• Mao-Lin Yang,
• Min Liu and
• Ming-Wu Ding

Beilstein J. Org. Chem. 2022, 18, 286–292, doi:10.3762/bjoc.18.32

• /addition/nucleophilic substitution reactions. Keywords: aza-Wittig reaction; 3,4-dihydroquinazoline; 4H-3,1-benzothiazine; nucleophilic substitution; Passerini reaction; Staudinger reaction; Introduction The chemistry of 3,4-dihydroquinazolines and 4H-3,1-benzothiazines is of constant interest owing to

• polysubstituted 3,4-dihydroquinazolines and 4H-3,1-benzothiazines under mild reaction conditions is still of high demand in the discovery of biologically active compounds. The Passerini reaction is an isocyanide-based multicomponent reaction, which has been used in preparing various α-acyloxy adducts starting

• -azidobenzaldehyde (1a), benzoic acid (2a) and tert-butyl isocyanide (3a) as the reactants (Scheme 2). When a mixture of 1a, 2a, and 3a in CH2Cl2 was stirred at room temperature for 48 h, the three-component Passerini reaction was carried out smoothly and the azide 4a (R = Ph) was finally obtained in 87% yield

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

• library of androstanic derivatives 21 (Figure 2B) and their reduced analogues bearing the 3β-hydroxy group were biologically tested showing antifungal activity against Fusarium virguliforme and Fusarium solani. The generation of this compound library suffered from the formation of the Passerini reaction

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

• synthesis of telaprevir 64, a protease inhibitor used in the treatment of hepatitis C, through a very short and efficient synthetic strategy involving as key steps two IMCRs (Ugi and Passerini) [28]. The strategy involved the synthesis of isocyanide 58 via a Passerini reaction using aldehyde 56, cyclopropyl

• diastereomers. After converting 68 into aldehyde 69, this was reacted with cyclopropyl isocyanide 57 and acetic acid (Passerini reaction) furnishing compound 70, which was converted to telaprevir (64) in three additional steps. Macrocyclic peptoid synthesis Dömling et al. performed the combination of two

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

• the Passerini reaction for the first time in a sequential multicomponent tandem reaction approach. After evaluation of all possible linker components and a suitable solvent system, highly functionalized dihydropyrimidone–α-acyloxycarboxamide compounds were obtained in good to excellent yields. In a

• first reaction step, different 3,4-dihydropyrimidin-2(1H)-one acids were synthesized, isolated and fully characterized. These products were subsequently used in a Passerini reaction utilizing a dichloromethane/dimethyl sulfoxide solvent mixture. By variation of the components in both multicomponent

• ; multicomponent reactions; Passerini reaction; tandem reactions; Introduction Multicomponent reactions (MCRs) are fascinating straightforward reactions for the preparation of diversely substituted products starting from three or more precursor molecules, forming products containing atoms/moieties of all

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

• microwave (MW) reactor (3 min at 80 °C) to provide the peptoid 7 in 77–87% yield. Peptoid 7 was subjected to hydrolysis in the presence of LiOH (THF/H2O, 0 °C, 2.5 h) followed by treatment with 2 M NaHSO4 providing the corresponding acid 8 in 92–100% yield. Acid 8 was then employed in a Passerini reaction

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

• ideally suited for automated synthesis [14][15][16][17][18]. Among the MCRs, the isocyanide-based multicomponent reactions (IMCRs), such as the Ugi and the Passerini reaction, are the most relevant reactions for constructing peptidomimetics since they give access to (depsi)peptide-like structures. However

• . the incorporation of bifunctional substrates or by activation of functionalized substrates in the initial MCR [19]. The Passerini reaction The first isocyanide-based MCR was described by Mario Passerini in 1921 and named after him. The Passerini reaction is a three-component reaction (3-CR) and

• reported for the first time by Ivar Ugi in 1959. This Ugi four-component reaction (U-4CR) furnishes α-acylamino amides 11 by combining oxo-substrates, carboxylic acids, amines and isocyanides in one-pot and like the Passerini reaction a wide variety of substrates is tolerated. In contrast to the Passerini

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

• , with competitive Passerini reaction in the latter case [28][29]. With the general process in place, the MCR approach was employed to generate a library of synthetic derivatives of 1 with the hope of gaining a first glimpse of structure–activity relationships (SAR), and to give hints for further

Recent advances in direct C–H arylation: Methodology, selectivity and mechanism in oxazole series

• Cécile Verrier,
• Pierrik Lassalas,
• Laure Théveau,
• Guy Quéguiner,
• François Trécourt,
• Francis Marsais and
• Christophe Hoarau

Beilstein J. Org. Chem. 2011, 7, 1584–1601, doi:10.3762/bjoc.7.187

• analysis [35]. Nevertheless, subsequent cross-coupling reactions under palladium catalysis were successfully achieved. Similarly to the Passerini reaction, it was hypothesized that the crucial transmetalation step proceeds throught a nucleophilic displacement of the halogen from the σ-arylpalladium complex

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

• chelated enolates and subsequent oxidation/Passerini reaction. This protocol works with both, aldehyde and ketone intermediates, as long as the ketones are activated by electron-withdrawing groups. In principle Ugi reactions are also possible, allowing the generation of diamino acid derivatives. Keywords

• isonitrile-based MCRs (IMCR) especially have developed exceptionally well during the last few decades [7][8]. Based on the pioneering work of Passerini, who observed the first three-component coupling of carbonyls with carboxylic acids and isonitriles in 1921 [9], the so-called Passerini reaction became a

Multicomponent reactions

• Thomas J. J. Müller

Beilstein J. Org. Chem. 2011, 7, 960–961, doi:10.3762/bjoc.7.107

• Passerini reaction and the conclusions he drew from this. Now the major conceptual challenge comprises the engineering of novel types of MCR. Most advantageously and practically, MCR can often be extended into combinatorial, solid phase or flow syntheses promising manifold opportunities for developing novel