Multicomponent reactions driving the discovery and optimization of agents targeting central nervous system pathologies

• Lucía Campos-Prieto,
• Aitor García-Rey,
• Eddy Sotelo and
• Ana Mallo-Abreu

Beilstein J. Org. Chem. 2024, 20, 3151–3173, doi:10.3762/bjoc.20.261

• obtain α-acylaminoamides. Innovation in recent years with alternative reagents, like N-hydroxyimides or nitric acid in place of an acid, N-alkylated hydrazines, or nitrobenzene derivatives (reduced in situ to anilines) instead of amines, and in situ-prepared isocyanides, makes it a versatile method for

• reaction (Scheme 1). A wide variety of isatins were suitable for performing the 4-center 3-component Ugi reaction (U4C-3CR), as well as isocyanides. Using 3-aminopropanoic acid (or β-alanine) and 4-aminobutanoic acid (or γ-aminobutyric acid), the corresponding β- and γ-lactam derivatives were obtained

• single step. The oxazepine scaffold can be easily accessed using the Ugi four-component reaction. By modifying this scaffold, the researchers aimed to reduce the hydrogen-bond donating properties. The Passerini reaction, employing bifunctional salicylaldehydes and isocyanides successfully yielded

Synthesis of the 1,5-disubstituted tetrazole-methanesulfonylindole hybrid system via high-order multicomponent reaction

• Cesia M. Aguilar-Morales,
• América A. Frías-López,
• Nadia V. Emilio-Velázquez,
• Alejandro Islas-Jácome,
• Angelica Judith Granados-López,
• Jorge Gustavo Araujo-Huitrado,
• Yamilé López-Hernández,
• Hiram Hernández-López,
• Luis Chacón-García,
• Jesús Adrián López and
• Carlos J. Cortés-García

Beilstein J. Org. Chem. 2024, 20, 3077–3084, doi:10.3762/bjoc.20.256

• ; isocyanides; MCF-7 cell line; methanesulfonylindoles; Ugi-azide reaction; Introduction Nitrogen-containing heterocyclic moieties, such as 1,5-disubstituted tetrazoles and indoles, are considered pharmacophoric fragments due to their pivotal interactions with several targets involved in many diseases. They

• studies, we employed benzaldehyde derivatives with various stereoelectronic decoration, excluding aliphatic ones due to their decreased reactivity resulting in failures to proceed [24][25][26][27]. Commercially available isocyanides utilized were cyclohexyl and tert-butyl isocyanide. Notably, an isolation

Synthesis of pyrrole-fused dibenzoxazepine/dibenzothiazepine/triazolobenzodiazepine derivatives via isocyanide-based multicomponent reactions

• Marzieh Norouzi,
• Mohammad Taghi Nazeri,
• Ahmad Shaabani and
• Behrouz Notash

Beilstein J. Org. Chem. 2024, 20, 2870–2882, doi:10.3762/bjoc.20.241

• .20.241 Abstract An efficient and facile synthesis of pyrrole-fused dibenzoxazepine/dibenzothiazepine/triazolobenzodiazepine derivatives was developed through the isocyanide-based multicomponent reaction of isocyanides, gem-diactivated olefins, and cyclic imines such as dibenzoxazepine, dibenzothiazepine

• great attention in biomedical applications, clinical diagnostics, and conjugate materials. Keywords: cyclic imines; dibenzothiazepine; dibenzoxazepine; isocyanides; multicomponent reactions; pyrrole; triazolobenzodiazepine; Introduction Pyrroles and their derivatives are important N-heterocyclic

• addition to the application of isocyanides in a variety of MCRs, one of the unique reactions involves the formation of zwitterions from isocyanides upon reaction with acetylene and active olefin compounds such as alkyl acetylenedicarboxylates and gem-diactivated olefins. Due to having nucleophilic and

Synthesis of spiroindolenines through a one-pot multistep process mediated by visible light

• Francesco Gambuti,
• Jacopo Pizzorno,
• Chiara Lambruschini,
• Renata Riva and
• Lisa Moni

Beilstein J. Org. Chem. 2024, 20, 2722–2731, doi:10.3762/bjoc.20.230

• efficient methods for the synthesis of heterocycles by multicomponent processes and domino reactions [16][17][18][19][20], here we disclosed the oxidative one-pot four-step synthesis of 2-amino-3,3’-spiroindolenines using readily available tertiary amines, electron-rich anilines and isocyanides as starting

• -pot multistep synthesis of unprecedent 2,3-diaminoindolenines using graphene oxide (GO) as heterogeneous catalyst [21]. The protocol involves the three-component Ugi (3C-Ugi) reaction between aldehydes, isocyanides and 2 equivalents of electron-rich anilines to give α-aminoamidines, which undergo a C

• Supporting Information File 1). Having the optimized conditions in our hands, we moved on to establish the scope (Scheme 3). Different N-arylated-THIQs, isocyanides and electron-rich anilines have been combined. The overall yields of the protocol are good considering its multistep behavior. Very good results

A review of recent advances in electrochemical and photoelectrochemical late-stage functionalization classified by anodic oxidation, cathodic reduction, and paired electrolysis

• Nian Li,
• Ruzal Sitdikov,
• Ajit Prabhakar Kale,
• Joost Steverlynck,
• Bo Li and
• Magnus Rueping

Beilstein J. Org. Chem. 2024, 20, 2500–2566, doi:10.3762/bjoc.20.214

• method for the formation of C–S bonds [25]. This method achieves the difunctionalization of a carbon atom by reacting isocyanide 2-isocyanoacetate with a thiophenol and an alcohol. The scope is very broad for thiophenols, alcohols, and isocyanides, and even alkyl thiols are compatible. In addition to

Deuterated reagents in multicomponent reactions to afford deuterium-labeled products

• Kevin Schofield,
• Shayna Maddern,
• Yueteng Zhang,
• Grace E. Mastin,
• Rachel Knight,
• Wei Wang,
• James Galligan and
• Christopher Hulme

Beilstein J. Org. Chem. 2024, 20, 2270–2279, doi:10.3762/bjoc.20.195

• significantly enhanced metabolic stability, a key parameter for property-based design efforts. Keywords: deuterated aldehydes; deuterated formamides; deuterated isocyanides; DHPs; kinetic isotope effect; Leuckart–Wallach; microsomal stability; multicomponent reactions; Introduction Multicomponent reactions

• (MCRs) are one-pot reactions that utilize three or more readily available starting materials [1][2][3][4]. Typically, MCRs use reactive functional groups such as ketones or aldehydes, carboxylic acids, amines, and isocyanides where these simple building blocks can be utilized to form large libraries of

• exposure [7][8][9]. Herein, we describe applications of deuterium-labeled reagents with MCRs through use of deuterated aldehydes and deuterated isocyanides, an area of study with sparingly few examples. One example by Srivastava obtained a 65% deuterated Passerini product starting from a 65% deuterated

Efficacy of radical reactions of isocyanides with heteroatom radicals in organic synthesis

• Akiya Ogawa and
• Yuki Yamamoto

Beilstein J. Org. Chem. 2024, 20, 2114–2128, doi:10.3762/bjoc.20.182

• is a promising synthetic reagent not only as a one-carbon homologation reagent but also as a nitrogen source for nitrogen-containing molecules. Because of their isoelectronic structure with carbon monoxide, isocyanides also react with nucleophiles, electrophiles, carbon radicals, and transition metal

• reagents, and are widely used in organic synthesis. On the other hand, the use of isocyanides in reactions with heteroatom radicals is limited. However, the reaction of isocyanides with heteroatom radicals is a promising synthetic tool for the construction of nitrogen-containing organic molecules modified

• with a variety of heteroatoms. In this Perspective, we review the addition and cyclization reactions of heteroatom radicals with isocyanides and discuss the synthetic prospects of the reaction of isocyanides with heteroatom radicals. Keywords: aza-Bergman cyclization; heteroatom-mixed system; imidoyl

The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162

• /bjoc.20.162 Abstract The Groebke–Blackburn–Bienaymé (GBB) three-component reaction, discovered in 1998, is a very efficient strategy to assemble imidazo[1,2-a]-heterocycles starting from amidines, aldehydes and isocyanides. This review aims to exhaustively describe innovative aspects of this reaction

• achieved during the last five years, and classifies them into five categories: synthetic methods, building blocks, scaffolds, biological activities and physical properties. Keywords: Groebke–Blackburn–Bienaymé reaction; multicomponent reactions; heterocycles; imidazo[1,2-a]pyridines; isocyanides

• , was not observed. In 2016, Sashidhara et al. reported the catalytic effect of Ag(OTf) on GBB reactions, postulating its role in activating the attack of the isocyanides onto the imine intermediates [7]; some years later Liu et al. reported a similar role of AgOAc [8]. Although the reaction was tested

Ugi bisamides based on pyrrolyl-β-chlorovinylaldehyde and their unusual transformations

• Alexander V. Tsygankov,
• Vladyslav O. Vereshchak,
• Tetiana O. Savluk,
• Serhiy M. Desenko,
• Valeriia V. Ananieva,
• Oleksandr V. Buravov,
• Yana I. Sakhno,
• Svitlana V. Shishkina and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2024, 20, 1773–1784, doi:10.3762/bjoc.20.156

• University, Svobody sq., 4, 61022, Kharkiv, Ukraine 10.3762/bjoc.20.156 Abstract By one-pot four- and three-component Ugi reactions involving convertible isocyanides and unexplored pyrrole-containing β-chlorovinylaldehyde, a small library of 20 bisamides with unusual behavior in post-Ugi transformations was

• heterylidenepyruvic acid. An optimized synthetic protocol for this transformation was elaborated and a plausible sequence involving the elimination of the 2-chloroacetamide moiety and the conversion of the β-chlorovinyl fragment into a vinyl one is provided. Keywords: convertible isocyanides; multicomponent reaction

• -called convertible isocyanides [27][28][29][30][31][32][33][34][35][36] in Ugi-4CR makes it possible to obtain carboxylic acids or esters after hydrolysis of the secondary amide group in the Ugi products (Scheme 2) [27][28][29][31][32][34][35][36]. Ugi bisamides modified in this way may be subsequently

Harnessing unprotected deactivated amines and arylglyoxals in the Ugi reaction for the synthesis of fused complex nitrogen heterocycles

• Javier Gómez-Ayuso,
• Pablo Pertejo,
• Tomás Hermosilla,
• Israel Carreira-Barral,
• Roberto Quesada and
• María García-Valverde

Beilstein J. Org. Chem. 2024, 20, 1758–1766, doi:10.3762/bjoc.20.154

• protecting groups, as the reduced nucleophilic character of the amino group of the anthranilic acid would prevent its participation in the Ugi reaction. In this way, the Ugi reaction was performed using arylglyoxals 1, anthranilic acid derivatives 2, amines 3 and isocyanides 4 following the most common

• strategy with aromatic amines [24], pyrrole-2-carboxylic acid and N-phenylglycine, and carried out their reactions with arylglyoxals, alkylamines and isocyanides (Scheme 5). As we expected, the cyclization product 9 was observed, although the complete cyclization of the Ugi adduct, found as the enol

Syntheses and medicinal chemistry of spiro heterocyclic steroids

• Laura L. Romero-Hernández,
• Ana Isabel Ahuja-Casarín,
• Penélope Merino-Montiel,
• Sara Montiel-Smith,
• José Luis Vega-Báez and
• Jesús Sandoval-Ramírez

Beilstein J. Org. Chem. 2024, 20, 1713–1745, doi:10.3762/bjoc.20.152

• through a one-pot multicomponent reaction (MCR) involving the reaction of substituted 2-aminopyridines, isocyanides, and the cholestanone derivatives 56 [36]. The reactions were conducted in dimethyl sulfoxide at 70 °C, and catalysed by propylphosphonic anhydride (T3P®), providing high yields in all cases

Rapid construction of tricyclic tetrahydrocyclopenta[4,5]pyrrolo[2,3-b]pyridine via isocyanide-based multicomponent reaction

• Xiu-Yu Chen,
• Ying Han,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2024, 20, 1436–1443, doi:10.3762/bjoc.20.126

• )-pentacarboxylates was developed by a three-component reaction. In the absence of any catalyst, the three-component reaction of alkyl isocyanides, dialkyl but-2-ynedioates and 5,6-unsubstituted 1,4-dihydropyridines in refluxing acetonitrile afforded polyfunctionalized tetrahydrocyclopenta[4,5]pyrrolo[2,3-b]pyridine

• carbon atom of isocyanide has both a lone electron pair and empty orbitals, so it has outstanding electrophilic and nucleophilic reactivity. At the same time, isocyanide also has good coordination ability to coordinate with metals to form diverse metal complexes [1][2][3]. Therefore, isocyanides have

• , Orru reaction and Van Leusen reaction, in which isocyanides were employed as key substrates have become the most powerful tools for rapid construction of various nitrogen-containing organic compounds [7][8][9][10][11][12][13][14]. On the other hand, the reactive Huisgen’ 1,4-dipoles can be in situ

Innovative synthesis of drug-like molecules using tetrazole as core building blocks

• Jingyao Li,
• Ajay L. Chandgude,
• Qiang Zheng and
• Alexander Dömling

Beilstein J. Org. Chem. 2024, 20, 950–958, doi:10.3762/bjoc.20.85

• moiety is introduced in a late-stage-modification approach, mostly from nitriles or isocyanides (Figure 1b) [13]. On the other hand, accessing diverse tetrazole scaffolds from MCRs, typically involves first de novo construction of the tetrazole scaffold and subsequent post-modifications (Figure 1c) [14

• use in MCRs to access diverse molecular scaffolds. To do that, we first developed an efficient and scalable MCR-based route of the building blocks, in order to provide useful quantities by utilizing diverse isocyanides, azide and paraformaldehyde. Then, this novel tetrazole building block was used in

• isocyanide component (Scheme 1). Aliphatic isocyanides, such as tert-octyl and tert-butyl isocyanide (1b and 1c) were well-tolerated in the Passerini-tetrazole reaction, leading to the corresponding tetrazole products in moderate to good yields of 74% and 52%, respectively. β-Cyanoethyl isocyanide (1d) was

HPW-Catalyzed environmentally benign approach to imidazo[1,2-a]pyridines

• Luan A. Martinho and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2024, 20, 628–637, doi:10.3762/bjoc.20.55

• activities. The most direct way of obtaining this nucleus is the Groebke–Blackburn–Bienaymé three-component reaction (GBB-3CR) between aminopyridines, aldehydes, and isocyanides under both Lewis and Brønsted acid catalysis. However, several catalysts for this reaction have major drawbacks such as being

• conditions and the employment of relatively complex starting materials [19]. A more efficient way of obtaining this nucleus is through the Groebke–Blackburn–Bienaymé three-component reaction (GBB-3CR) between amidines (aminoazoles), aldehydes, and isocyanides under both Lewis and Brønsted acid catalysis [20

• 1, aromatic/heteroaromatic aldehydes 2, and isocyanides 3 to obtain the imidazo[1,2-a]pyridine derivatives 4 (Scheme 2). In general, the efficiency of the HPW-catalyzed GBB reaction is very dependent upon the type of 2-aminopyridine or isocyanide compound used, and not influenced by different

N-Sulfenylsuccinimide/phthalimide: an alternative sulfenylating reagent in organic transformations

• Fatemeh Doraghi,
• Seyedeh Pegah Aledavoud,
• Mehdi Ghanbarlou,
• Bagher Larijani and
• Mohammad Mahdavi

Beilstein J. Org. Chem. 2023, 19, 1471–1502, doi:10.3762/bjoc.19.106

• HCl-promoted 1,2-thiofunctionalization of aromatic alkenes. Coupling reaction of diazo compounds with N-sulfenylsuccinimides. Multicomponent reactions of disulfides with isocyanides and other nucleophiles. α-Sulfenylation and β-sulfenylation of α,β-unsaturated carbonyl compounds.

Synthesis of imidazo[1,2-a]pyridine-containing peptidomimetics by tandem of Groebke–Blackburn–Bienaymé and Ugi reactions

• Oleksandr V. Kolomiiets,
• Alexander V. Tsygankov,
• Maryna N. Kornet,
• Aleksander A. Brazhko,
• Vladimir I. Musatov and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2023, 19, 727–735, doi:10.3762/bjoc.19.53

• peptidomimetic chain was already described in 2010 [32]. Thus, the corresponding acid components were synthesized with GBB-3CR and used in Ugi and Paserini reactions with various aldehydes, amines (for Ugi) and isocyanides. Moreover, in 2016 [33], an alternative route to use GBB-3CR products in Ugi reaction as

• temperature and the reaction time. After a series of experiments, it was found that stirring the isocyanides 3a–d, heterocyclic acids 4a–c, aldehydes 5a–e, and primary amines 6a–d at 50 °C in methanol for 24–48 hours (depending on the nature of the starting materials) allowed obtaining the Ugi target products

Nucleophile-induced ring contraction in pyrrolo[2,1-c][1,4]benzothiazines: access to pyrrolo[2,1-b][1,3]benzothiazoles

• Ekaterina A. Lystsova,
• Maksim V. Dmitriev,
• Andrey N. Maslivets and
• Ekaterina E. Khramtsova

Beilstein J. Org. Chem. 2023, 19, 646–657, doi:10.3762/bjoc.19.46

• -benzothiazol-2-yl(diazo)acetates (Scheme 1, entry 3) [12], dearomative [3 + 2] cycloaddition reactions of benzothiazoles with cyclopropanes (Scheme 1, entry 4) [13][14][15], multicomponent reactions (MCRs) of benzothiazoles, isocyanides and 2-methylidenemalonates (Scheme 1, entry 5) [16], 1,3-dipolar

Group 13 exchange and transborylation in catalysis

• Dominic R. Willcox and
• Stephen P. Thomas

Beilstein J. Org. Chem. 2023, 19, 325–348, doi:10.3762/bjoc.19.28

• hydroboration of imines [87][92][97], nitriles [92][98][99][100][101], carbodiimides [92][100][102], pyridine [92], and isocyanides [92] with HBpin (Scheme 23). These generally follow a similar proposed catalytic cycle; aluminium-mediated reduction, followed by Al‒N/B‒H exchange with HBpin (Scheme 23). The

NaI/PPh₃-catalyzed visible-light-mediated decarboxylative radical cascade cyclization of N-arylacrylamides for the efficient synthesis of quaternary oxindoles

• Dan Liu,
• Yue Zhao and
• Frederic W. Patureau

Beilstein J. Org. Chem. 2023, 19, 57–65, doi:10.3762/bjoc.19.5

• /cyclization cascades from acrylamides for the synthesis of oxindoles [39][40][41]. The radicals are typically generated from alkyl halides [42][43][44], carboxylic acids [45][46][47], simple alkanes [48], alkylboronic acids [49], isocyanides [50], or other [51][52][53]. In this context, the group of Fu

Dissecting Mechanochemistry III

• Lars Borchardt and
• José G. Hernández

Beilstein J. Org. Chem. 2022, 18, 1454–1456, doi:10.3762/bjoc.18.150

• the use of halogenated compounds and include the mechanochemical preparation of isocyanides [10], formylated and acetylated amines [11], and the mechanosynthesis of unsymmetrical salens ligands for preparing metal–salen catalysts [12]. This illustrates the broad applicability of mechanochemical

From amines to (form)amides: a simple and successful mechanochemical approach

• Federico Casti,
• Rita Mocci and
• Andrea Porcheddu

Beilstein J. Org. Chem. 2022, 18, 1210–1216, doi:10.3762/bjoc.18.126

• products [1][9]. N-Formyl derivatives were used as building blocks in Vilsmeier–Haack reactions [10][11] and for preparing molecule drug substances, various heterocycles, formamidines, isocyanates, and isocyanides [12][13][14][15][16][17]. The large number of procedures reported in the literature witnesses

• reactions [35][36][37][38][39][40][41][42]. In our effort to develop green and sustainable methodologies using mechanochemistry [43][44][45][46], we recently studied a protocol for synthesizing isocyanides using p-tosyl chloride (Ts-Cl) in basic conditions, starting from the corresponding formamides [47

• compatible means in the view of a one-pot methodology for preparing isocyanides directly from amines [56]. When the amine 1 was reacted in the presence of Et3N, HCOOH, and p-Ts-Im [58] (Table 1, entry 5), the formamide was accompanied by a significant amount of sulfonamide (formamide/sulfonamide ratio: 70:30

A trustworthy mechanochemical route to isocyanides

• Francesco Basoccu,
• Federico Cuccu,
• Federico Casti,
• Rita Mocci,
• Claudia Fattuoni and
• Andrea Porcheddu

Beilstein J. Org. Chem. 2022, 18, 732–737, doi:10.3762/bjoc.18.73

• Francesco Basoccu Federico Cuccu Federico Casti Rita Mocci Claudia Fattuoni Andrea Porcheddu Dipartimento di Scienze Chimiche e Geologiche, Università degli Studi di Cagliari, Cittadella Universitaria, Monserrato, 09042 Cagliari, Italy 10.3762/bjoc.18.73 Abstract Isocyanides are hardly produced

• straightforward procedure. Keywords: green chemistry; isocyanide; isonitriles; mechanochemistry; Introduction Isocyanides were first discovered more than a century ago by Lieke in Göttingen after having handled allyl iodide and potassium cyanide to synthesize crotonic acid. This attempt, instead, brought to the

• envisioned the feasibility of producing isocyanides from primary formamides by using anhydrides as dehydrating agents. Therefore, we focused our attention on acetic, trifluoroacetic, and isatoic anhydrides to achieve this. First attempts were made on acetic and trifluoroacetic anhydrides. The best results

Cs₂CO₃-Promoted reaction of tertiary bromopropargylic alcohols and phenols in DMF: a novel approach to α-phenoxyketones

• Ol'ga G. Volostnykh,
• Olesya A. Shemyakina,
• Anton V. Stepanov and
• Igor' A. Ushakov

Beilstein J. Org. Chem. 2022, 18, 420–428, doi:10.3762/bjoc.18.44

• )pyrroles [15]. The CsF-promoted nucleophilic addition of isocyanides to bromoacetylenes furnished the functionalized bromovinyl amides followed by Pd-catalyzed formation of 5-iminopyrrolone [16]. Sequential nucleophilic addition/intramolecular cyclization of amidine with bromoacetylenes led to imidazoles

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

• isocyanides 3 produced the azide intermediates 4, which were treated sequentially with triphenylphosphine, isocyanates (or CS2), and secondary amines to give polysubstituted 3,4-dihydroquinazolines 8 and 4H-3,1-benzothiazines 11 in good overall yields through consecutive Passerini/Staudinger/aza-Wittig

• product 8a was 53%. Therefore, the reaction conditions of entry 1 in Table 1 were optimal for the above transformation. The optimal reaction conditions were then utilized for the sequential reactions of different 2-azidobenzaldehydes 1, benzoic acid (2a), isocyanides 3, isocyanates and secondary amines

Recent advances in the tandem annulation of 1,3-enynes to functionalized pyridine and pyrrole derivatives

• Yi Liu,
• Puying Luo,
• Yang Fu,
• Tianxin Hao,
• Xuan Liu,
• Qiuping Ding and
• Yiyuan Peng

Beilstein J. Org. Chem. 2021, 17, 2462–2476, doi:10.3762/bjoc.17.163

• products 52 were obtained efficiently through the cascade reactions of enynals 51, primary amines, aliphatic isocyanides, and trimethylsilyl azide. The following reaction involves Ag-catalyzed intramolecular 5-endo-dig cyclization and base (DMAP)-promoted oxidative isomerization. The presence of DMAP is