One-pot Ugi-azide and Heck reactions for the synthesis of heterocyclic systems containing tetrazole and 1,2,3,4-tetrahydroisoquinoline

• Jiawei Niu,
• Yuhui Wang,
• Shenghu Yan,
• Yue Zhang,
• Xiaoming Ma,
• Qiang Zhang and
• Wei Zhang

Beilstein J. Org. Chem. 2024, 20, 912–920, doi:10.3762/bjoc.20.81

• schistosomiasis [22][23][24][25]. The combination of the privileged heterocycles tetrazole and tetrahydroisoquinoline in one molecule generates new molecules which could have biological activities. A standard Ugi four-component reaction (Ugi-4CR) of an aldehyde, amine, isocyanide, and a carboxylic acid produces

• highly diverse peptidic structures A with up to four points of substitution (Scheme 1) [26][27]. By replacing the carboxylic acid with a nucleophilic azide reagent XN3 (generally TMSN3), the Ugi-azide four-component reaction (UA-4CR) of an aldehyde, amine, isocyanide, and azide gives 1,5-disubstituted 1H

• reaction for the synthesis of tetrazolyl-1,2,3,4-tetrahydroisoquinoline scaffolds 6 and 8 (Scheme 3). The first step is the Ugi-azide reaction of a 2-bromobenzoaldehyde 1, allylamine hydrochloride (2), azidotrimethylsilane (TMSN3, 3), and an isocyanide 4 affording tetrazoles 5. If ethyl isocyanoacetate is

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

• our hands, when we tried to reproduce the reaction between 2-aminopyridine (1a), benzaldehyde (2), and tert-butyl isocyanide (3a), following in detail the reported protocol using exactly the same reaction conditions, the reaction failed completely in 20 minutes (followed by TLC) and after 72 h only 46

• -Aminopyridine (1a), 4-nitrobenzaldehyde (2a), and tert-butyl isocyanide (3a) were chosen as model substrates and different conditions were screened (Table 1). Glycerol, a green and sustainable solvent, was tried first, but unfortunately, the expected intense orange solid product 4a was obtained in low yields

• 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

Recent advancements in iodide/phosphine-mediated photoredox radical reactions

• Tinglan Liu,
• Yu Zhou,
• Junhong Tang and
• Chengming Wang

Beilstein J. Org. Chem. 2023, 19, 1785–1803, doi:10.3762/bjoc.19.131

• and a PPh3–I radical III. The subsequent isocyanide 44 SOMOphilic insertion reaction led to the formation of an imidoyl radical B. This radical then underwent rapid addition onto the C–C double bond, resulting in the release of the desired phenanthridine products 45. Importantly, this process also

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

• in the presence of TEMPO, followed by insertion of an isocyanide molecule 166 or other nucleophiles 161 (Scheme 72) [102]. By studying the spectroscopic evidence, the authors found that both sulfenyl halide 165 and N-sulfenylsuccinimide 1 intermediates were involved in the reaction. Removal of TEMPO

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

• –Bienaymé reaction; imidazo[1,2-a]pyridine; isocyanide; multicomponent reaction; peptidomimetic; Ugi reaction; Introduction The use of isocyanide multicomponent reactions (IMCR) to prepare biologically active compounds is one of the most promising tools in modern organic and medicinal chemistry. Therefore

• , isocyanide multicomponent reactions are the way to prepare the necessary drugs "of tomorrow", and the possibility to combine such reactions gives a powerful method to rapidly and qualitatively expand the molecular diversity of biologically active compounds. The following possible combinations of IMCR have

• been described till today: Ugi and Ugi, azido-Ugi and Ugi, Ugi and Passerini, Groebke–Blackburn–Bienaymé (GBB-3CR) and Ugi, GBB-3CR and GBB-3CR, GBB-3CR and Passerini, Orru and Ugi, Orru and Passerini [1] (Scheme 1). However, the issue of whether certain isocyanide multicomponent reactions can be

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

• ]. In this work, we aimed to set compatible conditions to access formamides, envisioning the possibility of generating the isocyanide in a one-pot, two-step reaction. However, to the best of our knowledge, despite the notable improvement in the mechanochemical synthesis of the amide moiety [44][48][49

New azodyrecins identified by a genome mining-directed reactivity-based screening

• Atina Rizkiya Choirunnisa,
• Kuga Arima,
• Yo Abe,
• Noritaka Kagaya,
• Kei Kudo,
• Hikaru Suenaga,
• Junko Hashimoto,
• Manabu Fujie,
• Noriyuki Satoh,
• Kazuo Shin-ya,
• Kenichi Matsuda and
• Toshiyuki Wakimoto

Beilstein J. Org. Chem. 2022, 18, 1017–1025, doi:10.3762/bjoc.18.102

• facilitate the subsequent isolation process of the target molecules. This strategy has been successfully applied for detecting a range of peculiar functional groups, such as ureido [7], isocyanide [8], and alkyne [9][10]. A combination of reactivity-based screening and genome-based prioritization would allow

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

• synthetic pathways usually involve employing strong conditions and toxic reagents. The current paper intends to provide a conceptually innovative synthetic protocol for mechanochemical isocyanide preparation, simultaneously lowering the related reagents' toxicity and improving their purification in a

• 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

• accidental synthesis of an isocyanide which was recognizable by its revolting smell, as reported by Lieke [1]. A deepening of the topic arrived, though, only in the following century, when a natural and potential pharmaceutical compound was discovered, namely xanthocillin [2]. Finally, after two decades, the

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

• 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

Selective sulfonylation and isonitrilation of para-quinone methides employing TosMIC as a source of sulfonyl group or isonitrile group

• Chuanhua Qu,
• Run Huang,
• Yong Li,
• Tong Liu,
• Yuan Chen and
• Guiting Song

Beilstein J. Org. Chem. 2021, 17, 2822–2831, doi:10.3762/bjoc.17.193

• -toluenesulfonylmethyl isocyanide (TosMIC) by using respectively zinc iodide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as catalysts were developed. The distinguishing feature of this method is that TosMIC plays a dual role from the same substrates in the reaction: as a sulfonyl source or as an isonitrile source. The

• . Therefore, there is great need to develop a more effective and rapid method for preparing diaryl methyl sulfones. p-Toluenesulfonylmethyl isocyanide (TosMIC), a versatile synthon in organic chemistry, has been widely used to synthesize a myriad of valuable chemicals due to its high reactivity shown by the

• preparation of highly valuable diarylmethyl sulfones are relatively scarce [24]. In addition, the important link between structural diversity and complexity with bioactivity represented by sulfones has led to the goal of developing strategies to as many these pivotal scaffolds as possible. Isocyanide is an

Asymmetric organocatalyzed synthesis of coumarin derivatives

• Natália M. Moreira,
• Lorena S. R. Martelli and
• Arlene G. Corrêa

Beilstein J. Org. Chem. 2021, 17, 1952–1980, doi:10.3762/bjoc.17.128

• acid (4) as catalyst [30]. Based on this pioneer work, our research group described an efficient, highly stereoselective, one-pot process comprising an organocatalytic conjugate addition of dimedone or 4-hydroxycoumarin 1 to α,β-unsaturated aldehydes 2 followed by an intramolecular isocyanide-based

A recent overview on the synthesis of 1,4,5-trisubstituted 1,2,3-triazoles

• Pezhman Shiri,
• Ali Mohammad Amani and
• Thomas Mayer-Gall

Beilstein J. Org. Chem. 2021, 17, 1600–1628, doi:10.3762/bjoc.17.114

• through an isocyanide insertion. The significant benefits of this strategy were simple substrates, few synthetic steps, and high diversity. A range of o‐azidophenols 148 as well as the compounds 150 and 151, along with alkynes 149 and isocyanides, were employed to survey the diversity of highly

• treated with aryl and aliphatic alkyne partners and then with tert-butyl and cyclohexyl isocyanide to give 1,2,3‐triazole-fused oxazines 152. The reaction was extended to 2‐(azidophenyl)methanol species 150, which were treated with ethynylbenzene and cyclohexyl isocyanide, and in all cases, the

• corresponding oxazepines 153 were obtained in good yield [63]. The 1-azido-2-bromobenzenes 151 with H, Me, F, Cl, and CF3 substituents, respectively, on the phenyl ring were then tested in the reaction with phenylacetylene (149a), followed by treatment with tert‐butyl isocyanide or cyclohexyl isocyanide under

One-step synthesis of imidazoles from Asmic (anisylsulfanylmethyl isocyanide)

• Louis G. Mueller,
• Allen Chao,
• Embarek AlWedi and
• Fraser F. Fleming

Beilstein J. Org. Chem. 2021, 17, 1499–1502, doi:10.3762/bjoc.17.106

• Substituted imidazoles are readily prepared by condensing the versatile isocyanide Asmic, anisylsulfanylmethylisocyanide, with nitrogenous π-electrophiles. Deprotonating Asmic with lithium hexamethyldisilazide effectively generates a potent nucleophile that efficiently intercepts nitrile and imine

• to imidazoles [11][12], the condensation of metalated isocyanides with nitrogenous π-electrophiles is distinguished by excellent efficiency and modularity. Deprotonating an isocyanide 1 affords an isocyanide-stabilized anion 2 whose condensation with an imidate or nitrile generates a transient imine

• 3 that readily cyclizes to afford imidazole 4 (Scheme 1). The excellent efficiency is somewhat countered by requiring isocyanides that are readily deprotonated; metalation of alkylisocyanides is challenging except for methyl isocyanide which is why most isocyanides employed in accessing imidazoles

Synthesis of 1-indolyl-3,5,8-substituted γ-carbolines: one-pot solvent-free protocol and biological evaluation

• Premansh Dudhe,
• Mena Asha Krishnan,
• Kratika Yadav,
• Diptendu Roy,
• Krishnan Venkatasubbaiah,
• Biswarup Pathak and
• Venkatesh Chelvam

Beilstein J. Org. Chem. 2021, 17, 1453–1463, doi:10.3762/bjoc.17.101

• has limited their development as environment-friendly synthetic protocols. More recently, an acid-catalyzed cyclization of α-indol-2-ylmethyl TosMIC (tosylmethyl isocyanide) derivatives to synthesize heterocycles [19] has been thoroughly studied (Scheme 1), including the synthesis of the carboline

Design, synthesis and photophysical properties of novel star-shaped truxene-based heterocycles utilizing ring-closing metathesis, Clauson–Kaas, Van Leusen and Ullmann-type reactions as key tools

• Shakeel Alvi and
• Rashid Ali

Beilstein J. Org. Chem. 2021, 17, 1374–1384, doi:10.3762/bjoc.17.96

• the required triformyltruxene 19 as a major product along with a minor amount of diformyltruxene 18 (Scheme 6). Later, both the di- and triformylated truxene systems 18/19 were subjected to oxazole formation involving p-toluenesulfonylmethyl isocyanide (TosMIC) in Van Leusen fashion to provide the

Microwave-assisted multicomponent reactions in heterocyclic chemistry and mechanistic aspects

• Shivani Gulati,
• Stephy Elza John and
• Nagula Shankaraiah

Beilstein J. Org. Chem. 2021, 17, 819–865, doi:10.3762/bjoc.17.71

• electrostatic interaction between carboxylate and iminium moieties undergoes a nucleophilic attack by isocyanide to generate nitrilium ion B. The intramolecular acylation of B forms C followed by Mumm rearrangement results in the formation of the desired products 22. The intermediate D may exist in equilibrium

• cancer cell lines along with good antimicrobial activity (Scheme 24). The proposed mechanism (Scheme 25) involved a Knoevenagel condensation between aldehyde 5 and malononitrile (51) to form arylidene intermediate A. Then A reacts with isocyanide 21 to produce intermediate B which coordinates with 1,10

• first systemic synthesis of biologically interesting bisheterocycles. A three-component microwave-assisted reaction of substituted benzimidazole-linked aminopyridine 135, aldehydes 5 and isocyanide 21 using Sc(OTf)3 as the catalyst under solvent-free conditions resulted in substituted benzimidazole

Effective microwave-assisted approach to 1,2,3-triazolobenzodiazepinones via tandem Ugi reaction/catalyst-free intramolecular azide–alkyne cycloaddition

• Maryna O. Mazur,
• Oleksii S. Zhelavskyi,
• Eugene M. Zviagin,
• Svitlana V. Shishkina,
• Vladimir I. Musatov,
• Maksim A. Kolosov,
• Elena H. Shvets,
• Anna Yu. Andryushchenko and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2021, 17, 678–687, doi:10.3762/bjoc.17.57

• a few steps and constitutes one of the most actual and promising synthetic routes of modern organic chemistry. Among a wide variety of tandem strategies combination of an isocyanide-based multicomponent Ugi reaction with secondary transformations is one of the most powerful tools and provides access

• , amines 5, and phenylpropargylic acid (3a) or propargylic acid (3b, Scheme 3). In most cases, the reactions were carried under standard conditions for Ugi-4CR mentioned in the literature. Aldehyde and amine were premixed for 2 hours in methanol, then acid and isocyanide were sequentially added. Stirring

• ). Ugi product 6aaa (first letter – isocyanide code, second letter – amine code, third – carboxylic acid code) was the first to isolate in our trials and its structure was confirmed by X-ray analysis (Figure 3) in addition to mass spectrometry, elemental analysis, 1H and 13C NMR data. Compound 6

Amino- and polyaminophthalazin-1(2H)-ones: synthesis, coordination properties, and biological activity

• Zbigniew Malinowski,
• Emilia Fornal,
• Agata Sumara,
• Renata Kontek,
• Karol Bukowski,
• Beata Pasternak,
• Dariusz Sroczyński,
• Joachim Kusz,
• Magdalena Małecka and
• Monika Nowak

Beilstein J. Org. Chem. 2021, 17, 558–568, doi:10.3762/bjoc.17.50

• -bromobenzoate via palladium-catalyzed isocyanide insertion [32][33] (a method that is limited to tertiary-substituted isocyanides) or 2) the palladium or copper-catalyzed coupling of bromolactams with amines (a method that requires the usually lengthy synthesis of the bromoprecursors) [19][34]. Therefore, the

Direct synthesis of anomeric tetrazolyl iminosugars from sugar-derived lactams

• Michał M. Więcław and
• Bartłomiej Furman

Beilstein J. Org. Chem. 2021, 17, 115–123, doi:10.3762/bjoc.17.12

• undergoes a subsequent addition of an isocyanide moiety (intermediate V), followed by an azide anion addition. Intermediate VI undergoes a cyclization, producing VII, a silylated derivative of the expected product. The hydrolysis of VII most likely occurs during the reaction’s work-up. Preliminary DTF

Progress in the total synthesis of inthomycins

• Bidyut Kumar Senapati

Beilstein J. Org. Chem. 2021, 17, 58–82, doi:10.3762/bjoc.17.7

• elimination (Scheme 1) [35]. The oxazole vinylstannane 24 was prepared from commercially available butyne 21. The tri-n-butyltin hydride addition to 21, followed by Swern oxidation and direct oxazole formation with tosylmethyl isocyanide (TosMIC) gave the fragment 24, which was used immediately for the next

Controlling the stereochemistry in 2-oxo-aldehyde-derived Ugi adducts through the cinchona alkaloid-promoted electrophilic fluorination

• Yuqing Wang,
• Gaigai Wang,
• Anatoly A. Peshkov,
• Ruwei Yao,
• Muhammad Hasan,
• Manzoor Zaman,
• Chao Liu,
• Stepan Kashtanov,
• Olga P. Pereshivko and
• Vsevolod A. Peshkov

Beilstein J. Org. Chem. 2020, 16, 1963–1973, doi:10.3762/bjoc.16.163

• ][7][8][9][10][11][12][13] in general and isocyanide-based MCRs [14][15][16][17][18] in particular represent powerful tools of modern synthetic chemistry that allow to generate structurally diverse and complex products in a step and atom-economic manner from simple and accessible precursors. Three

• associated with controlling their stereochemical outcome [33][34][35] severely restrict their applicability in medicinal chemistry [36]. The typical Passerini three-component reaction (P-3CR) of a carboxylic acid 1, an aldehyde 2, and an isocyanide 3 being conducted in a polar-aprotic solvent such as THF or

• -component reaction (U-4CR) a carboxylic acid 1, an aldehyde 2, and an isocyanide 3 are complemented by a primary amine 5 that altogether undergo a condensation into a peptide-like adduct 6. These reactions are typically conducted in polar protic solvents such as methanol or water. Several examples of

Photocatalyzed syntheses of phenanthrenes and their aza-analogues. A review

• Alessandra Del Tito,
• Havall Othman Abdulla,
• Davide Ravelli,
• Stefano Protti and
• Maurizio Fagnoni

Beilstein J. Org. Chem. 2020, 16, 1476–1488, doi:10.3762/bjoc.16.123

• construct the phenanthridine core, somophilic (radical) isocyanide addition [45][46][47] is probably the most adopted one, in view of the versatility and low cost of the starting substrates. Accordingly, several protocols for the synthesis under photocatalytic conditions of phenanthridines starting from 2

• α‐carbonyl radicals was likewise reported [50]. On the contrary, the Mn(acac)3 photocatalyzed ring opening of cyclopropanol 6.2 gave an easy access to a β‐carbonyl radical 6.5·, which in turn added onto 2-biphenyl isocyanide 6.1 to give the corresponding 6-β-ketoalkyl phenanthridine 6.3 in a good

Oxime radicals: generation, properties and application in organic synthesis

• Igor B. Krylov,
• Stanislav A. Paveliev,
• Alexander S. Budnikov and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2020, 16, 1234–1276, doi:10.3762/bjoc.16.107

• authors noted the effect of substituents in the phenyl fragment attached to the oxime group (R1): high yields were obtained with para- and meta-substituted substrates; however, when ortho-substituents were present, the product 121 was not observed. Two aryl groups at the vinyl fragment of the isocyanide

Recent applications of porphyrins as photocatalysts in organic synthesis: batch and continuous flow approaches

• Rodrigo Costa e Silva,
• Luely Oliveira da Silva,
• Aloisio de Andrade Bartolomeu,
• Timothy John Brocksom and
• Kleber Thiago de Oliveira

Beilstein J. Org. Chem. 2020, 16, 917–955, doi:10.3762/bjoc.16.83

• direct addition of isocyanide and carboxylic acid. The Ugi products were obtained in 41–89% and 72–96% yields from 1,2,3,4-tetrahydroisoquinoline (Scheme 60) and dibenzylamine (Scheme 61), respectively [102]. Furthermore, Che and co-workers obtained a wide range of Mannich-type products by coupling N

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