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12 pages, 3217 KB

Open AccessArticle

Decarboxylation-Driven Double Annulations: Innovative Multi-Component Reaction Pathways

by Desheng Zhan, Gang Yang, Tieli Zhou, Sashirekha Nallapati and Xiaofeng Zhang

Molecules 2025, 30(7), 1594; https://doi.org/10.3390/molecules30071594 - 2 Apr 2025

Viewed by 668

A concerted five-component reaction strategy has been developed, featuring double [3+2] cycloadditions utilizing aspartic acid. This approach provides valuable insights into mechanistic pathways, allowing for the distinction between concerted and stepwise processes based on reaction efficiency and diastereoselectivity. Both aspartic and glutamic acids [...] Read more.

A concerted five-component reaction strategy has been developed, featuring double [3+2] cycloadditions utilizing aspartic acid. This approach provides valuable insights into mechanistic pathways, allowing for the distinction between concerted and stepwise processes based on reaction efficiency and diastereoselectivity. Both aspartic and glutamic acids have been employed for a thorough evaluation and exploration of decarboxylation-driven double annulations. This method effectively constructs pyrrolizidine frameworks through a concerted double 1,3-dipolar cycloaddition with aspartic acid, as well as tetrahydropyrrolizinones via three-component double annulations, which include decarboxylative 1,3-dipolar cycloaddition and lactamization with glutamic acid. These highly convergent, decarboxylation-driven multicomponent reactions (MCRs) efficiently produce fused polyheterocyclic systems while being environmentally friendly, generating only CO₂ and water as byproducts. Full article

(This article belongs to the Special Issue Heterocyclic Chemistry with Applications (Second Edition))

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26 pages, 6195 KB

Open AccessArticle

Mapping of Some Further Alkylation-Initiated Pathways to Polyheterocyclic Compounds from Indigo and Indirubin

by Sarfaraz Ali, Patrick M. McCosker, Anthony C. Willis, Stephen G. Pyne, Christopher Richardson, John B. Bremner and Paul A. Keller

Molecules 2024, 29(17), 4242; https://doi.org/10.3390/molecules29174242 - 6 Sep 2024

Cited by 2 | Viewed by 1545

Abstract

The reaction of indigo with two equivalents of the electrophile ethyl bromoacetate with caesium carbonate as a base result in the formation of structurally complex polyheterocyclics, including a fused spiroimidazole and a spiro[1,3]oxazino derivative, together with a biindigoid-type derivative, through a convenient one-pot [...] Read more.

The reaction of indigo with two equivalents of the electrophile ethyl bromoacetate with caesium carbonate as a base result in the formation of structurally complex polyheterocyclics, including a fused spiroimidazole and a spiro[1,3]oxazino derivative, together with a biindigoid-type derivative, through a convenient one-pot reaction. Further assessment of the reaction using five equivalents of the electrophile gave rise to other molecules incorporating the 2-(7,13,14-trioxo-6,7,13,14-tetrahydropyrazino[1,2-a:4,3-a′]diindol-6-yl) scaffold. The reaction of ethyl bromoacetate with the less reactive indirubin resulted in the synthesis of three derivatives of a new class of polyheterocyclic system via a cascade process, although yields were low. These compounds were derived from the parent indolo[1,2-b]pyrrolo[4,3,2-de]isoquinoline skeleton. Despite the modest yields of the reactions, they represent quick cascade routes to a variety of heterocycles from cheap starting materials, with these structures otherwise being difficult to synthesise in a traditional stepwise manner. These outcomes also contribute significantly to the detailed understanding of the indigo/indirubin cascade reaction pathways initiated by base-catalysed N-alkylation. Full article

(This article belongs to the Section Organic Chemistry)

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11 pages, 3208 KB

Open AccessCommunication

Complexity-Building ESIPT-Assisted Synthesis of Fused Polyheterocyclic Sulfonamides

by Srinivas Beduru and Andrei G. Kutateladze

Molecules 2023, 28(18), 6549; https://doi.org/10.3390/molecules28186549 - 10 Sep 2023

Cited by 2 | Viewed by 1484

Abstract

Excited State Intramolecular Proton Transfer (ESIPT), originally discovered and explored in depth in a number of extensive photophysical studies, is more recently rediscovered as a powerful synthetic tool, offering rapid access to complex polyheterocycles. In our prior work we have employed ESIPT in [...] Read more.

Excited State Intramolecular Proton Transfer (ESIPT), originally discovered and explored in depth in a number of extensive photophysical studies, is more recently rediscovered as a powerful synthetic tool, offering rapid access to complex polyheterocycles. In our prior work we have employed ESIPT in aromatic o-keto amines and amides, leading to diverse primary photoproducts—complex quinolinols or azacanes possessing a fused lactam moiety—which could additionally be modified in short, high-yielding postphotochemical reactions to further grow complexity of the heterocyclic core scaffold and/or to decorate it with additional functional groups. Given that sulfonamides are generally known as privileged substructures, in this study we pursued two goals: (i) To explore whether sulfonamides could behave as proton donors in the context of ESIPT-initiated photoinduced reactions; (ii) To assess the scope of subsequent complexity-building photochemical and postphotochemical steps, which give access to polyheterocyclic molecular cores with fused cyclic sulfonamide moieties. In this work we show that this is indeed the case. Simple sulfonamide-containing photoprecursors produced the sought-after heterocyclic products in experimentally simple photochemical reactions accompanied by significant step-normalized complexity increases as corroborated by the Böttcher complexity scores. Full article

(This article belongs to the Special Issue Chemical Insights in Photofunctional Organic Compounds—a Themed Issue Dedicated to Professor Vaidhyanathan Ramamurthy)

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20 pages, 1970 KB

Open AccessArticle

Diverse Synthesis of Fused Polyheterocyclic Compounds via [3 + 2] Cycloaddition of In Situ-Generated Heteroaromatic N-Ylides and Electron-Deficient Olefins

by Zhen-Hua Wang, Tong Zhang, Li-Wen Shen, Xiu Yang, Yan-Ping Zhang, Yong You, Jian-Qiang Zhao and Wei-Cheng Yuan

Molecules 2023, 28(11), 4410; https://doi.org/10.3390/molecules28114410 - 29 May 2023

Cited by 5 | Viewed by 3235

Abstract

[3 + 2] Cycloaddition reactions of heteroaromatic N-ylides with electron-deficient olefins have been developed. The heteroaromatic N-ylides, in situ generated from N-phenacylbenzothiazolium bromides, can smoothly react with maleimides under very mild conditions, affording fused polycyclic octahydropyrrolo[3,4-c]pyrroles in good-to-excellent [...] Read more.

[3 + 2] Cycloaddition reactions of heteroaromatic N-ylides with electron-deficient olefins have been developed. The heteroaromatic N-ylides, in situ generated from N-phenacylbenzothiazolium bromides, can smoothly react with maleimides under very mild conditions, affording fused polycyclic octahydropyrrolo[3,4-c]pyrroles in good-to-excellent isolated yields. This reaction concept could also be extended to 3-trifluoroethylidene oxindoles and benzylidenemalononitriles as electron-deficient olefins for accessing highly functionalized polyheterocyclic compounds. A gram-scale experiment was also carried out to verify the practicability of the methodology. Full article

(This article belongs to the Section Organic Chemistry)

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14 pages, 1866 KB

Open AccessArticle

Copper-Catalyzed Asymmetric Dearomative [3+2] Cycloaddition of Nitroheteroarenes with Azomethines

by Yan Chen, Jian-Qiang Zhao, Yan-Ping Zhang, Ming-Qiang Zhou, Xiao-Mei Zhang and Wei-Cheng Yuan

Molecules 2023, 28(6), 2765; https://doi.org/10.3390/molecules28062765 - 19 Mar 2023

Cited by 5 | Viewed by 2795

Abstract

Catalytic asymmetric dearomative [3+2] cycloaddition of α-imino γ-lactones with either 3-nitroindoles or 2-nitrobenzofurans by using a chiral copper complex as the catalyst was developed. A wide range of structurally diverse polyheterocyclic compounds containing spirocyclic-fused butyrolactone-pyrrolidine-indoline and butyrolactone–pyrrolidine–dihydrobenzofuran skeletons could be smoothly [...] Read more.

Catalytic asymmetric dearomative [3+2] cycloaddition of α-imino γ-lactones with either 3-nitroindoles or 2-nitrobenzofurans by using a chiral copper complex as the catalyst was developed. A wide range of structurally diverse polyheterocyclic compounds containing spirocyclic-fused butyrolactone-pyrrolidine-indoline and butyrolactone–pyrrolidine–dihydrobenzofuran skeletons could be smoothly obtained with excellent results (>99:1 dr and 98% ee). The potential synthetic applications of this methodology were also demonstrated by the scale-up experiment and by the diverse transformations of one product. This method is characterized by high asymmetric induction, wide functional group tolerance and scalability, and attractive product diversification. Full article

(This article belongs to the Special Issue Recent Advances of Catalytic Asymmetric Synthesis)

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17 pages, 3997 KB

Open AccessArticle

An Easy Access to Furan-Fused Polyheterocyclic Systems

by Alice Benzi, Lara Bianchi, Gianluca Giorgi, Massimo Maccagno, Giovanni Petrillo, Domenico Spinelli and Cinzia Tavani

Molecules 2022, 27(10), 3147; https://doi.org/10.3390/molecules27103147 - 14 May 2022

Cited by 3 | Viewed by 2237

Abstract

Nitrostilbenes characterized by two different or differently substituted aryl moieties can be obtained from the initial ring-opening of 3-nitrobenzo[b]thiophene with amines. Such versatile building blocks couple the well-recognized double electrophilic reactivity of the nitrovinyl moiety (addition to the double bond, followed [...] Read more.

Nitrostilbenes characterized by two different or differently substituted aryl moieties can be obtained from the initial ring-opening of 3-nitrobenzo[b]thiophene with amines. Such versatile building blocks couple the well-recognized double electrophilic reactivity of the nitrovinyl moiety (addition to the double bond, followed by, e.g., intramolecular replacement of the nitro group) with the possibility to exploit a conjugated system of double bonds within an electrocyclization process. Herein, nitrostilbenes are reacted with different aromatic enols provided by a double (carbon and oxygen) nucleophilicity, leading to novel, interesting naphthodihydrofurans. From these, as a viable application, aromatization and electrocyclization lead in turn to valuable polycondensed, fully aromatic O-heterocycles. Full article

(This article belongs to the Section Organic Chemistry)

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24 pages, 4066 KB

Open AccessArticle

Synthesis of Some Novel Fused Pyrimido[4″,5″:5′,6′]-[1,2,4]triazino[3′,4′:3,4] [1,2,4]triazino[5,6-b]indoles with Expected Anticancer Activity

by Rania S. Ali and Hosam A. Saad

Molecules 2018, 23(3), 693; https://doi.org/10.3390/molecules23030693 - 19 Mar 2018

Cited by 14 | Viewed by 5674

Abstract

Our current goal is the synthesis of polyheterocyclic compounds starting from 3-amino-[1,2,4]triazino[5,6-b]indole 1 and studying their anticancer activity to determine whether increasing of the size of the molecules increases the anticancer activity or not. 1-Amino[1,2,4]triazino[3′,4′:3,4]-[1,2,4]triazino[5,6-b]indole-2-carbonitrile (4) was [...] Read more.

Our current goal is the synthesis of polyheterocyclic compounds starting from 3-amino-[1,2,4]triazino[5,6-b]indole 1 and studying their anticancer activity to determine whether increasing of the size of the molecules increases the anticancer activity or not. 1-Amino[1,2,4]triazino[3′,4′:3,4]-[1,2,4]triazino[5,6-b]indole-2-carbonitrile (4) was prepared by the diazotization of 3-amino[1,2,4]-triazino[5,6-b]indole 1 followed by coupling with malononitrile in basic medium then cyclization under reflux to get 4. Also, new fused pyrimido[4″,5″:5′,6′][1,2,4]triazino-[3′,4′:3,4][1,2,4]triazino[5,6-b]indole derivative 6 was prepared and used to obtain polycyclic heterocyclic systems. Confirmation of the synthesized compounds’ structures was carried out using elemental analyses and spectral data (IR, ¹H-NMR and ¹³C-NMR and mass spectra). The anticancer activity of some of the synthesized compounds was tested against HepG2, HCT-116 and MCF-7 cell lines. The anticancer screening results showed that some derivatives display good activity which was more potent than that of the reference drug used. Molecular docking was used to predict the binding between some of the synthesized compounds and the prostate cancer 2q7k hormone and breast ‎cancer 3hb5 receptors. Full article

(This article belongs to the Collection Heterocyclic Compounds)

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11 pages, 1283 KB

Open AccessArticle

Fused-Ring Oxazolopyrrolopyridopyrimidine Systems with Gram-Negative Activity

by Yiyuan Chen, Jonathan G. Moloney, Kirsten E. Christensen and Mark G. Moloney

Antibiotics 2017, 6(1), 2; https://doi.org/10.3390/antibiotics6010002 - 13 Jan 2017

Cited by 9 | Viewed by 5460

Abstract

Fused polyheterocyclic derivatives are available by annulation of a tetramate scaffold, and been shown to have antibacterial activity against a Gram-negative, but not a Gram-positive, bacterial strain. While the activity is not potent, these systems are structurally novel showing, in particular, a high [...] Read more.

Fused polyheterocyclic derivatives are available by annulation of a tetramate scaffold, and been shown to have antibacterial activity against a Gram-negative, but not a Gram-positive, bacterial strain. While the activity is not potent, these systems are structurally novel showing, in particular, a high level of polarity, and offer potential for the optimization of antibacterial activity. Full article

(This article belongs to the Special Issue Antibiotic Synthesis)

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5 pages, 735 KB

Open AccessShort Note

(8R,10aS)-Methyl 2,4-diamino-8-(tert-butyl)-6-oxo-6,8,10,10a-tetrahydrooxazolo[3′′,4′′:1′,5′]-pyrrolo[3′,4′:5,6]pyrido[2,3-d]pyrimidine-10a-carboxylate

by Georgia Clarke and Mark G. Moloney

Molbank 2015, 2015(4), M875; https://doi.org/10.3390/M875 - 23 Nov 2015

Cited by 1 | Viewed by 3296

Abstract

A fused polyheterocyclic derivative is available by annulation of a tetramate scaffold, and has been shown to have some Gram-negative, but not Gram-positive, antibacterial activity. Full article

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