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14 pages, 1069 KiB

Open AccessArticle

Pd/Ligand-Free Synthesis of 2-Alkynylated Pyrano[4,3-d]imidazol-4-ones via One-Pot Cu-Mediated Tandem Sonogashira Coupling/Regioselective 6-endo-dig Oxacyclization Reaction

by Abir Ayachi, Abdellatif Tikad, Vincent Lazeran, Hassan Allouchi, Marc Bletry, Rafâa Besbes, Mohamed Abarbri and Badr Jismy

Molecules 2025, 30(14), 3045; https://doi.org/10.3390/molecules30143045 - 21 Jul 2025

Viewed by 347

Abstract

Herein, we report a one-pot palladium- and ligand-free tandem Sonogashira coupling/regioselective 6-endo-dig oxacyclization reaction of 2,4-diiodo-1-methyl-imidazole-5-carboxylic acid with terminal alkynes mediated by Copper(I). This impressive approach offers a straightforward, practical, and efficient tandem procedure for accessing 2-alkynylated pyrano[4,3-d]imidazol-4-one [...] Read more.

Herein, we report a one-pot palladium- and ligand-free tandem Sonogashira coupling/regioselective 6-endo-dig oxacyclization reaction of 2,4-diiodo-1-methyl-imidazole-5-carboxylic acid with terminal alkynes mediated by Copper(I). This impressive approach offers a straightforward, practical, and efficient tandem procedure for accessing 2-alkynylated pyrano[4,3-d]imidazol-4-one in moderate to good yields with an exclusive 6-endo-dig oxacyclization. Notably, this cost-effective methodology demonstrates broad substrate compatibility with various commercially available aliphatic and (hetero)aromatic terminal alkynes. Furthermore, DFT studies were performed to elucidate the origin of this regioselective 6-endo-dig oxacyclization reaction. Full article

(This article belongs to the Special Issue Synthesis of Natural or Non-natural Molecules with Specific Activities)

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16 pages, 2692 KiB

Open AccessArticle

tert-Butyl Nitrite-Induced Radical Nitrile Oxidation Cycloaddition: Synthesis of Isoxazole/Isoxazoline-Fused Benzo 6/7/8-membered Oxacyclic Ketones

by Jian-Kang Cao, Tian-Zheng Cao, Qian-Wen Yue, Ying Ma, Chuan-Ming Yang, Hong-Xi Zhang, Ya-Chen Li, Qiao-Ke Dong, Yan-Ping Zhu and Yuan-Yuan Sun

Molecules 2024, 29(6), 1202; https://doi.org/10.3390/molecules29061202 - 7 Mar 2024

Cited by 1 | Viewed by 2260

Abstract

A practical metal-free and additive-free approach for the synthesis of 6/7/8-membered oxacyclic ketone-fused isoxazoles/isoxazolines tetracyclic or tricyclic structures is reported through C_sp³–H bond radical nitrile oxidation and the intramolecular cycloaddition of alkenyl/alkynyl-substituted aryl methyl ketones. This convenient approach enables the [...] Read more.

A practical metal-free and additive-free approach for the synthesis of 6/7/8-membered oxacyclic ketone-fused isoxazoles/isoxazolines tetracyclic or tricyclic structures is reported through C_sp³–H bond radical nitrile oxidation and the intramolecular cycloaddition of alkenyl/alkynyl-substituted aryl methyl ketones. This convenient approach enables the simultaneous formation of isoxazole/isoxazoline and 6/7/8-membered oxacyclic ketones to form polycyclic architectures by using tert-butyl nitrite (TBN) as a non-metallic radical initiator and N–O fragment donor. Full article

(This article belongs to the Special Issue Metal-Catalyzed Organic Transformations: Expanding Horizons in Synthetic Methodology)

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14 pages, 3391 KiB

Open AccessArticle

Diastereoselective Synthesis of cis-2,6-Disubstituted Dihydropyrane Derivatives through a Competitive Silyl-Prins Cyclization versus Alternative Reaction Pathways

by Laura F. Peña, Enol López, Ángel Sánchez-González and Asunción Barbero

Molecules 2023, 28(7), 3080; https://doi.org/10.3390/molecules28073080 - 30 Mar 2023

Cited by 2 | Viewed by 2781

Abstract

A convenient regioselective synthesis of allyl- and vinylsilyl alcohols, from a common precursor, was described, by selecting the appropriate reaction conditions. Allyl- and vinylsilyl alcohols were tested in silyl-Prins cyclizations for the preparation of disubstituted oxygenated heterocycles in a one-pot sequential reaction. The [...] Read more.

A convenient regioselective synthesis of allyl- and vinylsilyl alcohols, from a common precursor, was described, by selecting the appropriate reaction conditions. Allyl- and vinylsilyl alcohols were tested in silyl-Prins cyclizations for the preparation of disubstituted oxygenated heterocycles in a one-pot sequential reaction. The methodology was sensitive to the structure of the starting alkenylsilyl alcohol and reaction conditions, with competitive pathways observed (particularly for allylsilyl alcohols), such as Peterson elimination and oxonia-Cope reactions. However, the use of vinylsilyl alcohols allowed the preparation of differently disubstituted cis-2,6-dihydropyrans in moderate to good yields. Computational studies support the proposed mechanism. Full article

(This article belongs to the Special Issue Green and Highly Efficient One-Pot Synthesis and Catalysis)

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17 pages, 1722 KiB

Open AccessArticle

Efficient Synthesis of 1H-Benzo[4,5]imidazo[1,2-c][1,3]oxazin-1-one Derivatives Using Ag₂CO₃/TFA-Catalyzed 6-endo-dig Cyclization: Reaction Scope and Mechanistic Study

by Abdelkarim El Qami, Badr Jismy, Mohamed Akssira, Johan Jacquemin, Abdellatif Tikad and Mohamed Abarbri

Molecules 2023, 28(5), 2403; https://doi.org/10.3390/molecules28052403 - 6 Mar 2023

Cited by 2 | Viewed by 2452

Abstract

A small library of 1H-benzo[4,5]imidazo[1,2-c][1,3]oxazin-1-one derivatives was prepared in good to excellent yields, involving a Ag₂CO₃/TFA-catalyzed intramolecular oxacyclization of N-Boc-2-alkynylbenzimidazole substrates. In all experiments, the 6-endo-dig cyclization was exclusively achieved since [...] Read more.

A small library of 1H-benzo[4,5]imidazo[1,2-c][1,3]oxazin-1-one derivatives was prepared in good to excellent yields, involving a Ag₂CO₃/TFA-catalyzed intramolecular oxacyclization of N-Boc-2-alkynylbenzimidazole substrates. In all experiments, the 6-endo-dig cyclization was exclusively achieved since the possible 5-exo-dig heterocycle was not observed, indicating the high regioselectivity of this process. The scope and limitations of the silver catalyzed 6-endo-dig cyclization of N-Boc-2-alkynylbenzimidazoles as substrates, bearing various substituents, were investigated. While ZnCl₂ has shown limits for alkynes with an aromatic substituent, Ag₂CO₃/TFA demonstrated its effectiveness and compatibility regardless of the nature of the starting alkyne (aliphatic, aromatic or heteroaromatic), providing a practical regioselective access to structurally diverse 1H-benzo[4,5]imidazo[1,2-c][1,3]oxazin-1-ones in good yields. Moreover, the rationalization of oxacyclization selectivity in favor of 6-endo-dig over 5-exo-dig was explained by a complementary computational study. Full article

(This article belongs to the Special Issue Recent Progress in Heteroorganic Chemistry)

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9 pages, 1890 KiB

Open AccessArticle

Development of a New Methodology for Dearomative Borylation of Coumarins and Chromenes and Its Applications to Synthesize Boron-Containing Retinoids

by Bhaskar C. Das, Pratik Yadav, Sasmita Das, Mariko Saito and Todd Evans

Molecules 2023, 28(3), 1052; https://doi.org/10.3390/molecules28031052 - 20 Jan 2023

Cited by 4 | Viewed by 2798

Abstract

Dearomative borylation of coumarins and chromenes via conjugate addition represents a relatively unexplored and challenging task. To address this issue, herein, we report a new and general copper (I) catalyzed dearomative borylation process to synthesize boron-containing oxacycles. In this report, the borylation of [...] Read more.

Dearomative borylation of coumarins and chromenes via conjugate addition represents a relatively unexplored and challenging task. To address this issue, herein, we report a new and general copper (I) catalyzed dearomative borylation process to synthesize boron-containing oxacycles. In this report, the borylation of coumarins, chromones, and chromenes comprising functional groups, such as esters, nitriles, carbonyls, and amides, has been achieved. In addition, the method generates different classes of potential boron-based retinoids, including the ones with oxadiazole and anthocyanin motifs. The borylated oxacycles can serve as suitable intermediates to generate a library of compounds. Full article

(This article belongs to the Section Chemical Biology)

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15 pages, 2344 KiB

Open AccessArticle

Cembrane Diterpenes Possessing Nonaromatic Oxacycles from the Hainan Soft Coral Sarcophyton mililatensis

by Ling Zhang, Min Yang, Zi-Hui Chen, Zeng-Yue Ge, Song-Wei Li, Xian-Yun Yan, Li-Gong Yao, Lin-Fu Liang and Yue-Wei Guo

Int. J. Mol. Sci. 2023, 24(3), 1979; https://doi.org/10.3390/ijms24031979 - 19 Jan 2023

Cited by 5 | Viewed by 2073

Abstract

Documents on the chemical composition of the soft coral Sarcophyton mililatensis are sparse. The present investigation of the Hainan soft coral S. mililatensis resulted in the discovery of six new cembrane diterpenes, sarcoxacyclols A–F (1–6) and four known analogs [...] Read more.

Documents on the chemical composition of the soft coral Sarcophyton mililatensis are sparse. The present investigation of the Hainan soft coral S. mililatensis resulted in the discovery of six new cembrane diterpenes, sarcoxacyclols A–F (1–6) and four known analogs (7–10). Their structures were elucidated by extensive spectroscopic analysis along with a comparison with the data in current literature. The nonaromatic oxacycles in their structures were the rarely found tetrahydrofuran ether across C-1 and C-12 and tetrahydropyran ether across C-1 and C-11, respectively. Moreover, the absolute configuration of compound 4 was established unambiguously by X-ray diffraction analysis using Ga Kα radiation (λ = 1.34139 Å). Based on the biogenetical consideration, the absolute configurations of other five new compounds were tentatively assumed. Assessment of the bioactivity for these secondary metabolites revealed that compound 1 exhibited significant tumor necrosis factor (TNF)-α inhibitory activity (IC₅₀ = 9.5 μmol/L), similar to the positive control dexamethasone (IC₅₀ = 8.7 μmol/L), but no obvious cytotoxicity towards RAW264.7 cells (CC₅₀ > 50 μmol/L). The preliminary molecular docking suggested the crucial roles of the hydroxyl and acetoxyl groups in the computational prediction of the binding mode between the diterpene and the protein. Full article

(This article belongs to the Section Macromolecules)

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11 pages, 3943 KiB

Open AccessArticle

Influence of the Substituents on the Opening of Silylepoxy Alcohols: 5-exo-Cyclization towards Tetrahydrofurans vs. Unexpected Side Reaction Leading to Tetrahydropyrans

by Carlos Díez-Poza and Asunción Barbero

Molecules 2021, 26(23), 7386; https://doi.org/10.3390/molecules26237386 - 6 Dec 2021

Cited by 1 | Viewed by 2243

Abstract

The regioselective ring opening of epoxy alcohols is an effective method for the synthesis of different types of oxacycles. The 5-exo opening being preferred vs. the 6-endo mode, according to Baldwin rules, the use of silyl-substituted oxiranes has been reported as [...] Read more.

The regioselective ring opening of epoxy alcohols is an effective method for the synthesis of different types of oxacycles. The 5-exo opening being preferred vs. the 6-endo mode, according to Baldwin rules, the use of silyl-substituted oxiranes has been reported as a possible method to favor the 6-endo cyclization. However, there is a need for a detailed study on the different factors (structural factors, catalyst nature or conditions) that influence this process. In this paper, the acid-catalyzed cyclization of epoxysilyl alcohols was studied, focusing on the effect of substituents and reaction conditions on the outcome of the process. Two types of heterocycles (tetrahydrofurans or tetrahydropyrans) were selectively obtained depending on the structure of the initial epoxysilyl alcohol. Interestingly, cyclization of hindered epoxysilyl alcohols mainly proceeds through an unexpected side reaction, which implies a previous isomerization to an aldehyde. A mechanistic proposal for the formation of the different products is presented. Full article

(This article belongs to the Special Issue Molecules from Side Reactions II)

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12 pages, 2150 KiB

Open AccessFeature PaperArticle

Intramolecular Nicholas Reaction Enables the Stereoselective Synthesis of Strained Cyclooctynes

by Diego M. Monzón, Juan Manuel Betancort, Tomás Martín, Miguel Ángel Ramírez, Víctor S. Martín and David Díaz Díaz

Molecules 2021, 26(6), 1629; https://doi.org/10.3390/molecules26061629 - 15 Mar 2021

Cited by 6 | Viewed by 2974

Abstract

Cyclic products can be obtained through the intramolecular version of the Nicholas reaction, which requires having the nucleophile connected to the alkyne unit. Here, we report the synthesis of 1-oxa-3-cyclooctynes starting from commercially available (1R,3S)-camphoric acid. The strategy is [...] Read more.

Cyclic products can be obtained through the intramolecular version of the Nicholas reaction, which requires having the nucleophile connected to the alkyne unit. Here, we report the synthesis of 1-oxa-3-cyclooctynes starting from commercially available (1R,3S)-camphoric acid. The strategy is based on the initial preparation of propargylic alcohols, complexation of the triple bond with Co₂(CO)₈, and treatment with BF₃·Et₂O to induce an intramolecular Nicholas reaction with the free hydroxyl group as nucleophile. Finally, oxidative deprotection of the alkyne afforded the cyclooctynes in good yields. Notably, large-sized R substituents at the chiral center connected to the O atom were oriented in such a way that steric interactions were minimized in the cyclization, allowing the formation of cyclooctynes exclusively with (R) configuration, in good agreement with theoretical predictions. Moreover, preliminary studies demonstrated that these cyclooctynes were reactive in the presence of azides yielding substituted triazoles. Full article

(This article belongs to the Special Issue New Synthetic Methods for Organic Compounds)

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32 pages, 6016 KiB

Open AccessReview

Expanding Monomers as Anti-Shrinkage Additives

by Philipp Marx and Frank Wiesbrock

Polymers 2021, 13(5), 806; https://doi.org/10.3390/polym13050806 - 6 Mar 2021

Cited by 32 | Viewed by 6915

Abstract

Commonly, volumetric shrinkage occurs during polymerizations due to the shortening of the equilibrium Van der Waals distance of two molecules to the length of a (significantly shorter) covalent bond. This volumetric shrinkage can have severe influence on the materials’ properties. One strategy to [...] Read more.

Commonly, volumetric shrinkage occurs during polymerizations due to the shortening of the equilibrium Van der Waals distance of two molecules to the length of a (significantly shorter) covalent bond. This volumetric shrinkage can have severe influence on the materials’ properties. One strategy to overcome this volumetric shrinkage is the use of expanding monomers that show volumetric expansion during polymerization reactions. Such monomers exhibit cyclic or even oligocyclic structural motifs with a correspondingly dense atomic packing. During the ring-opening reaction of such monomers, linear structures with atomic packing of lower density are formed, which results in volumetric expansion or at least reduced volumetric shrinkage. This review provides a concise overview of expanding monomers with a focus on the elucidation of structure-property relationships. Preceded by a brief introduction of measuring techniques for the quantification of volumetric changes, the most prominent classes of expanding monomers will be presented and discussed, namely cycloalkanes and cycloalkenes, oxacycles, benzoxazines, as well as thiocyclic compounds. Spiroorthoesters, spiroorthocarbonates, cyclic carbonates, and benzoxazines are particularly highlighted. Full article

(This article belongs to the Collection Design and Synthesis of Polymers)

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9 pages, 310 KiB

Open AccessProceeding Paper

Intramolecular Cyclization of Alkenyl Alcohols: Towards the Synthesis of Oxacycles

by Paula González-Andrés, Carlos Díez-Poza, Laura Fernández-Peña, Alberto Cherubin, Yolanda Blanco and Asunción Barbero

Chem. Proc. 2021, 3(1), 117; https://doi.org/10.3390/ecsoc-24-08462 - 16 Nov 2020

Cited by 1 | Viewed by 2604

Abstract

The presence of tetrahydropyrans and other sized oxacycles in natural products with interesting pharmacological properties has prompted researchers to try to develop new strategies for their selective synthesis. Moreover, these methodologies enable the introduction of structural modifications in the molecule for the synthesis [...] Read more.

The presence of tetrahydropyrans and other sized oxacycles in natural products with interesting pharmacological properties has prompted researchers to try to develop new strategies for their selective synthesis. Moreover, these methodologies enable the introduction of structural modifications in the molecule for the synthesis of analogues with potential biological activity. An attractive atom economy process for the synthesis of these scaffolds is the intramolecular hydroalkoxylation of alkenes. However, this method has several drawbacks (such as the lack of generality and the presence of multiple side reactions) which have diminished its development. For many years, our research group has been devoted to developing different strategies for the regio- and stereoselective synthesis of oxygen and nitrogen heterocycles. Herein, we present our results on the effective acid catalyzed cyclization of alkenyl alcohols which bear a silyl group in their structure. As we will show, the presence of the silicon group is necessary for the cyclization to take place. Moreover, the cyclization towards tetrahydropyrans occurs with high stereoselectivity. Full article

(This article belongs to the Proceedings of The 24th International Electronic Conference on Synthetic Organic Chemistry)

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