Research

13 pages, 2004 KiB

Open AccessArticle

An Unusual Rearrangement of Pyrazole Nitrene and Coarctate Ring-Opening/Recyclization Cascade: Formal CH–Acetoxylation and Azide/Amine Conversion without External Oxidants and Reductants

by Elena Chugunova, Almir S. Gazizov, Daut Islamov, Victoria Matveeva, Alexander Burilov, Nurgali Akylbekov, Alexey Dobrynin, Rakhmetulla Zhapparbergenov, Nurbol Appazov, Beauty K. Chabuka, Kimberley Christopher, Daria I. Tonkoglazova and Igor V. Alabugin

Molecules 2023, 28(21), 7335; https://doi.org/10.3390/molecules28217335 - 30 Oct 2023

Cited by 1 | Viewed by 1509

Abstract

We report an unusual transformation where the transient formation of a nitrene moiety initiates a sequence of steps leading to remote oxidative C–H functionalization (R–CH₃ to R–CH₂OC(O)R’) and the concomitant reduction of the nitrene into an amino group. No external [...] Read more.

We report an unusual transformation where the transient formation of a nitrene moiety initiates a sequence of steps leading to remote oxidative C–H functionalization (R–CH₃ to R–CH₂OC(O)R’) and the concomitant reduction of the nitrene into an amino group. No external oxidants or reductants are needed for this formal molecular comproportionation. Detected and isolated intermediates and computational analysis suggest that the process occurs with pyrazole ring opening and recyclization. Full article

(This article belongs to the Special Issue Novelties in N-Heterocycles Chemistry: From Synthesis to Application)

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18 pages, 3012 KiB

Open AccessArticle

Regioselective Synthesis of NO-Donor (4-Nitro-1,2,3-triazolyl)furoxans via Eliminative Azide–Olefin Cycloaddition

by Irina A. Stebletsova, Alexander A. Larin, Ivan V. Ananyev and Leonid L. Fershtat

Molecules 2023, 28(19), 6969; https://doi.org/10.3390/molecules28196969 - 07 Oct 2023

Viewed by 1102

Abstract

A facile and efficient method for the regioselective [3 + 2] cycloaddition of 4-azidofuroxans to 1-dimethylamino-2-nitroethylene under p-TSA catalysis affording (4-nitro-1,2,3-triazolyl)furoxans was developed. This transformation is believed to proceed via eliminative azide–olefin cycloaddition resulting in its complete regioselectivity. The developed protocol has [...] Read more.

A facile and efficient method for the regioselective [3 + 2] cycloaddition of 4-azidofuroxans to 1-dimethylamino-2-nitroethylene under p-TSA catalysis affording (4-nitro-1,2,3-triazolyl)furoxans was developed. This transformation is believed to proceed via eliminative azide–olefin cycloaddition resulting in its complete regioselectivity. The developed protocol has a broad substrate scope and enables a straightforward assembly of the 4-nitro-1,2,3-triazole motif. Moreover, synthesized (4-nitro-1,2,3-triazolyl)furoxans were found to be capable of NO release in a broad range of concentrations, thus providing a novel platform for future drug design and related biomedical applications of heterocyclic NO donors. Full article

(This article belongs to the Special Issue Novelties in N-Heterocycles Chemistry: From Synthesis to Application)

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15 pages, 3443 KiB

Open AccessArticle

Synthesis of Pyridin-1(2H)-ylacrylates and the Effects of Different Functional Groups on Their Fluorescence

by Weiguang Yang, Danyang Luo, Guanrong Li, Qiaoli Luo, Martin G. Banwell and Lanmei Chen

Molecules 2023, 28(18), 6511; https://doi.org/10.3390/molecules28186511 - 08 Sep 2023

Viewed by 696

Abstract

While fluorescent organic materials have many potential as well as proven applications and so have attracted significant attention, pyridine–olefin conjugates remain a less studied subset of such systems. Herein, therefore, we report on the development of the straightforward syntheses of pyridin-1(2H)-ylacrylates [...] Read more.

While fluorescent organic materials have many potential as well as proven applications and so have attracted significant attention, pyridine–olefin conjugates remain a less studied subset of such systems. Herein, therefore, we report on the development of the straightforward syntheses of pyridin-1(2H)-ylacrylates and the outcomes of a study of the effects of substituents on their fluorescent properties. Such compounds were prepared using a simple, metal-free and three-component coupling reaction involving 2-aminopyridines, sulfonyl azides and propiolates. The fluorescent properties of the ensuing products are significantly affected by the positions of substituents on the cyclic framework, with those located in central positions having the greatest impact. Electron-withdrawing groups tend to induce blue shifts while electron-donating ones cause red shifts. This work highlights the capacity that the micro-modification of fluorescent materials provides for fine-tuning their properties such that they may be usefully applied to, for example, the study of luminescent materials. Full article

(This article belongs to the Special Issue Novelties in N-Heterocycles Chemistry: From Synthesis to Application)

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15 pages, 1694 KiB

Open AccessArticle

Palladium-Catalyzed Direct (Het)arylation Reactions of Benzo[1,2-d:4,5-d′]bis([1,2,3]thiadiazole and 4,8-Dibromobenzo[1,2-d:4,5-d′]bis([1,2,3]thiadiazole)

by Timofey N. Chmovzh, Timofey A. Kudryashev, Daria A. Alekhina and Oleg A. Rakitin

Molecules 2023, 28(9), 3977; https://doi.org/10.3390/molecules28093977 - 08 May 2023

Cited by 4 | Viewed by 1902

Abstract

Palladium-catalyzed direct (het)arylation reactions of strongly electron-withdrawing tricyclic benzo[1,2-d:4,5-d′]bis([1,2,3]thiadiazole) and its 4,8-dibromo derivative were studied; the conditions for the selective formation of mono- and bis-aryl derivatives were found. The reaction of 4,8-dibromobenzo[1,2-d:4,5-d′]bis([1,2,3]thiadiazole) with thiophenes in the presence of palladium acetate as a catalyst [...] Read more.

Palladium-catalyzed direct (het)arylation reactions of strongly electron-withdrawing tricyclic benzo[1,2-d:4,5-d′]bis([1,2,3]thiadiazole) and its 4,8-dibromo derivative were studied; the conditions for the selective formation of mono- and bis-aryl derivatives were found. The reaction of 4,8-dibromobenzo[1,2-d:4,5-d′]bis([1,2,3]thiadiazole) with thiophenes in the presence of palladium acetate as a catalyst and potassium pivalate as a base, depending on the conditions used, selectively gave both mono- and bis-thienylated benzo-bis-thiadiazoles in low to moderate yields; arenes were found to be inactive in these reactions. It was discovered that direct C–H arylation of benzo[1,2-d:4,5-d′]bis([1,2,3]thiadiazole with bromo(iodo)arenes and -thiophenes in the presence of Pd(OAc)2 and di-tert-butyl(methyl)phosphonium tetrafluoroborate salt is a powerful tool for the selective formation of 4-mono- and 4,8-di(het)arylated benzo-bis-thiadiazoles. Oxidative double C–H hetarylation of benzo[1,2-d:4,5-d′]bis([1,2,3]thiadiazole with thiophenes in the presence of Pd(OAc)₂ and silver (I) oxide in DMSO was successfully employed to prepare bis-thienylbenzo-bis-thiadiazoles in moderate yields. Full article

(This article belongs to the Special Issue Novelties in N-Heterocycles Chemistry: From Synthesis to Application)

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14 pages, 3092 KiB

Open AccessArticle

Synthesis of Non-Aromatic Pyrroles Based on the Reaction of Carbonyl Derivatives of Acetylene with 3,3-Diaminoacrylonitriles

by Pavel S. Silaichev, Lidia N. Dianova, Tetyana V. Beryozkina, Vera S. Berseneva, Andrey N. Maslivets and Vasiliy A. Bakulev

Molecules 2023, 28(8), 3576; https://doi.org/10.3390/molecules28083576 - 19 Apr 2023

Viewed by 935

Abstract

The reaction of 3,3-diaminoacrylonitriles with DMAD and 1,2-dibenzoylacetylene was studied. It is shown that the direction of the reaction depends on the structure both of acetylene and of diaminoacrylonitrile. In the reaction of DMAD with acrylonitriles bearing a monosubstituted amidine group, 1-substituted 5-amino-2-oxo-pyrrole-3(2 [...] Read more.

The reaction of 3,3-diaminoacrylonitriles with DMAD and 1,2-dibenzoylacetylene was studied. It is shown that the direction of the reaction depends on the structure both of acetylene and of diaminoacrylonitrile. In the reaction of DMAD with acrylonitriles bearing a monosubstituted amidine group, 1-substituted 5-amino-2-oxo-pyrrole-3(2H)ylidenes are formed. On the other hand, a similar reaction of acrylonitriles containing the N,N-dialkylamidine group affords 1-NH-5-aminopyrroles. In both cases, pyrroles containing two exocyclic double bonds are formed in high yields. A radically different type of pyrroles containing one exocyclic C=C bond and sp³ hybrid carbon in the cycle is formed in reactions of 3,3-diaminoacrylonitriles with 1,2-diaroylacetylenes. As in reactions with DMAD, the interaction of 3,3-diaminoacrylonitriles with 1,2-dibenzoylacetylene can lead, depending on the structure of the amidine fragment, both to NH- and 1-substituted pyrroles. The formation of the obtained pyrrole derivatives is explained by the proposed mechanisms of the studied reactions. Full article

(This article belongs to the Special Issue Novelties in N-Heterocycles Chemistry: From Synthesis to Application)

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13 pages, 2703 KiB

Open AccessArticle

Synthesis of the Indole-Based Inhibitors of Bacterial Cystathionine γ-Lyase NL1-NL3

by Konstantin V. Potapov, Roman A. Novikov, Maxim A. Novikov, Pavel N. Solyev, Yury V. Tomilov, Sergey N. Kochetkov, Alexander A. Makarov and Vladimir A. Mitkevich

Molecules 2023, 28(8), 3568; https://doi.org/10.3390/molecules28083568 - 19 Apr 2023

Cited by 1 | Viewed by 1305

Abstract

Bacterial cystathionine γ-lyase (bCSE) is the main producer of H₂S in pathogenic bacteria such as Staphylococcus aureus, Pseudomonas aeruginosa, etc. The suppression of bCSE activity considerably enhances the sensitivity of bacteria to antibiotics. Convenient methods for the efficient synthesis [...] Read more.

Bacterial cystathionine γ-lyase (bCSE) is the main producer of H₂S in pathogenic bacteria such as Staphylococcus aureus, Pseudomonas aeruginosa, etc. The suppression of bCSE activity considerably enhances the sensitivity of bacteria to antibiotics. Convenient methods for the efficient synthesis of gram quantities of two selective indole-based bCSE inhibitors, namely (2-(6-bromo-1H-indol-1-yl)acetyl)glycine (NL1), 5-((6-bromo-1H-indol-1-yl)methyl)- 2-methylfuran-3-carboxylic acid (NL2), as well as a synthetic method for preparation 3-((6-(7-chlorobenzo[b]thiophen-2-yl)-1H-indol-1-yl)methyl)- 1H-pyrazole-5-carboxylic acid (NL3), have been developed. The syntheses are based on the use of 6-bromoindole as the main building block for all three inhibitors (NL1, NL2, and NL3), and the designed residues are assembled at the nitrogen atom of the 6-bromoindole core or by the substitution of the bromine atom in the case of NL3 using Pd-catalyzed cross-coupling. The developed and refined synthetic methods would be significant for the further biological screening of NL-series bCSE inhibitors and their derivatives. Full article

(This article belongs to the Special Issue Novelties in N-Heterocycles Chemistry: From Synthesis to Application)

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21 pages, 1995 KiB

Open AccessArticle

[3+3]-Annulation of Cyclic Nitronates with Vinyl Diazoacetates: Diastereoselective Synthesis of Partially Saturated [1,2]Oxazino[2,3-b][1,2]oxazines and Their Base-Promoted Ring Contraction to Pyrrolo[1,2-b][1,2]oxazine Derivatives

by Yulia A. Antonova, Yulia V. Nelyubina, Sema L. Ioffe and Andrey A. Tabolin

Molecules 2023, 28(7), 3025; https://doi.org/10.3390/molecules28073025 - 28 Mar 2023

Viewed by 1916

Abstract

A rhodium(II)-catalyzed reaction of cyclic nitronates (5,6-dihydro-4H-1,2-oxazine N-oxides) with vinyl diazoacetates proceeds as a [3+3]-annulation producing bicyclic unsaturated nitroso acetals (4a,5,6,7-tetrahydro-2H-[1,2]oxazino[2,3-b][1,2]oxazines). Optimization of reaction conditions revealed the use of Rh(II) octanoate as the preferred catalyst in [...] Read more.

A rhodium(II)-catalyzed reaction of cyclic nitronates (5,6-dihydro-4H-1,2-oxazine N-oxides) with vinyl diazoacetates proceeds as a [3+3]-annulation producing bicyclic unsaturated nitroso acetals (4a,5,6,7-tetrahydro-2H-[1,2]oxazino[2,3-b][1,2]oxazines). Optimization of reaction conditions revealed the use of Rh(II) octanoate as the preferred catalyst in THF at room temperature, which allows the preparation of target products in good yields and excellent diastereoselectivity. Under basic conditions, namely, the combined action of DBU and alcohol, these nitroso acetals undergo ring contraction of an unsaturated oxazine ring into the corresponding pyrrole. Both transformations can be performed in a one-pot fashion, thus constituting a quick approach to oxazine-annulated pyrroles from available starting materials, such as nitroalkenes, olefins, and diazo compounds. Full article

(This article belongs to the Special Issue Novelties in N-Heterocycles Chemistry: From Synthesis to Application)

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12 pages, 6577 KiB

Open AccessArticle

Global Search for Stable C₄H₅NO Compounds—Guinness Molecules and Stability Islands

by Oleg A. Mikhaylov and Ilya D. Gridnev

Molecules 2023, 28(2), 728; https://doi.org/10.3390/molecules28020728 - 11 Jan 2023

Viewed by 1262

Abstract

Global reaction route mapping (GRRM) analysis for compounds with the formula C₄H₅NO allowed for the detection of the corresponding “Guinness molecules” 000 and 001, as well as around 150 other stable minima of the same composition. The results [...] Read more.

Global reaction route mapping (GRRM) analysis for compounds with the formula C₄H₅NO allowed for the detection of the corresponding “Guinness molecules” 000 and 001, as well as around 150 other stable minima of the same composition. The results suggest that compounds of similar functionality form a kind of “Stability Island” with their free energies of formation falling within s relatively limited range. Full article

(This article belongs to the Special Issue Novelties in N-Heterocycles Chemistry: From Synthesis to Application)

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16 pages, 1446 KiB

Open AccessArticle

Lewis Acid-Catalyzed Formal (4+2)-Cycloaddition between Cross-Conjugated Azatrienes and Styrylmalonates: The Way to Functionalized Quinolizidine Precursors

by Pavel G. Sergeev, Roman A. Novikov and Yury V. Tomilov

Molecules 2023, 28(1), 88; https://doi.org/10.3390/molecules28010088 - 22 Dec 2022

Cited by 2 | Viewed by 1418

Abstract

Quinolizidine and azaphenalene alkaloids are common in nature and exhibit a pharmaceutical activity, which stirs up increased interest in expanding the range of methods for the synthesis of the corresponding derivatives. In this work, we attempted to adapt our previously presented method for [...] Read more.

Quinolizidine and azaphenalene alkaloids are common in nature and exhibit a pharmaceutical activity, which stirs up increased interest in expanding the range of methods for the synthesis of the corresponding derivatives. In this work, we attempted to adapt our previously presented method for the synthesis of tetrahydropyridines to the preparation of potential precursors for these heterocycles as a separate development of a necessary intermediate stage. To this end, we studied the reactions of β-styrylmalonates with N-protected cross-conjugated azatrienes in the presence of Sn(OTf)₂. Moreover, the regioselectivity of the process involving unsymmetrically substituted azatrienes was estimated. The diene character of vinyltetrahydropyridines was studied in detail with the participation of PTAD. Finally, for the Ts-protected highly functionalized vinyltetrahydropyridines synthesized, a detosylation method to give new desired azadiene structures as precursors of the quinolizidine core was suggested. Full article

(This article belongs to the Special Issue Novelties in N-Heterocycles Chemistry: From Synthesis to Application)

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12 pages, 1521 KiB

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Anions Containing Tripoid Conjugated N₄⁻ System: Salts of 5-(Substituted Amino)-[1,2,3]triazolo[4,5-c][1,2,5]oxadiazol-5-ium-4-ides, as well as Their Synthesis, Structure, and Thermal Stability

by Alexey A. Voronin, Sofya P. Balabanova, Ivan V. Fedyanin, Aleksandr M. Churakov, Alla N. Pivkina, Yurii A. Strelenko, Michael S. Klenov and Vladimir A. Tartakovsky

Molecules 2022, 27(19), 6287; https://doi.org/10.3390/molecules27196287 - 23 Sep 2022

Cited by 2 | Viewed by 1579

Abstract

A strategy for the synthesis of 5-((2-cyanoethyl)-X-amino)-[1,2,3]triazolo[4,5-c][1,2,5]oxadiazol-5-ium-4-ides (X = H; CH₂CH₂CN; NO₂ (4a); CN (4b); CO₂Et (4c)) starting from 3-amino-4-azido-1,2,5-oxadiazole was developed. The key step in this strategy [...] Read more.

A strategy for the synthesis of 5-((2-cyanoethyl)-X-amino)-[1,2,3]triazolo[4,5-c][1,2,5]oxadiazol-5-ium-4-ides (X = H; CH₂CH₂CN; NO₂ (4a); CN (4b); CO₂Et (4c)) starting from 3-amino-4-azido-1,2,5-oxadiazole was developed. The key step in this strategy is the intramolecular thermolytic cyclization of the azido group and the bis(2-cyanoethyl)triazene group. Removal of the 2-cyanoethyl protecting group from amides 4a–c gave potassium salt of the corresponding nitramide and sodium salts of cyano- and ethoxycarbonylamide. The structure and thermal stability of the synthesized compounds were studied experimentally using multinuclear NMR spectroscopy, X-ray crystallography, thermogravimetry, and differential scanning calorimetry. Full article

(This article belongs to the Special Issue Novelties in N-Heterocycles Chemistry: From Synthesis to Application)

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12 pages, 1637 KiB

Open AccessArticle

Bicyclic Isoxazoline Derivatives: Synthesis and Evaluation of Biological Activity

by Kseniya N. Sedenkova, Kristian S. Andriasov, Marina G. Eremenko, Yuri K. Grishin, Vera A. Alferova, Anna A. Baranova, Nikolay A. Zefirov, Olga N. Zefirova, Vladimir V. Zarubaev, Yulia A. Gracheva, Elena R. Milaeva and Elena B. Averina

Molecules 2022, 27(11), 3546; https://doi.org/10.3390/molecules27113546 - 31 May 2022

Cited by 5 | Viewed by 2069

Abstract

The application of non-planar scaffolds in drug design allows for the enlargement of the chemical space, and for the construction of molecules that have more effective target–ligand interactions or are less prone to the development of resistance. Among the works of the last [...] Read more.

The application of non-planar scaffolds in drug design allows for the enlargement of the chemical space, and for the construction of molecules that have more effective target–ligand interactions or are less prone to the development of resistance. Among the works of the last decade, a literature search revealed spirothiazamenthane, which has served as a lead in the development of derivatives active against resistant viral strains. In this work, we studied the novel molecular scaffold, which resembles spirothiazamenthane, but combines isoxazoline as a heterocycle and cyclooctane ring as a hydrophobic part of the structure. The synthesis of new 3-nitro- and 3-aminoisoxazolines containing spiro-fused or 1,2-annelated cyclooctane fragments was achieved by employing 1,3-dipolar cycloaddition of 3-nitro-4,5-dihydroisoxazol-4-ol 2-oxide or tetranitromethane-derived alkyl nitronates with non-activated alkenes. A series of spiro-sulfonamides was obtained by the reaction of 3-aminoisoxazoline containing a spiro-fused cyclooctane residue with sulfonyl chlorides. Preliminary screening of the compounds for antiviral, antibacterial, antifungal and antiproliferative properties in vitro revealed 1-oxa-2-azaspiro[4.7]dodec-2-en-3-amine and 3a,4,5,6,7,8,9,9a-octahydrocycloocta[d]isoxazol-3-amine with activity against the influenza A/Puerto Rico/8/34 (H1N1) virus in the submicromolar range, and high values of selectivity index. Further study of the mechanism of the antiviral action of these compounds, and the synthesis of their analogues, is likely to identify new agents against resistant viral strains. Full article

(This article belongs to the Special Issue Novelties in N-Heterocycles Chemistry: From Synthesis to Application)

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14 pages, 2099 KiB

Open AccessArticle

Revisiting the Synthesis of Functionally Substituted 1,4-Dihydrobenzo[e][1,2,4]triazines

by Margarita A. Epishina, Alexander S. Kulikov and Leonid L. Fershtat

Molecules 2022, 27(8), 2575; https://doi.org/10.3390/molecules27082575 - 15 Apr 2022

Cited by 5 | Viewed by 1811

Abstract

A series of novel 1,4-dihydrobenzo[1,2,4][e]triazines bearing an acetyl or ester moiety as a functional group at the C(3) atom of the 1,2,4-triazine ring were synthesized. The synthetic protocol is based on an oxidative cyclization of functionally substituted amidrazones in the presence [...] Read more.

A series of novel 1,4-dihydrobenzo[1,2,4][e]triazines bearing an acetyl or ester moiety as a functional group at the C(3) atom of the 1,2,4-triazine ring were synthesized. The synthetic protocol is based on an oxidative cyclization of functionally substituted amidrazones in the presence of DBU and Pd/C. It was found that the developed approach is suitable for the preparation of 1,4-dihydrobenzo[e][1,2,4]triazines, but the corresponding Blatter radicals were isolated only in few cases. In addition, a previously unknown dihydrobenzo[e][1,2,4]triazolo[3,4-c][1,2,4]triazine tricyclic open-shell derivative was prepared. Studies of thermal behavior of the synthesized 1,4-dihydrobenzo[1,2,4][e]triazines revealed their high thermal stability (up to 240–250 °C), which enables their application potential as components of functional organic materials. Full article

(This article belongs to the Special Issue Novelties in N-Heterocycles Chemistry: From Synthesis to Application)

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