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14 pages, 3214 KiB

Open AccessCommunication

Nucleophilic Aromatic Substitution of Polyfluoroarene to Access Highly Functionalized 10-Phenylphenothiazine Derivatives

by Kotaro Kikushima, Haruka Koyama, Kazuki Kodama and Toshifumi Dohi

Molecules 2021, 26(5), 1365; https://doi.org/10.3390/molecules26051365 - 04 Mar 2021

Cited by 6 | Viewed by 3386

Abstract

Nucleophilic aromatic substitution (S_NAr) reactions can provide metal-free access to synthesize monosubstituted aromatic compounds. We developed efficient S_NAr conditions for p-selective substitution of polyfluoroarenes with phenothiazine in the presence of a mild base to afford the corresponding 10-phenylphenothiazine [...] Read more.

Nucleophilic aromatic substitution (S_NAr) reactions can provide metal-free access to synthesize monosubstituted aromatic compounds. We developed efficient S_NAr conditions for p-selective substitution of polyfluoroarenes with phenothiazine in the presence of a mild base to afford the corresponding 10-phenylphenothiazine (PTH) derivatives. The resulting polyfluoroarene-bearing PTH derivatives were subjected to a second S_NAr reaction to generate highly functionalized PTH derivatives with potential applicability as photocatalysts for the reduction of carbon–halogen bonds. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Organic Synthesis)

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22 pages, 4365 KiB

Open AccessArticle

Oligosilanylated Silocanes

by Mohammad Aghazadeh Meshgi, Alexander Pöcheim, Judith Baumgartner, Viatcheslav V. Jouikov and Christoph Marschner

Molecules 2021, 26(1), 244; https://doi.org/10.3390/molecules26010244 - 05 Jan 2021

Cited by 4 | Viewed by 2464

Abstract

A number of mono- and dioligosilanylated silocanes were prepared. Compounds included silocanes with 1-methyl-1-tris(trimethylsilyl)silyl, 1,1-bis[tris(trimethylsilyl)silyl], and 1,1-bis[tris(trimethylsilyl)germyl] substitution pattern as well as two examples where the silocane silicon atom is part of a cyclosilane or oxacyclosilane ring. The mono-tris(trimethylsilyl)silylated compound could be converted [...] Read more.

A number of mono- and dioligosilanylated silocanes were prepared. Compounds included silocanes with 1-methyl-1-tris(trimethylsilyl)silyl, 1,1-bis[tris(trimethylsilyl)silyl], and 1,1-bis[tris(trimethylsilyl)germyl] substitution pattern as well as two examples where the silocane silicon atom is part of a cyclosilane or oxacyclosilane ring. The mono-tris(trimethylsilyl)silylated compound could be converted to the respective silocanylbis(trimethylsilyl)silanides by reaction with KO^tBu and in similar reactions the cyclosilanes were transformed to oligosilane-1,3-diides. However, the reaction of the 1,1-bis[tris(trimethylsilyl)silylated] silocane with two equivalents of KO^tBu leads to the replacement of one tris(trimethylsilyl)silyl unit with a tert-butoxy substituent followed by silanide formation via KO^tBu attack at one of the SiMe₃ units of remaining tris(trimethylsilyl)silyl group. For none of the silylated silocanes, signs of hypercoordinative interaction between the nitrogen and silicon silocane atoms were detected either in the solid state. by single crystal XRD analysis, nor in solution by ²⁹Si-NMR spectroscopy. This was further confirmed by cyclic voltammetry and a DFT study, which demonstrated that the N-Si distance in silocanes is not only dependent on the energy of a potential N-Si interaction, but also on steric factors and through-space interactions of the neighboring groups at Si and N, imposing the orientation of the p_z(N) orbital relative to the N-Si-X axis. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Organic Synthesis)

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21 pages, 5362 KiB

Open AccessArticle

Generation of Mixed Anhydrides via Oxidative Fragmentation of Tertiary Cyclopropanols with Phenyliodine(III) Dicarboxylates

by Dzmitry M. Zubrytski, Gábor Zoltán Elek, Margus Lopp and Dzmitry G. Kananovich

Molecules 2021, 26(1), 140; https://doi.org/10.3390/molecules26010140 - 30 Dec 2020

Cited by 1 | Viewed by 2452

Abstract

Oxidative fragmentation of tertiary cyclopropanols with phenyliodine(III) dicarboxylates in aprotic solvents (dichloromethane, chloroform, toluene) produces mixed anhydrides. The fragmentation reaction is especially facile with phenyliodine(III) reagents bearing electron-withdrawing carboxylate ligands (trifluoroacetyl, 2,4,6-trichlorobenzoyl, 3-nitrobenzoyl), and affords 95−98% yields of the corresponding mixed anhydride products. [...] Read more.

Oxidative fragmentation of tertiary cyclopropanols with phenyliodine(III) dicarboxylates in aprotic solvents (dichloromethane, chloroform, toluene) produces mixed anhydrides. The fragmentation reaction is especially facile with phenyliodine(III) reagents bearing electron-withdrawing carboxylate ligands (trifluoroacetyl, 2,4,6-trichlorobenzoyl, 3-nitrobenzoyl), and affords 95−98% yields of the corresponding mixed anhydride products. The latter can be straightforwardly applied for the acylation of various nitrogen, oxygen and sulfur-centered nucleophiles (primary and secondary amines, hydroxylamines, primary alcohols, phenols, thiols). Intramolecular acylation yielding macrocyclic lactones can also be performed. The developed transformation has bolstered the synthetic utility of cyclopropanols as pluripotent intermediates in diversity-oriented synthesis of bioactive natural products and their synthetic congeners. For example, it was successfully applied for the last-stage modification of a cyclic peptide to produce a precursor of a known histone deacetylase inhibitor. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Organic Synthesis)

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15 pages, 5746 KiB

Open AccessArticle

Photooxidation of 2-(tert-Butyl)-3-Methyl-2,3,5,6,7,8-Hexahydroquinazolin-4(1H)-one, an Example of Singlet Oxygen ene Reaction

by Adrian Méndez, Jonathan Román Valdez-Camacho and Jaime Escalante

Molecules 2020, 25(21), 5008; https://doi.org/10.3390/molecules25215008 - 29 Oct 2020

Cited by 1 | Viewed by 2170

Abstract

Singlet oxygen ene reactions produce 2-(tert-butyl)-4a-hydroperoxy-3-methyl-2,4a, 5,6,7,8-hexahydroquinazolin-4(3H)-one quantitatively during diffusion crystallization of 2-(tert-butyl)-3-methyl-2,3,5,6,7,8-hexahydroquinazolin-4(1H)-one in n-hexane/CH₂Cl₂ solvent mixture. To confirm this photo-oxidation, a ¹H-NMR study in CDCl₃ was performed with [...] Read more.

Singlet oxygen ene reactions produce 2-(tert-butyl)-4a-hydroperoxy-3-methyl-2,4a, 5,6,7,8-hexahydroquinazolin-4(3H)-one quantitatively during diffusion crystallization of 2-(tert-butyl)-3-methyl-2,3,5,6,7,8-hexahydroquinazolin-4(1H)-one in n-hexane/CH₂Cl₂ solvent mixture. To confirm this photo-oxidation, a ¹H-NMR study in CDCl₃ was performed with exposure to ambient conditions (light and oxygen), with neither additional reactants nor catalysts. A theoretical study at the B3LyP/6311++G** level using the QST2 method of locating transition states suggests a two-step mechanism where the intermediate, which unexpectedly did not come from the peroxide intermediate, has a low activation energy. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Organic Synthesis)

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14 pages, 1384 KiB

Open AccessFeature PaperArticle

Construction of Unusual Indole-Based Heterocycles from Tetrahydro-1H-pyridazino[3,4-b]indoles

by Cecilia Ciccolini, Lucia De Crescentini, Fabio Mantellini, Giacomo Mari, Stefania Santeusanio and Gianfranco Favi

Molecules 2020, 25(18), 4124; https://doi.org/10.3390/molecules25184124 - 09 Sep 2020

Cited by 1 | Viewed by 2359

Abstract

Herein, we report the successful syntheses of scarcely represented indole-based heterocycles which have a structural connection with biologically active natural-like molecules. The selective oxidation of indoline nucleus to indole, hydrolysis of ester and carbamoyl residues followed by decarboxylation with concomitant aromatization of the [...] Read more.

Herein, we report the successful syntheses of scarcely represented indole-based heterocycles which have a structural connection with biologically active natural-like molecules. The selective oxidation of indoline nucleus to indole, hydrolysis of ester and carbamoyl residues followed by decarboxylation with concomitant aromatization of the pyridazine ring starting from tetrahydro-1H-pyridazino[3,4-b]indole derivatives lead to fused indole-pyridazine compounds. On the other hand, non-fused indole-pyrazol-5-one scaffolds are easily prepared by subjecting the same C2,C3-fused indoline tetrahydropyridazines to treatment with trifluoroacetic acid (TFA). These methods feature mild conditions, easy operation, high yields in most cases avoiding the chromatographic purification, and broad substrate scope. Interestingly, the formation of indole linked pyrazol-5-one system serves as a good example of the application of the umpolung strategy in the synthesis of C3-alkylated indoles. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Organic Synthesis)

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20 pages, 1852 KiB

Open AccessArticle

Synthesis, In Silico and In Vitro Evaluation for Acetylcholinesterase and BACE-1 Inhibitory Activity of Some N-Substituted-4-Phenothiazine-Chalcones

by Thai-Son Tran, Minh-Tri Le, Thi-Cam-Vi Nguyen, The-Huan Tran, Thanh-Dao Tran and Khac-Minh Thai

Molecules 2020, 25(17), 3916; https://doi.org/10.3390/molecules25173916 - 27 Aug 2020

Cited by 10 | Viewed by 3605

Abstract

Acetylcholinesterase (AChE) and beta-secretase (BACE-1) are two attractive targets in the discovery of novel substances that could control multiple aspects of Alzheimer’s disease (AD). Chalcones are the flavonoid derivatives with diverse bioactivities, including AChE and BACE-1 inhibition. In this study, a series of [...] Read more.

Acetylcholinesterase (AChE) and beta-secretase (BACE-1) are two attractive targets in the discovery of novel substances that could control multiple aspects of Alzheimer’s disease (AD). Chalcones are the flavonoid derivatives with diverse bioactivities, including AChE and BACE-1 inhibition. In this study, a series of N-substituted-4-phenothiazine-chalcones was synthesized and tested for AChE and BACE-1 inhibitory activities. In silico models, including two-dimensional quantitative structure–activity relationship (2D-QSAR) for AChE and BACE-1 inhibitors, and molecular docking investigation, were developed to elucidate the experimental process. The results indicated that 13 chalcone derivatives were synthesized with relatively high yields (39–81%). The bioactivities of these substances were examined with pIC₅₀ 3.73–5.96 (AChE) and 5.20–6.81 (BACE-1). Eleven of synthesized chalcones had completely new structures. Two substances AC4 and AC12 exhibited the highest biological activities on both AChE and BACE-1. These substances could be employed for further researches. In addition to this, the present study results suggested that, by using a combination of two types of predictive models, 2D-QSAR and molecular docking, it was possible to estimate the biological activities of the prepared compounds with relatively high accuracy. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Organic Synthesis)

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20 pages, 1874 KiB

Open AccessArticle

Chromene- and Quinoline-3-Carbaldehydes: Useful Intermediates in the Synthesis of Heterocyclic Scaffolds

by Djenisa H. A. Rocha, Vasco F. Batista, Emanuel J. F. Balsa, Diana C. G. A. Pinto and Artur M. S. Silva

Molecules 2020, 25(17), 3791; https://doi.org/10.3390/molecules25173791 - 20 Aug 2020

Cited by 2 | Viewed by 2619

Abstract

Chromenes and quinolines are recognized as important scaffolds in medicinal chemistry. Herein, the efficient use of chromene- and quinoline-3-carbaldehydes to synthesize other valuable heterocycles is described. These carbaldehydes are obtained in excellent yields through the Vilsmeyer-Haack reaction of flavanones and azaflavanones. Protocols towards [...] Read more.

Chromenes and quinolines are recognized as important scaffolds in medicinal chemistry. Herein, the efficient use of chromene- and quinoline-3-carbaldehydes to synthesize other valuable heterocycles is described. These carbaldehydes are obtained in excellent yields through the Vilsmeyer-Haack reaction of flavanones and azaflavanones. Protocols towards the synthesis of new heterocycles, such as 3H-chromeno[3–c]quinolines, (Z/E)-2-aryl-4-chloro-3-styryl-2H-chromenes, and (E)-2-aryl-4-chloro-3-styrylquinoline-1(2H)-carbaldehydes were established. Altogether, we demonstrate the value of chromene- and quinoline-3-carbaldehydes as building blocks. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Organic Synthesis)

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21 pages, 5573 KiB

Open AccessArticle

High-Resolution Magic Angle Spinning (HR-MAS) NMR-Based Fingerprints Determination in the Medicinal Plant Berberis laurina

by Sher Ali, Gul Badshah, Caroline Da Ros Montes D’Oca, Francinete Ramos Campos, Noemi Nagata, Ajmir Khan, Maria de Fátima Costa Santos and Andersson Barison

Molecules 2020, 25(16), 3647; https://doi.org/10.3390/molecules25163647 - 11 Aug 2020

Cited by 9 | Viewed by 4529

Abstract

Berberis laurina (Berberidaceae) is a well-known medicinal plant used in traditional medicine since ancient times; however, it is scarcely studied to a large-scale fingerprint. This work presents a broad-range fingerprints determination through high-resolution magical angle spinning (HR-MAS) nuclear magnetic resonance (NMR) spectroscopy, a [...] Read more.

Berberis laurina (Berberidaceae) is a well-known medicinal plant used in traditional medicine since ancient times; however, it is scarcely studied to a large-scale fingerprint. This work presents a broad-range fingerprints determination through high-resolution magical angle spinning (HR-MAS) nuclear magnetic resonance (NMR) spectroscopy, a well-established flexible analytical method and one of most powerful “omics” platforms. It had been intended to describe a large range of chemical compositions in all plant parts. Beyond that, HR-MAS NMR allowed the direct investigation of botanical material (leaves, stems, and roots) in their natural, unaltered states, preventing molecular changes. The study revealed 17 metabolites, including caffeic acid, and berberine, a remarkable alkaloid from the genus Berberis L. The metabolic pattern changes of the leaves in the course of time were found to be seasonally dependent, probably due to the variability of seasonal and environmental trends. This metabolites overview is of great importance in understanding plant (bio)chemistry and mediating plant survival and is influenceable by interacting environmental means. Moreover, the study will be helpful in medicinal purposes, health sciences, crop evaluations, and genetic and biotechnological research. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Organic Synthesis)

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23 pages, 5525 KiB

Open AccessArticle

Design of Curcumin and Flavonoid Derivatives with Acetylcholinesterase and Beta-Secretase Inhibitory Activities Using in Silico Approaches

by Thai-Son Tran, Minh-Tri Le, Thanh-Dao Tran, The-Huan Tran and Khac-Minh Thai

Molecules 2020, 25(16), 3644; https://doi.org/10.3390/molecules25163644 - 10 Aug 2020

Cited by 21 | Viewed by 4782

Abstract

Acetylcholinesterase (AChE) and beta-secretase (BACE-1) are the two crucial enzymes involved in the pathology of Alzheimer’s disease. The former is responsible for many defects in cholinergic signaling pathway and the latter is the primary enzyme in the biosynthesis of beta-amyloid as the main [...] Read more.

Acetylcholinesterase (AChE) and beta-secretase (BACE-1) are the two crucial enzymes involved in the pathology of Alzheimer’s disease. The former is responsible for many defects in cholinergic signaling pathway and the latter is the primary enzyme in the biosynthesis of beta-amyloid as the main component of the amyloid plaques. These both abnormalities are found in the brains of Alzheimer’s patients. In this study, in silico models were developed, including 3D-pharmacophore, 2D-QSAR (two-dimensional quantitative structure-activity relationship), and molecular docking, to screen virtually a database of compounds for AChE and BACE-1 inhibitory activities. A combinatorial library containing more than 3 million structures of curcumin and flavonoid derivatives was generated and screened for drug-likeness and enzymatic inhibitory bioactivities against AChE and BACE-1 through the validated in silico models. A total of 47 substances (two curcumins and 45 flavonoids), with remarkable predicted pIC₅₀ values against AChE and BACE-1 ranging from 4.24–5.11 (AChE) and 4.52–10.27 (BACE-1), were designed. The in vitro assays on AChE and BACE-1 were performed and confirmed the in silico results. The study indicated that, by using in silico methods, a series of curcumin and flavonoid structures were generated with promising predicted bioactivities. This would be a helpful foundation for the experimental investigations in the future. Designed compounds which were the most feasible for chemical synthesis could be potential candidates for further research and lead optimization. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Organic Synthesis)

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14 pages, 3514 KiB

Open AccessArticle

Selective Arylation of 2-Bromo-4-chlorophenyl-2-bromobutanoate via a Pd-Catalyzed Suzuki Cross-Coupling Reaction and Its Electronic and Non-Linear Optical (NLO) Properties via DFT Studies

by Usman Nazeer, Nasir Rasool, Aqsa Mujahid, Asim Mansha, Muhammad Zubair, Naveen Kosar, Tariq Mahmood, Ali Raza Shah, Syed Adnan Ali Shah, Zainul Amiruddin Zakaria and Muhammad Nadeem Akhtar

Molecules 2020, 25(15), 3521; https://doi.org/10.3390/molecules25153521 - 31 Jul 2020

Cited by 10 | Viewed by 3206

Abstract

In the present study, 2-bromo-4-chlorophenyl-2-bromobutanoate (3) was synthesized via the reaction of 2-bromo-4-chlorophenol with 2-bromobutanoyl bromide in the presence of pyridine. A variety of 2-bromo-4-chlorophenyl-2-bromobutanoate derivatives (5a–f) were synthesized with moderate to good yields via a Pd-catalyzed [...] Read more.

In the present study, 2-bromo-4-chlorophenyl-2-bromobutanoate (3) was synthesized via the reaction of 2-bromo-4-chlorophenol with 2-bromobutanoyl bromide in the presence of pyridine. A variety of 2-bromo-4-chlorophenyl-2-bromobutanoate derivatives (5a–f) were synthesized with moderate to good yields via a Pd-catalyzed Suzuki cross-coupling reaction. To find out the reactivity and electronic properties of the compounds, Frontier molecular orbital analysis, non-linear optical properties, and molecular electrostatic potential studies were performed. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Organic Synthesis)

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20 pages, 1093 KiB

Open AccessArticle

Antioxidant and Anticancer Activity of Novel Derivatives of 3-[(4-Methoxyphenyl)amino]propanehydrazide

by Ingrida Tumosienė, Kristina Kantminienė, Arnas Klevinskas, Vilma Petrikaitė, Ilona Jonuškienė and Vytautas Mickevičius

Molecules 2020, 25(13), 2980; https://doi.org/10.3390/molecules25132980 - 29 Jun 2020

Cited by 18 | Viewed by 3012

Abstract

Series of novel 3-[(4-methoxyphenyl)amino]propanehydrazide derivatives bearing semicarbazide, thiosemicarbazide, thiadiazole, triazolone, triazolethione, thiophenyltriazole, furan, thiophene, naphthalene, pyrrole, isoindoline-1,3-dione, oxindole, etc. moieties were synthesized and their molecular structures were confirmed by IR, ¹H-, ¹³C-NMR spectroscopy and mass spectrometry data. The antioxidant activity of [...] Read more.

Series of novel 3-[(4-methoxyphenyl)amino]propanehydrazide derivatives bearing semicarbazide, thiosemicarbazide, thiadiazole, triazolone, triazolethione, thiophenyltriazole, furan, thiophene, naphthalene, pyrrole, isoindoline-1,3-dione, oxindole, etc. moieties were synthesized and their molecular structures were confirmed by IR, ¹H-, ¹³C-NMR spectroscopy and mass spectrometry data. The antioxidant activity of the synthesized compounds was screened by DPPH radical scavenging method. The antioxidant activity of N-(1,3-dioxoisoindolin-2-yl)-3-((4-methoxyphenyl)amino)propanamide and 3-((4-methoxyphenyl)amino)-N’-(1-(naphthalen-1-yl)-ethylidene)propanehydrazide has been tested to be ca. 1.4 times higher than that of a well-known antioxidant ascorbic acid. Anticancer activity was tested by MTT assay against human glioblastoma U-87 and triple-negative breast cancer MDA-MB-231 cell lines. In general, the tested compounds were more cytotoxic against U-87 than MDA-MB-231 cell line. 1-(4-Fluorophenyl)-2-((5-(2-((4-methoxyphenyl)amino)ethyl)-4-phenyl-4H-1,2,4-triazol-3-yl)thio)ethanone has been identified as the most active compound against the glioblastoma U-87 cell line. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Organic Synthesis)

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23 pages, 3024 KiB

Open AccessArticle

Stereodivergent Synthesis of Camphor-Derived Diamines and Their Application as Thiourea Organocatalysts

by Sebastijan Ričko, Franc Požgan, Bogdan Štefane, Jurij Svete, Amalija Golobič and Uroš Grošelj

Molecules 2020, 25(13), 2978; https://doi.org/10.3390/molecules25132978 - 29 Jun 2020

Cited by 6 | Viewed by 4268

Abstract

A series of 18 regio- and stereo-chemically diverse chiral non-racemic 1,2-, 1,3-, and 1,4-diamines have been synthesized from commercial (1S)-(+)-ketopinic acid and (1S)-(+)-10-camphorsulfonic acid. The structures of the diamines are all based on the d-(+)-camphor scaffold and feature [...] Read more.

A series of 18 regio- and stereo-chemically diverse chiral non-racemic 1,2-, 1,3-, and 1,4-diamines have been synthesized from commercial (1S)-(+)-ketopinic acid and (1S)-(+)-10-camphorsulfonic acid. The structures of the diamines are all based on the d-(+)-camphor scaffold and feature isomeric diversity in terms of regioisomeric attachment of the primary and the tertiary amine function and the exo/endo-isomerism. Diamines were transformed into the corresponding noncovalent bifunctional thiourea organocatalysts, which have been evaluated for catalytic activity in the conjugative addition of 1,3-dicarbonyl nucleophiles (dimethyl malonate, acetylacetone, and dibenzoylmethane) to trans-β-nitrostyrene. The highest enantioselectivity was achieved in the reaction with acetylacetone as nucleophile using endo-1,3-diamine derived catalyst 52 (91.5:8.5 er). All new organocatalysts 48–63 have been fully characterized. The structures and the absolute configurations of eight intermediates and thiourea derivative 52 were also determined by X-ray diffraction. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Organic Synthesis)

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13 pages, 2487 KiB

Open AccessArticle

Chiral Phase Transfer Catalysis in the Asymmetric Synthesis of a 3,3-Disubstituted Isoindolinone and Determination of Its Absolute Configuration by VCD Spectroscopy

by Guglielmo Monaco, Maximilian Tiffner, Antonia Di Mola, Wouter Herrebout, Mario Waser and Antonio Massa

Molecules 2020, 25(10), 2272; https://doi.org/10.3390/molecules25102272 - 12 May 2020

Cited by 7 | Viewed by 2809 | Correction

Abstract

In this work we report our endeavors toward the development of an asymmetric synthesis of a 3,3-disubstituted isoindolinone, dimethyl 2-(1-methyl-3-oxoisoindolin-1-yl)malonate, via asymmetric cascade reaction of 2-acetylbenzonitrile with dimethylmalonate and the determination of its absolute configuration (AC) by vibrational circular dichroism (VCD). Bifunctional ammonium [...] Read more.

In this work we report our endeavors toward the development of an asymmetric synthesis of a 3,3-disubstituted isoindolinone, dimethyl 2-(1-methyl-3-oxoisoindolin-1-yl)malonate, via asymmetric cascade reaction of 2-acetylbenzonitrile with dimethylmalonate and the determination of its absolute configuration (AC) by vibrational circular dichroism (VCD). Bifunctional ammonium salts, derived from trans-1,2-cyclohexanediamine in combination with inorganic bases under phase transfer conditions, were the most effective catalytic systems, leading to the target in high yields and moderate enantioselectivity. An efficient process of heterochiral crystallization allowed the increase of the enantiopurity up to 96% ee and in an acceptable overall yield. An important aim of the present work is the comparison of different VCD methodologies for AC determination of the target compound. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Organic Synthesis)

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16 pages, 5007 KiB

Open AccessArticle

Induced Wide Nematic Phase by Seven-Ring Supramolecular H-Bonded Systems: Experimental and Computational Evaluation

by Latifah Abdullah Alshabanah, Laila A. Al-Mutabagani, Hoda A. Ahmed and Mohamed Hagar

Molecules 2020, 25(7), 1694; https://doi.org/10.3390/molecules25071694 - 07 Apr 2020

Cited by 8 | Viewed by 1888

Abstract

New seven-ring systems of dipyridine derivative liquid crystalline 2:1 supramolecular H-bonded complexes were formed between 4-n-alkoxyphenylazo benzoic acids and 4-(2-(pyridin-4-yl)diazenyl)phenyl nicotinate. Mesomorphic behaviors of the prepared complexes were investigated using a combination of differential scanning calorimetry (DSC) and polarizing optical microscopy (POM). Fermi [...] Read more.

New seven-ring systems of dipyridine derivative liquid crystalline 2:1 supramolecular H-bonded complexes were formed between 4-n-alkoxyphenylazo benzoic acids and 4-(2-(pyridin-4-yl)diazenyl)phenyl nicotinate. Mesomorphic behaviors of the prepared complexes were investigated using a combination of differential scanning calorimetry (DSC) and polarizing optical microscopy (POM). Fermi bands attributed to the presence of intermolecular H-bond interactions were confirmed by FT–IR spectroscopy. All prepared complexes possessed an enantiotropic nematic phase with a broad temperature nematogenic range. Phases were confirmed by miscibility with a standard nematic (N) compound. A comparison was constructed to investigate the influence of the incorporation of the azophenyl moiety on the mesomeric behavior of corresponding five-membered complexes. It was found that the present complexes observed induced a wide nematic phase with relatively higher temperature ranges than the five aromatic systems. Density functional theory (DFT) suggested the nonlinear geometry of the formed complex. The results of the DFT explained the nematic mesophase formation. Moreover, the π–π stacking of the aromatic moiety in the phenylazo acid plays an effective role in the mesomorphic thermal stability. The energy difference between the frontier molecular orbitals, HOMO (highest occupied) and LUMO (lowest occupied), and the molecular electrostatic potential (MEP) of the prepared complexes were estimated by DFT calculations. The results were used to illustrate the observed nematic phase for all H-bonded supramolecular complexes. Finally, photophysical studies were discussed which were carried out by UV spectroscopy connected to a hot stage. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Organic Synthesis)

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21 pages, 4056 KiB

Open AccessArticle

2,3-Diaminopropanols Obtained from d-Serine as Intermediates in the Synthesis of Protected 2,3-l-Diaminopropanoic Acid (l-Dap) Methyl Esters

by Andrea Temperini, Donatella Aiello, Fabio Mazzotti, Constantinos M. Athanassopoulos, Pierantonio De Luca and Carlo Siciliano

Molecules 2020, 25(6), 1313; https://doi.org/10.3390/molecules25061313 - 13 Mar 2020

Cited by 9 | Viewed by 3963

Abstract

A synthetic strategy for the preparation of two orthogonally protected methyl esters of the non-proteinogenic amino acid 2,3-l-diaminopropanoic acid (l-Dap) was developed. In these structures, the base-labile protecting group 9-fluorenylmethyloxycarbonyl (Fmoc) was paired to the p-toluensulfonyl (tosyl, Ts) or [...] Read more.

A synthetic strategy for the preparation of two orthogonally protected methyl esters of the non-proteinogenic amino acid 2,3-l-diaminopropanoic acid (l-Dap) was developed. In these structures, the base-labile protecting group 9-fluorenylmethyloxycarbonyl (Fmoc) was paired to the p-toluensulfonyl (tosyl, Ts) or acid-labile tert-butyloxycarbonyl (Boc) moieties. The synthetic approach to protected l-Dap methyl esters uses appropriately masked 2,3-diaminopropanols, which are obtained via reductive amination of an aldehyde prepared from the commercial amino acid N^α-Fmoc-O-tert-butyl-d-serine, used as the starting material. Reductive amination is carried out with primary amines and sulfonamides, and the process is assisted by the Lewis acid Ti(OⁱPr)₄. The required carboxyl group is installed by oxidizing the alcoholic function of 2,3-diaminopropanols bearing the tosyl or benzyl protecting group on the 3-NH₂ site. The procedure can easily be applied using the crude product obtained after each step, minimizing the need for chromatographic purifications. Chirality of the carbon atom of the starting d-serine template is preserved throughout all synthetic steps. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Organic Synthesis)

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Review

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18 pages, 5531 KiB

Open AccessReview

Synthesis of Nitroaromatic Compounds via Three-Component Ring Transformations

by Song Thi Le, Haruyasu Asahara and Nagatoshi Nishiwaki

Molecules 2021, 26(3), 639; https://doi.org/10.3390/molecules26030639 - 26 Jan 2021

Cited by 5 | Viewed by 2612

Abstract

1-Methyl-3,5-dinitro-2-pyridone serves as an excellent substrate for nucleophilic-type ring transformation because of the electron deficiency and presence of a good leaving group. In this review, we focus on the three-component ring transformation (TCRT) of dinitropyridone involving a ketone and a nitrogen source. When [...] Read more.

1-Methyl-3,5-dinitro-2-pyridone serves as an excellent substrate for nucleophilic-type ring transformation because of the electron deficiency and presence of a good leaving group. In this review, we focus on the three-component ring transformation (TCRT) of dinitropyridone involving a ketone and a nitrogen source. When dinitropyridone is allowed to react with a ketone in the presence of ammonia, TCRT proceeds to afford nitropyridines that are not easily produced by alternative procedures. Ammonium acetate can be used as a nitrogen source instead of ammonia to undergo the TCRT, leading to nitroanilines in addition to nitropyridines. In these reactions, dinitropyridone serves as a safe synthetic equivalent of unstable nitromalonaldehyde. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Organic Synthesis)

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31 pages, 9594 KiB

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Difunctionalization of Alkenes and Alkynes via Intermolecular Radical and Nucleophilic Additions

by Hongjun Yao, Wenfei Hu and Wei Zhang

Molecules 2021, 26(1), 105; https://doi.org/10.3390/molecules26010105 - 28 Dec 2020

Cited by 69 | Viewed by 6260

Abstract

Popular and readily available alkenes and alkynes are good substrates for the preparation of functionalized molecules through radical and/or ionic addition reactions. Difunctionalization is a topic of current interest due to its high efficiency, substrate versatility, and operational simplicity. Presented in this article [...] Read more.

Popular and readily available alkenes and alkynes are good substrates for the preparation of functionalized molecules through radical and/or ionic addition reactions. Difunctionalization is a topic of current interest due to its high efficiency, substrate versatility, and operational simplicity. Presented in this article are radical addition followed by oxidation and nucleophilic addition reactions for difunctionalization of alkenes or alkynes. The difunctionalization could be accomplished through 1,2-addition (vicinal) and 1,n-addition (distal or remote) if H-atom or group-transfer is involved in the reaction process. A wide range of moieties, such as alkyl (R), perfluoroalkyl (R_f), aryl (Ar), hydroxy (OH), alkoxy (OR), acetatic (O₂CR), halogenic (X), amino (NR₂), azido (N₃), cyano (CN), as well as sulfur- and phosphorous-containing groups can be incorporated through the difunctionalization reactions. Radicals generated from peroxides or single electron transfer (SET) agents, under photoredox or electrochemical reactions are employed for the reactions. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Organic Synthesis)

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19 pages, 4186 KiB

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Bio-Catalysis in Multicomponent Reactions

by Ndze Denis Jumbam and Wayiza Masamba

Molecules 2020, 25(24), 5935; https://doi.org/10.3390/molecules25245935 - 15 Dec 2020

Cited by 10 | Viewed by 3539

Abstract

Enzyme catalysis is a very active research area in organic chemistry, because biocatalysts are compatible with and can be adjusted to many reaction conditions, as well as substrates. Their integration in multicomponent reactions (MCRs) allows for simple protocols to be implemented in the [...] Read more.

Enzyme catalysis is a very active research area in organic chemistry, because biocatalysts are compatible with and can be adjusted to many reaction conditions, as well as substrates. Their integration in multicomponent reactions (MCRs) allows for simple protocols to be implemented in the diversity-oriented synthesis of complex molecules in chemo-, regio-, stereoselective or even specific modes without the need for the protection/deprotection of functional groups. The application of bio-catalysis in MCRs is therefore a welcome and logical development and is emerging as a unique tool in drug development and discovery, as well as in combinatorial chemistry and related areas of research. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Organic Synthesis)

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26 pages, 6126 KiB

Open AccessReview

Recent Advances in the Synthesis and Biological Activity of 8-Hydroxyquinolines

by Haythem A. Saadeh, Kamal A. Sweidan and Mohammad S. Mubarak

Molecules 2020, 25(18), 4321; https://doi.org/10.3390/molecules25184321 - 21 Sep 2020

Cited by 42 | Viewed by 5199 | Correction

Abstract

Compounds containing the 8-hydroxyquinoline (8-HQ) 1 nucleus exhibit a wide range of biological activities, including antimicrobial, anticancer, and antifungal effects. The chemistry and biology of this group have attracted the attention of chemists, medicinal chemists, and professionals in health sciences. A number of [...] Read more.

Compounds containing the 8-hydroxyquinoline (8-HQ) 1 nucleus exhibit a wide range of biological activities, including antimicrobial, anticancer, and antifungal effects. The chemistry and biology of this group have attracted the attention of chemists, medicinal chemists, and professionals in health sciences. A number of prescribed drugs incorporate this group, and numerous 8-HQ- based molecules can be used to develop potent lead compounds with good efficacy and low toxicity. This review focusses on the recent advances in the synthesis of 8-HQ derivatives with different pharmacological properties, including anticancer, antiviral, and antibacterial activities. For this purpose, recent relevant references were searched in different known databases and search engines, such as MEDLINE (PubMed), Google Scholar, Science Direct, Scopus, Cochrane, Scientific Information Database (SID), SciFinder, and Institute for Scientific Information (ISI) Web of Knowledge. This review article provides a literature overview of the various synthetic strategies and biological activities of 8-HQ derivatives and covers the recent related literature. Taken together, compounds containing the 8-HQ moiety have huge therapeutic value and can act as potential building blocks for various pharmacologically active scaffolds. In addition, several described compounds in this review could act leads for the development of drugs against numerous diseases including cancer. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Organic Synthesis)

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25 pages, 3104 KiB

Open AccessReview

Empowering the Medicinal Applications of Bisphosphonates by Unveiling their Synthesis Details

by Jéssica S. Barbosa, Susana Santos Braga and Filipe A. Almeida Paz

Molecules 2020, 25(12), 2821; https://doi.org/10.3390/molecules25122821 - 18 Jun 2020

Cited by 10 | Viewed by 3613

Abstract

Bisphosphonates (BPs), well-known medicinal compounds used for osteoporosis management, are currently the target of intensive research, from basic pre-formulation studies to more advanced stages of clinical practice. The high demand by the pharmaceutical industry inherently requires an easy, efficient and quick preparation of [...] Read more.

Bisphosphonates (BPs), well-known medicinal compounds used for osteoporosis management, are currently the target of intensive research, from basic pre-formulation studies to more advanced stages of clinical practice. The high demand by the pharmaceutical industry inherently requires an easy, efficient and quick preparation of BPs. Current synthetic procedures are, however, still far from ideal. This work presents a comprehensive compilation of reports on the synthesis of the commercially available bisphosphonates that are pharmaceutical active ingredients. Current limitations to the conventional synthesis are assessed, and paths towards their improvement are described, either through the use of alternative solvents and/or by selecting appropriate ratios of the reactants. Innovative processes, such as microwave-assisted synthesis, are presented as more environmental-friendly and effective methods. The main advantages and setbacks of all syntheses are provided as a way to clarify and promote the development of simpler and improved procedures. Only in this way one will be able to efficiently respond to the future high demand of BPs, mostly due to the increase in life span in occidental countries. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Organic Synthesis)

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