Search Results (159)

A novel 3,6-dicarbonyl-substituted derivative of 2-chloropyrazine has been synthesized for the first time via regioselective dilithiation using lithium 2,2,6,6-tetramethylpiperidide (LiTMP) and subsequent trapping with methyl benzoate. The structure was unambiguously confirmed through Sonogashira coupling and diagnostic NMR analysis, establishing selective substitution at both the 3- and 6-positions. This result demonstrates that symmetrical 3,6-functionalization of 2-chloropyrazine is feasible under mild conditions, overcoming long-standing limitations of multiple metalations in electron-deficient heterocycles and opening new pathways for the synthesis of polyfunctional pyrazine frameworks. Full article

In this study, an efficient and regioselective synthetic method was developed for the preparation of 3-hydroxy-3-((2-(naphthalen-2-yloxy)-2-oxoethoxy)carbonyl)pentanedioic acid, a multifunctional ether–ester compound of potential interest for pharmaceutical and material science applications. The target compound was synthesized via the nucleophilic substitution (SN2) and esterification reactions of 2-naphthyl chloroacetate with the monosodium salt of citric acid. Optimization of the reaction conditions was carried out by varying the molar ratio of the reagents, reaction temperature, and duration. The highest yield of 83% was achieved under the conditions of a 2:1 molar ratio of chloroacetate to citrate, a temperature of 70–80 °C, and a reaction time of 6 h. The enhanced product yield observed under these conditions is attributed to the dual reactivity of the citric acid monosodium salt, which contains a free hydroxyl group capable of undergoing SN2 etherification, and free carboxylic acid groups that participate in esterification with the electrophilic 2-naphthyl chloroacetate. The stoichiometric 2:1 ratio ensures that both reactive centers on the citrate anion are fully utilized, leading to efficient and selective transformation into the desired product. Mechanistically, the ether bond formation proceeds through the classical Williamson ether synthesis pathway, where the alkoxide formed from the hydroxyl group attacks the electrophilic carbon of the chloroacetate, displacing the chloride ion. Concurrently, esterification enhances molecular complexity and stability. The results underline the synthetic utility of citric acid derivatives in forming complex organic architectures via environmentally benign routes. This study not only contributes a practical approach to multifunctional molecule synthesis but also reinforces the applicability of green chemistry principles in ester–ether coupling strategies. Full article

The naphthoquinone juglone (5-hydroxynaphthalene-1,4-dione) (1) occurs abundantly in nature, especially in species belonging to the Juglandaceae family. Due to its multifaceted biological activities, this compound is considered a privileged structure in Medicinal Chemistry for the development of new prototypes with several biological and pharmacological actions. However, the regioselective synthesis of 2-substituted juglones is challenging due to the non-symmetric naphthoquinone nucleus. Starting from non-symmetric 2,3-unsubstituted naphthalenes, in this paper we describe two general synthetic routes to juglone derivatives bearing an unsaturated or an oxygenated aliphatic side chain at C(2) or C(3). In an MTT test, a few products were more active than the parent unsubstituted juglone as inhibitors of the viability of human lung cancer H460 and breast cancer MCF-7 cells. The most potent compound featured a 1′-acetoxyhomoprenyl sidechain at the carbon C(2) of juglone. Full article

In this work, we report the divergent synthesis of a novel corrole macrocycle with a T-shaped geometry, functionalized with triphenylamine (TPA) units. The synthetic route involved a green preparation of 5-(pentafluorophenyl)dipyrromethane, condensation with pentafluorobenzaldehyde, and DDQ oxidation to afford the target corrole. In parallel, a TPA-based chalcone derivative was obtained and introduced via regioselective nucleophilic aromatic substitution. The resulting photoactive corrole–TPA conjugate exhibited efficient electropolymerization, retaining the corrole chromophore while forming conductive TPB-linked films (TPB, tetraphenylbenzidine). Spectroelectrochemical studies confirmed reversible redox activity, color switching, and electrochromic behavior, highlighting its potential as a building block for photo- and electroactive devices. Full article

The catalytic chloroacetylation of phenol and methoxyphenols was studied using FeCl₃ and FeCl₃·6H₂O as Lewis acid catalysts to assess the effect of catalyst hydration on selectivity. Both catalysts effectively promoted the reaction, but FeCl₃ favored O-acylation, while FeCl₃·6H₂O enhanced C-acylation to hydroxyphenacyl chlorides. Spectroscopic analyses (IR, UV–Vis, NMR) confirmed product structures and reaction pathways. Methoxy substitution significantly affected regioselectivity through resonance and inductive effects. The results demonstrate that catalyst hydration critically controls reactivity and product distribution, offering insights for selective synthesis of chloroacetylated aromatics relevant to pharmaceutical and fine chemical applications. Full article

An excellent regioselectivity of vapor-phase catalytic transfer hydrogenation (CTH) of substituted oxiranes (methyl-, n-butyl-, and phenyloxirane) with alkanols (EtOH, 2-PrOH or 2-PeOH) as hydrogen donors in the presence of magnesium oxide as a catalyst was attained. In the vapor phase, all of these oxiranes as well as 1,2-epoxycyclohexane were hydrogenated. Moreover, it was found that primary alcohols were always the main products of CTH of methyl-, n-butyl-, and phenyloxirane with very good regioselectivity towards the alcohols: 93, 73, and 100%, respectively. It was shown that vapor-phase CTH of methyloxirane with 2-pentanol led to three products, two regioisomeric propanols, (1-PrOH and 2-PrOH), and also 1-(2-pentyloxy)-2-propanol. Their yields were 48%, 4%, and 35%, respectively. Two regioisomeric hexanols (1-HeOH, 54% yield and 2-HeOH, 20% yield) and 2-hexanone (14% yield) were found as products of the CTH of n-butyloxirane with 2-propanol as the hydrogen donor. For vapor-phase CTH of phenyloxirane, only 2-phenylethanol (95% yield) was observed together with minor amounts of phenylacetaldehyde. In vapor-phase CTH of 1,2-epoxycyclohexane, the presence of the transfer hydrogenation products (2-cyclohexenone, cyclohexanol, and cyclopentylmethanol) as well as isomerization products (cyclohexanone, 2-cyclohexenol, and 3-cyclohexenol) were found. It was noted that at 623 K, the yields of the former products were 18, 22, and 14%, respectively. Liquid-phase CTH of n-butyl- or phenyloxirane with 2-pentanol (b.p. 392 K) was unsuccessful. Full article

The regioselectivity of the Claisen rearrangement with different meta-substituted and meta- and para-substituted allyl phenyl ethers was investigated. The main results were that in meta-substituted Claisen rearrangements the regioselectivity depends roughly on the electronic nature of the substituent, with electron-donating groups favoring migration further from the meta-substituent while electron-withdrawing groups favor migration towards the meta-substituent. Different para-substituents were tested with two meta-substituents, Me, and Cl. Most of the para-substituent tested had a clear effect on the product ratio, in all but one case enhancing the proportion of the major product favored by the meta-substituent. Population analysis was performed with Mulliken, Löwdin, Hirshfeld, and natural population analysis to analyze the influence of the substituents on the atomic charges on the reaction sites. It was observed that the atomic charge on the carbon that forms the major isomer is of higher negativity than the atomic charge on the carbon that forms the minor isomer. Full article

Anhydro-aldose oximes were employed to generate in situ nitrile oxides via a halogenation/base-induced elimination sequence in the presence of NCS and Et₃N, which were then used in 1,3-dipolar cycloadditions with alkenes and alkynes to afford 5-substituted 3-(β-d-glycopyranosyl)isoxazole and -isoxazoline derivatives exclusively. These newly synthesized glycomimetics were evaluated for their potential to act as antagonists of A2780 ovarian cancer cells and as inhibitors of glycogen phosphorylase; however, they exhibited no significant activity. Full article

A synthesis of substituted 1,4-benzodiazepines has been developed via palladium-catalyzed cyclization of N-tosyl-disubstituted 2-aminobenzylamines with propargylic carbonates. The reaction proceeds through the formation of π-allylpalladium intermediates, which undergo intramolecular nucleophilic attack by the amide nitrogen to afford seven-membered benzodiazepine cores. In reactions involving unsymmetrical diaryl-substituted carbonates, regioselectivity was observed to favor nucleophilic attack at the alkyne terminus substituted with the more electron-rich aryl group, suggesting that electronic effects play a key role in determining product distribution. The versatility of this reaction was further demonstrated by constructing a benzodiazepine framework found in bioactive molecules, indicating its potential utility in medicinal chemistry. Mechanistic insights supported by stereochemical outcomes and X-ray crystallographic analysis of key intermediates reinforce the proposed reaction pathway. This palladium-catalyzed protocol thus offers an efficient and practical approach to access structurally diverse benzodiazepine derivatives. Full article

Thyroid hormones, biosynthesized in the follicular cells in the thyroid gland, play a crucial role in regulating various important biological processes. The thyroid hormone is synthesized as pro-hormone L-thyroxine (T4), while the active form is primarily produced through the phenolic ring deiodination of T4 by iodothyronine deiodinase enzymes (DIOs). Three distinct isoforms of the enzyme are known, which, despite having almost similar amino acid sequences in their active site, differ in their regioselectivity of deiodination towards T4 and its metabolites. However, the precise mechanism and the origin of the differences in the regioselectivity of deiodination by DIOs are still not fully understood. Over the years, several research groups have attempted to mimic this system with small molecules to gain some insight into the reactivity and mechanism. In this review, we will explore the recent developments on the biomimetic deiodination of T4 and its derivatives by using selenium-based enzyme mimetics. For example, naphthalene-based molecules, featuring a 1,8-dichalcogen atom, have been shown to perform tyrosyl ring deiodination of T4 and T3, producing rT3 and 3,3′-T2, respectively. The modification of the electron density around the phenolic ring through substitutions in the 4′-hydroxyl group can alter the regioselectivity of the deiodination by deiodinase mimics. Additionally, we will highlight the recent progress in the development of a dipeptide-based DIO1 mimic, as well as the deiodination of other halogenated thyronine derivatives by mimics. Full article

The aim of this study was to synthesize new racemic and optically pure aryl-substituted purine bioisosteres using ultrasound-assisted Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition. Regioselective synthesis of α-azido alcohols was applied to afford heterocycles with a 2-hydroxyeth-1-yl linker. Catalytic asymmetric synthesis using halohydrin dehalogenase in the ring-opening of epoxides gave enantioenriched azido alcohols, which subsequently afforded R- and S-enantiomers of purine and pyrrolo[2,3-d]pyrimidines with a 1-hydroxyeth-2-yl linker. The newly synthesized compounds were evaluated in vitro for their antiproliferative activity against four malignant tumor cell lines. The influence of regioisomerism and the stereochemistry of the hydroxyethyl group, as well as a N-heterocyclic scaffold linked to the aryl moiety on cytostatic activity was evaluated. Of all the compounds tested, purine 40a and pyrrolo[2,3-d]pyrimidine 45a derivatives with p-trifluoromethyl-substituted aryl connected to 1,2,3-triazole via a 2-hydroxyeth-1-yl spacer showed promising submicromolar antiproliferative activity. In addition, compound 45a exhibited selectivity towards the tumor cell line, with a selectivity index (SI) of 40, moderate clearance, and good membrane permeability. Full article

The 4-aminoquinazoline scaffold is a privileged structure in medicinal chemistry. Regioselective nucleophilic aromatic substitution (S_NAr) for replacing the chlorine atom at the 4-position of 2,4-dichloroquinazoline precursors is well documented in the scientific literature and has proven useful in synthesizing 2-chloro-4-aminoquinazolines and/or 2,4-diaminoquinazolines for various therapeutic applications. While numerous reports describe reaction conditions involving different nucleophiles, solvents, temperatures, and reaction times, discussions on the regioselectivity of the S_NAr step remain scarce. In this study, we combined DFT calculations with 2D-NMR analysis to characterize the structure and understand the electronic factors underlying the regioselective S_NAr of 2,4-dichloroquinazolines for the synthesis of bioactive 4-aminoquinazolines. DFT calculations revealed that the carbon atom at the 4-position of 2,4-dichloroquinazoline has a higher LUMO coefficient, making it more susceptible to nucleophilic attack. This observation aligns with the calculated lower activation energy for nucleophilic attack at this position, supporting the regioselectivity of the reaction. To provide guidance for the structural confirmation of 4-amino-substituted product formation when multiple regioisomers are possible, we employed 2D-NMR methods to verify the 4-position substitution pattern in synthesized bioactive 2-chloro-4-aminoquinazolines. These findings are valuable for future research, as many synthetic reports assume regioselective outcomes without sufficient experimental verification. Full article

A method for the synthesis of C4-benzhydryl-functionalized 3,4-dihydropyridin-2-ones using complementary addition of benzhydryllithium and/or benzhydrylmagnesiate reagents to 2-pyridones, with high regioselectivity triggered by substituents, is described. A partially stereoselective cyclization was successfully demonstrated using TfOH and/or TIPSOTf as Brønsted and Lewis acids, respectively, leading to C6-phenyl-functionalized 7,8-benzomorphanones. It is also shown that the use of functionalized δ-enelactams obtained with an active methoxy-substituted benzyl group at C3 enabled the preparation of a new C3–C6 bridged system within the δ-lactam framework. Full article

Ψ-1,4-naphthoquinones (Ψ-NQ) are non-quinoid compounds in which aromaticity—found in 1,4-naphthoquinones—is broken by the introduction of an angular methyl at C-4a or -8a. This series was designed to act as prodrugs of 1,4-naphthoquinones in an oxidative environment. Furthermore, from a medicinal chemistry point of view, the loss of planarity of the scaffold might lead to an improved solubility and circumvent the bad reputation of quinones in the pharmaceutical industry. In this work, we illustrated the concept by the synthesis of Ψ -plasmodione regioisomers as prodrugs of the antimalarial plasmodione. The presence of a chiral center introduces a new degree of freedom to be controlled by enantioselectivity and regioselectivity of the cycloaddition in the Diels–Alder reaction. The first strategy that was followed was based on the use of a chiral enantiopure sulfoxide to govern the stereoselective formation of (+)Ψ-NQ or (−)Ψ-NQ, depending on the chirality of the sulfoxide (R or S). New sulfinylquinones were synthesized but were found to be ineffective in undergoing cycloaddition with different dienes under a wide range of conditions (thermal, Lewis acid). The second strategy was based on the use of boronic acid-substituted benzoquinones as auxiliaries to control the regioselectivity. Using this methodology to prepare the (±)Ψ-NQ racemates, promising results (very fast cycloaddition time: ~2 h) were obtained with boronic acid-based quinones 25 and 27 in the presence of 1-methoxy-1,3-butadiene, to generate the 4a- and the 8a-Ψ-plasmodione regioisomers 1 and 2 (synthesized in six steps with a total yield of 10.5% and 4.1%, respectively. As the expected prodrug effect can only be revealed if the molecule undergoes an oxidation of the angular methyl, e.g., in blood-feeding parasites that digest hemoglobin from the host, the antimalarial and the antischistosomal properties of both (±)Ψ-NQ regioisomers were determined in drug assays with Plasmodium falciparum and Schistosoma mansoni. Metabolic studies under quasi-physiological conditions and LC-MS analyses were undertaken to reveal the generation of plasmodione from both the 4a- and the 8a-Ψ-plasmodione regioisomers. Full article

By treatment of the peracetylated methylester of 4-acetylamino-2,4-dideoxy-d-glycero-d-galacto-octonic acid (ADOA-PAE) with nitrosyl tetrafluoroborate, a serendipitous formation of a highly functionalized carbohydrate–pyrazole conjugate was observed in 95% yield. This observation is remarkable, as it involves a five-step one-pot synthesis that proceeds via an 1,3-acyl shift and a 1,5-electrocyclization, which usually requires thermal conditions; however, the reaction occurred at a temperature of 0 °C. Additionally, the excellent yield of the carbohydrate-decorated pyrazole and the regiospecificity of the cyclization are of particular interest, as regioselectivity is always a challenge in pyrazole synthesis. Subsequently, this novel access to pyrazoles starting from N-acetyl-allyl amides via nitrosation and electrocyclization was investigated. In addition, mechanistic studies for the formation of substituted pyrazoles of type were carried out. Full article