Search Results (108)

Fluorinated organic molecules have become indispensable in modern chemistry, owing to the unique properties imparted by fluorine to other compounds, including enhanced metabolic stability, controlled lipophilicity, and improved bioavailability. The site-selective incorporation of fluorine atoms into organic frameworks is essential in pharmaceutical, agrochemical, and material science research. In recent years, catalytic fluorination has become an important methodology for the efficient and selective incorporation of fluorine atoms into complex molecular architectures. This review highlights advances in catalytic fluorination reactions over the past six years and describes the contributions of transition metal catalysts, photocatalysts, organocatalysts, and electrochemical systems that have enabled site-selective fluorination under a variety of conditions. Particular attention is given to the use of well-defined fluorinating agents, including Selectfluor, N-fluorobenzenesulfonimide (NFSI), AlkylFluor, Synfluor, and hypervalent iodine reagents. These reagents have been combined with diverse catalytic systems, such as AgNO₃, Rh(II), Mo-based complexes, Co(II)-salen, and various organocatalysts, including β,β-diaryl serine catalysts, isothiourea catalysts, and chiral phase-transfer catalysts. This review summarizes proposed mechanisms reported in the original studies and discusses examples of electrophilic, nucleophilic, radical, photoredox, and electrochemical fluorination pathways. Recent developments in stereoselective and more sustainable protocols are also examined. By consolidating these strategies, this article provides an up-to-date perspective on catalytic fluorination and its impact on synthetic organic chemistry. Full article

The intramolecular Diels–Alder (IMDA) reactions of four substituted deca-1,3,9-trienes and one N-methyleneocta-5,7-dien-1-aminium with different electrophilic/nucleophilic activations have been studied within the Molecular Electron Density Theory (MEDT) and compared to their intermolecular processes. The topological analysis of the electron density and DFT-based reactivity indices reveal that substitution does not modify neither the electronic structure nor the reactivity of the reagents relative to those involved in the intermolecular processes. The analysis of the relative energies establishes that the accelerations found in the polar IMDA reactions follow the same trend as those found in the intermolecular processes. The geometries and the electronic structures of the five transition state structures involved in the IMDA reactions are highly similar to those found in the intermolecular processes. A relative interacting atomic energy (RIAE) analysis of Diels–Alder and IMDA reactions allows for the establishment of the substituent effects on the activation energies. Although the nucleophilic frameworks are destabilized, the electrophilic frameworks are further stabilized, resulting in a reduction in the activation energies. The present MEDT study demonstrates the remarkable electronic and energetic similarity between the intermolecular and intramolecular Diels–Alder reactions. Only the lower, unfavorable activation entropy associated with the latter renders it 10⁴ times faster than the former. Full article

The complex of hypofluorous acid with acetonitrile—HOF•CH₃CN—is the only substance possessing a truly electrophilic oxygen. This fact makes it the only tool suitable for transferring oxygen atoms to sites that are not accessible to this vital element. We will review here most of the known organic reactions with this complex, which is easily made by bubbling dilute fluorine through aqueous acetonitrile. The reactions of HOF•CH₃CN with double bonds produce epoxides in a matter of minutes at room temperature, even when the olefin is electron-depleted and cannot be epoxidized by any other means. The electrophilic oxygen can also substitute deactivated tertiary C-H bonds via electrophilic substitution, proceeding with full retention of configuration. Using this complex enables transferring oxygen atoms to a carbonyl and oxidizing alcohols and ethers to ketones. The latter could be oxidized to esters via the Baeyer–Villiger reaction, proving once again the validity of the original Baeyer mechanism. Azines are usually avoided as protecting groups for carbonyl since their removal is problematic. HOF•CH₃CN solves this problem, as it is very effective in recreating carbonyls from the respective azines. A bonus of the last reaction is the ability to replace the common ¹⁶O isotope of the carbonyl with the heavier ¹⁷O or ¹⁸O in the simplest and cheapest possible way. The reagent can transfer oxygen to most nitrogen-containing molecules. Thus, it turns practically any azide or amine into nitro compounds, including amino acids. This helps to produce novel α-alkylamino acids. It also attaches oxygen atoms to most tertiary nitrogen atoms, including certain aromatic ones, which could not be obtained before. HOF•CH₃CN was also used to make five-member cyclic poly-NO derivatives, many of them intended to be highly energetic materials. The nucleophilic sulfur atom also reacts very smoothly with the reagent in a wide range of compounds to form sulfone derivatives. While common sulfides are easily converted to sulfones by many orthodox reagents, electron-depleted ones, such as R_f-S-Ar, can be oxidized to R_f-SO₂-Ar only with this reagent. The mild reaction conditions also make it possible to synthesize a whole range of novel episulfones and offer, as a bonus, a very easy way to make S^xO₂, x being any isotope variation of oxygen. These mild conditions also helped to oxidize thiophene to thiophen-S,S-dioxide without the Diels–Alder dimerizations, which usually follow such dioxide formation. The latter reaction was a prelude to a series of preparations of [all]-S,S-dioxo-oligothiophenes, which are important for the efficient preparation of active layers in field-effect transistors (FETs), as such oligomers are considered to be important for organic semiconductors for light-emitting diodes (LEDs). Several types of these oligothiophenes were prepared, including partly or fully oxygenated ones, star-oligothiophenes, and fused ones. Several [all]-S,S-dioxo-oligo-thienylenevinylenes were also successfully prepared despite the fact that they also possess carbon–carbon p centers in their molecules. All oxygenated derivatives have been prepared for the first time and have lower HOMO-LUMO gaps compared to their parent compounds. HOF•CH₃CN was also used to oxidize the surface of the nanoparticles of oligothiophenes, leaving the core of the nanoparticle unchanged. Several highly interesting features have been detected, including their ability to photostimulate the retinal neurons, especially the inner retinal ones. HOF•CH₃CN was also used on elements other than carbon, such as selenium and phosphor. Various selenides were oxidized to the respective selenodioxide derivatives (not a trivial task), while various phosphines were converted efficiently to the corresponding phosphine oxides. Full article

A facile strategy to increase the chemoselectivity of domino reactions was proposed and successfully applied in the α-functionalization of ketones. The strategy involved widening the activation energy of the main reaction and side reaction through intermolecular interactions, thereby increasing the chemoselectivity of the domino reaction. In the proposed α-functionalization reaction, TMSCF₃ acted as an excellent reagent which increased the nucleophilicity of DMF through the Van der Waals force and reduced the nucleophilicity of H₂O through a hydrogen bond. We found that TMSCF₃ can increase the activation energy difference between the main reaction and side reaction using DFT calculations, which greatly increased chemoselectivity and avoided the formation of by-products. TMSCF₃ was recycled by rectification, and the average recovery rate was 87.2%. DFT calculations, XRD experiments, and control experiments were performed to support this mechanism. We are confident that this strategy has the potential to deliver significant practical advancements while simultaneously fostering broader innovation in the field of domino synthesis. Full article

A rapid synthesis of structurally novel s-indacene-1,5-dione and cyclopentanone-fused isoxazole derivatives in generally moderate yields was achieved through the NaNO₂-catalyzed/involved transformation of cyclopentenone-MBH acetates. Under similar reaction conditions, two different reaction pathways were observed depending on the type of aryl substituent on MBH acetates. In the formation of s-indacene-1,5-diones, NaNO₂ is proposed to act as a nucleophilic catalyst to initiate the stepwise dimeric cyclization/oxidative aromatization, whereas in the formation of isoxazole derivatives, it plays the role of nucleophilic reagent of (3+2) cycloaddition. Using NaNO₂ as an inexpensive and readily available catalyst or reaction component, mild reaction conditions, operational simplicity, and metal-free transition are the main advantages of this work. Full article

A straightforward synthetic route towards DAB-1 scaffolded dimeric iminosugars is described here, starting from readily available bis-glycosylamines. The method allows the integration of a variety of linkages (aryl, alkyl, polyethyleneglycol chains) between both iminosugars through the choice of the bis-amine used in the first step. Moreover, an additional substituent (allyl, ethynyl) may be inserted into the structure via nucleophilic addition of an organometallic reagent to the starting bis-glycosylamine. A symmetrical ethynyl-iminosugar proved susceptible to intramolecular Glaser coupling, affording the corresponding macrocyclic structure. Dimeric iminosugars were tested towards a series of commercial glycosidases to uncover potencies and selectivities when compared to DAB-1, their monomeric counterpart. Whereas a significant drop in inhibition potencies was observed towards glucosidases, some compounds displayed unexpected potent inhibition of β-galactosidase. Full article

Herein, we developed a colorimetric method for the determination of Cu²⁺ and Zn²⁺ using NBD-G as a novel selective metal sensor. NBD-G was easily synthesized by a nucleophilic substitution reaction between 4-chloro-7-nitro-2,1,3-benzoxadiazole (NBD-Cl) and Girard’s Reagent P. The NBD-G solution is yellow, but when it reacts with Cu²⁺ and Zn²⁺, its color changes selectively to red (510 nm) and orange (480 nm), respectively. NBD-G was used as a sensor for Cu²⁺ and Zn²⁺, showing a high sensitivity down to 0.77 µM for Cu²⁺ and 1.66 µM for Zn²⁺. NBD-G could determine both metals simultaneously; thus, it was applied to determine them in multimineral supplements, which showed excellent recoveries. Next, a filter paper impregnated with NBD-G was prepared as a test paper, and a simple, selective, and rapid onsite method for quantifying Cu²⁺ was developed as, interestingly, the paper showed no change upon the addition of Zn²⁺. Next, Cu²⁺ could be quantified with high selectivity and accuracy by photographing the color change with a smartphone camera and processing the image with Image J. The detection limit for Cu²⁺ using this method was 3.9 µM. Finally, the NBD-G test paper method was able to satisfactorily quantify Cu²⁺ spiked into the rainwater. Full article

N,N′-Dialkylimidazolium-based ionic liquids are capable of completely dissolving lignocellulosic biomass at elevated temperatures and are considered as promising green solvents for future biorefining technologies. However, the obtained ionic liquid lignin preparations may contain up to several percent nitrogen. This indicates strong interactions between the biopolymer and the IL cation, the nature of which has not yet been clarified. The present study investigates mechanisms and pathways of the formation of nitrogen-containing lignin compounds. To achieve this goal, eight monomeric lignin-related phenols bearing different functional groups (ketone, aldehyde, hydroxyl, carbon–carbon double bonds) were treated with 1-butyl-3-methylimidazolium acetate (BmimOAc) under typical conditions of IL-assisted lignocellulose fractionation (80–150 °C). A number of the resulting products were tentatively identified, for all the studied model compounds, by two-dimensional NMR spectroscopy and high-performance liquid chromatography—high-resolution mass spectrometry. They all possess covalently bonded Bmim residues and occur through the nucleophilic addition of an N-heterocyclic carbene (deprotonated Bmim cation) to electron-deficient groups. The reactivity of lignin functional groups in their interaction with Bmim is greatly affected by the temperature and dissolved oxygen. IL’s thermal degradation products act as additional reactive species toward lignin, further complicating the range of products formed. The obtained results made it possible to answer the question posed in this article’s title and to assert that N,N′-dialkylimidazolium-based ILs act as active reagents with respect to lignin during the dissolution of lignocellulose. Full article

BODIPY compounds are important organic dyes with exceptional spectral and photophysical properties and numerous applications in different scientific fields. Their widespread applications have flourished due to their easy structural modifications, which enable the preparation of different molecular structures with tunable spectral and photophysical properties. To date, researchers have mostly devoted their efforts to modifying BODIPY meso-position or pyrrole rings, whereas the substitution of fluorine atoms remains largely unexplored. However, chemistry of the boron atom is possible, and it enables tuning of the photophysical properties of the dyes, without tackling their spectral properties. Furthermore, modifications of boron affect the solubility and aggregation propensity of the molecules. This review article highlights methods for the preparation of 4-substituted compounds and the most important reactions on the boron of the BODIPY dyes. They were divided into reactions promoted by Lewis acid (AlCl₃ or BCl₃), or bases such as alkoxides and organometallic reagents. By using these two methodologies, it is possible to cleave B–F bonds and substitute them with B–C, B–N, or B–O bonds from different nucleophiles. A special emphasis in this review is given to still underdeveloped photochemical reactions of the boron atom of BODIPY dyes. These reactions have the potential to be used in the development of a new line of BODIPY photo-cleavable protective groups (also known as photocages) with bio-medicinal and photo-pharmacological applications, such as drug delivery. Full article

Selenium-containing molecules represent a valuable class of compounds with a variety of applications in chemical and biological fields. Selenated reagents are used as intermediates to introduce functional groups (e.g., double bonds) onto different substrates or in the synthesis of various selenated derivatives. Among the variety of selenium-containing reagents, silyl selenides are frequently used to transfer a selenated moiety due to the smooth functionalization of the Se-Si bond, which allows for the generation of selenium nucleophilic species under mild conditions. While the use of the analogous sulfur nucleophiles, namely silyl sulfides, has been widely explored, a relatively limited number of reports on selenosilanes have been provided. This contribution will focus on the application of selenosilanes as nucleophiles in a variety of organic transformations, as well as under radical and redox conditions. The use of silyl selenides to prepare metal complexes and as selenium precursors of materials for atomic layer deposition will also be discussed. Full article

2-Chloropyridine-3-carbonitrile derivative 1 was utilized as a key precursor to build a series of linear and angular annulated pyridines linked to a 6-hydroxy-4,7-dimethoxybenzofuran moiety. Reaction of substrate 1 with various hydrazines afforded pyrazolo[3,4-b]pyridines. Treatment of substrate 1 with 1,3-N,N-binucleophiles including 3-amino-1,2,4-triazole, 5-amino-1H-tetrazole, 3-amino-6-methyl-1,2,4-triazin-5(4H)-one and 2-aminobenzimidazole produced the novel angular pyrido[3,2-e][1,2,4]triazolo[4,3-a]pyrimidine, pyrido[3,2-e][1,2,4]tetrazolo[1,5-a]pyrimidine, pyrido[3′,2′:5,6] pyrimido[2,1-c][1,2,4]triazine and benzo[4,5]imidazo[1,2-a]pyrido[3,2-e]pyrimidine, respectively. Reaction of substrate 1 with 1,3-C,N-binucleophiles including cyanoacetamides and 1H-benzimidazol-2-ylacetonitrile furnished 1,8-naphthyridines and benzoimidazonaphthyridine. Moreover, reacting substrate 1 with 5-aminopyrazoles gave pyrazolo[3,4-b][1,8]naphthyridines. Finally, reaction of compound 1 with 6-aminouracils as cyclic enamines yielded pyrimido[4,5-b][1,8]naphthyridines. Some of the synthesized products showed noteworthy antimicrobial efficiency against all types of microbial strains. Structures of the produced compounds were established using analytical and spectroscopic tools. Full article

The reagent system based on the combined use of Et₃SiH/I₂ acts as an efficient N-glycosidation promoter for the synthesis of natural and sugar-modified nucleosides. An analysis of reaction stereoselectivity in the absence of C2-positioned stereodirecting groups revealed high selectivity with six-membered substrates, depending on the nucleophilic character of the nucleobase or based on anomerization reactions. The synthetic utility of the Et₃SiH/I₂-mediated N-glycosidation reaction was highlighted by its use in the synthesis of the investigational drug apricitabine. Full article

In light of the small ring strain of five/six-membered cyclic ethers, constructing complex molecules via ring-opening reactions has consistently been a highly challenging topic in organic synthesis. Induced by Lewis acids, the charge redistribution in cyclic ethers forms oxonium ylide intermediates, thereby activating the C–O bond and subsequently facilitating nucleophilic attack for ring opening. In recent years, a variety of novel Lewis acids, encompassing those with new metal centers and frustrated Lewis pairs (FLPs), have been effectively utilized to induce the formation of oxonium ylides, offering a diverse array of methods for the ring opening of five/six-membered cyclic ethers. This review conveys the extensive application advancements of diverse Lewis acid types for cyclic ether ring-opening reactions over the past two decades, originating from the perspective of the classification of Lewis acids. Furthermore, the substrate applicability and chemical transformation efficiency of these Lewis acids in the ring-opening reactions of cyclic ethers have also been discussed herein. Full article

Currently, the copper-mediated radiofluorination of aryl pinacol boronates (arylBPin) using the commercially available, air-stable Cu(OTf)2Py4 catalyst is one of the most efficient synthesis approaches, greatly facilitating access to a range of radiotracers, including drug-like molecules with nonactivated aryl scaffolds. Further adjustment of this methodology, in particular, the [¹⁸F]fluoride recovery step for the routine preparation of radiotracers, has been the focus of recent research. In our recent study, an organic solution of 4-dimethylaminopyridinium trifluoromethanesulfonate (DMAPOTf) was found to be an efficient PTC for eluting radionuclides retained on the weak anion exchange cartridge, Oasis WAX 1cc, employing the inverse sorption–elution protocol. Notably, the following Cu-mediated radiofluorination of arylBPin precursors in the presence of the Cu(OTf)2(Py)4 catalyst can be performed with high efficiency in the same solvent, bypassing not only the conventional azeotropic drying procedure but any solvent replacement. In the current study, we aimed to translate this methodology, originally developed for remote-controlled operation with manual interventions, into the automated synthesis module on the TRACERlab automation platform. The adjustment of the reagent amounts and solvents allowed for high efficiency in the radiofluorination of a series of model arylBPin substrates on the TRACERlab FXFE Pro synthesis module, which was adapted for nucleophilic radiofluorinations. The practical applicability of the developed radiofluorination approach with DMAPOTf elution was demonstrated in the automated synthesis of 6-L-[¹⁸F]FDOPA. The radiotracer was obtained with an activity yield (AY; isolated, not decay-corrected) of 5.2 ± 0.5% (n = 3), with a synthesis time of ca. 70 min on the TRACERlab FX N Pro automation platform. The obtained AY was comparable with one reported by others (6 ± 1%) using the same boronate precursor, while a slightly higher AY of 6-L-[¹⁸F]FDOPA (14.5 ± 0.5%) was achieved in our previous work using commercially available Bu₄NOTf as the PTC. Full article

Carbon dioxide (CO₂) is a non-toxic, abundant and recoverable source of carbon monoxide. Despite its thermodynamically stable and kinetically inert nature, research on CO₂ utilisation is ongoing. CO₂-based aryne reactions, crucial for synthesising ortho-substituted benzoic acids and their cyclisation products, have garnered significant attention, and multi-component reactions (MCRs) involving CO₂, aryne and nucleophilic reagents have been extensively studied. This review highlights recent advancements in CO₂ capture reactions utilising phenylalkyne reactive intermediates. Mechanistic insights into these reactions are provided together with prospects for further development in this field. Full article