RESUMEN

Nucleosides with a substituent at the 4'-position have received much attention as antiviral drugs and as raw materials for oligonucleotide therapeutics. 4'-Modified nucleosides are generally synthesized using ionic reactions through the introduction of electrophilic or nucleophilic substituents at the 4'-position. However, their synthetic methods have some drawbacks; e.g., (i) it is difficult to control stereoselectivity at the 4'-position; (ii) complex protection-deprotection processes are required; (iii) the range of electrophiles and nucleophiles is limited. With this background, we considered that a carbon radical generated at the 4'-position would be a useful intermediate for the synthesis of 4'-modified nucleosides. In this review, two novel methods for the generation of 4'-carbon radicals are summarized. The first utilizes radical deformylation involving ß-fragmentation of a hydroxymethyl group at the 4'-position. The other utilizes radical decarboxylation and 1,5-hydrogen atom transfer (1,5-HAT), which enables the generation of 4'-carbon radicals while retaining the hydroxymethyl group at the 4'-position. These methods enable the rapid and facile generation of 4'-carbon radicals and provide various 4'-modified nucleosides including 2',4'-bridged structures.

Asunto(s)

RESUMEN

Allylic C-H amination has emerged as a powerful tool to construct allylamines, common motifs in molecular therapeutics. Such reaction implies an oxidative path for C-H activation but furnishes reductive amines, inferring mild oxidants' inactivity for C-H oxidation but strong oxidants' detriment to products. Herein we report a heterogeneous catalytic approach that manipulates halogen-vacancies of perovskite photocatalyst and exploits halogenated-solvents (i.e. CH2Cl2, CH2Br2) as mild oxidants for selective C-H allyl amination with 19,376 turnover. CsPbBr3 nanocrystals induce cooperative hydrogen-atom-transfer (HAT, C-H oxidation, and halogen-vacancy CsPbBr3-x formation) and halogen-atom-transfer (XAT, CsPbBr3-x-induced solvent reduction) under a radical chain mechanism. Terminal/internal olefins are amenable to forge aromatic/aliphatic, cyclic/acyclic, secondary/tertiary allylamines (70 examples), including drugs or their derivatives.

RESUMEN

Developing methods to directly transform C(sp3) -H bonds is crucial in synthetic chemistry due to their prevalence in various organic compounds. While conventional protocols have largely relied on transition metal catalysis, recent advancements in organocatalysis, particularly with radical NHC catalysis have sparked interest in the direct functionalization of "inert" C(sp3) -H bonds for cross C-C coupling with carbonyl moieties. This strategy involves selective cleavage of C(sp3) -H bonds to generate key carbon radicals, often achieved via hydrogen atom transfer (HAT) processes. By leveraging the bond dissociation energy (BDE) and polarity effects, HAT enables the rapid functionalization of diverse C(sp3)-H substrates, such as ethers, amines, and alkanes. This mini-review summarizes the progress in carbene organocatalytic functionalization of inert C(sp3)-H bonds enabled by HAT processes, categorizing them into two sections: 1) C-H functionalization involving acyl azolium intermediates; and 2) functionalization of C-H bonds via reductive Breslow intermediates.

RESUMEN

Efficient metal-free synthesis of benzo[b]azepines and oxindoles is achieved via a radical relay cascade strategy employing halogen atom transfer (XAT) for aryl radical generation followed by intramolecular hydrogen atom transfer (HAT). Optimization yielded moderate to substantial yields under visible light irradiation. Preliminary biological assessments revealed promising anti-tumor activity for select compounds. This study underscores the potential of XAT-mediated radical relay cascades in medicinal chemistry and anticancer drug discovery.

RESUMEN

A theoretical thermodynamic study was conducted to investigate the antioxidant activity and mechanism of 1,3,4-oxadiazol-2-ylthieno[2,3-d]pyrimidin-4-amine derivatives (OTP) using a Density Functional Theory (DFT) approach. The study assessed how solvent environments influence the antioxidant properties of these derivatives. With the increasing prevalence of diseases linked to oxidative stress, such as cancer and cardiovascular diseases, antioxidants are crucial in mitigating the damage caused by free radicals. Previous research has demonstrated the remarkable scavenging abilities of 1,3,4-oxadiazole derivatives, prompting this investigation into their potential using computational methods. DFT calculations were employed to analyze key parameters, including bond dissociation enthalpy (BDE), ionization potential (IP), proton dissociation enthalpy (PDE), and electron transfer enthalpy (ETE), to delineate the antioxidant mechanisms of these compounds. Our findings indicate that specific electron-donating groups such as amine on the phenyl rings significantly enhance the antioxidant activities of these derivatives. The study also integrates global and local reactivity descriptors, such as Fukui functions and HOMO-LUMO energies, to predict the stability and reactivity of these molecules, providing insights into their potential as effective synthetic antioxidants in pharmaceutical applications.

RESUMEN

A cobalt-catalyzed intramolecular Markovnikov hydroalkoxycarbonylation and hydroaminocarbonylation of unactivated alkenes has been developed, enabling highly chemo- and regioselective synthesis of α-alkylated γ-lactones and α-alkylated γ-lactams in good yields. The mild reaction conditions allow use of mono-, di- and trisubstituted alkenes bearing a variety of functional groups. Preliminary mechanistic studies suggest the reaction proceeds through a CO-mediated hydrogen atom transfer (HAT) and radical-polar crossover (RPC) process, in which a cationic acylcobalt(IV) complex is proposed as the key intermediate.

RESUMEN

A combination of inter- and intramolecular 13C kinetic isotope effects and density functional theory analysis is used to evaluate the key mechanistic events of sequentially operating catalytic cycles in the dual photoredox-cobalt-catalyzed elimination of alkyl bromides. The results point to a mechanism proceeding via irreversible halogen-atom transfer (XAT) from the alkyl halide, resulting in an alkyl radical, which undergoes hydrogen-atom transfer (HAT) to a Co(II) intermediate to deliver the product olefin. Alternative pathways involving nucleophilic substitution by a Co(I) species and by ß-hydride elimination are discounted based on the poor agreement of experimental and predicted 13C KIEs. This mechanistic understanding is used to evaluate the origins of regioselectivity in the elimination step for an unsymmetrical alkyl halide catalyzed by electronically and sterically distinct cobaloxime catalysts. This study represents the experimental validation of the key features of the transition state structure of XAT by α-aminoalkyl radicals, an important class of atom transfer reactions that generate carbon-centered radicals from alkyl and aryl halides. Furthermore, it illustrates the power of 13C KIEs in probing complex mechanisms in metallaphotoredox catalysis.

RESUMEN

In this study, we introduce a novel intramolecular hydrogen atom transfer (HAT) reaction that efficiently yields azetidine, oxetane, and indoline derivatives through a mechanism resembling the carbon analogue of the Norrish-Yang reaction. This process is facilitated by excited triplet-state carbon-centered biradicals, enabling the 1,5-HAT reaction by suppressing the critical 1,4-biradical intermediates from undergoing the Norrish Type II cleavage reaction, and pioneering unprecedented 1,6-HAT reactions initiated by excited triplet-state alkenes. We demonstrate the synthetic utility and compatibility of this method across various functional groups, validated through scope evaluation, large-scale synthesis, and derivatization. Our findings are supported by control experiments, deuterium labeling, kinetic studies, cyclic voltammetry, Stern-Volmer experiments, and density functional theory (DFT) calculations.

RESUMEN

The escalating demand for plastics has resulted in a surge of plastic waste worldwide, posing a monumental environmental challenge. To address this issue, a versatile photo-oxidative degradation method applicable to seven distinct polymer families is proposed, comprising poly(isobutyl vinyl ether) (PIBVE), poly(2,3-dihydrofuran) (PDHF), poly(vinyl acetate) (PVAc), poly(n-butyl acrylate) (PBA), poly(methyl acrylate) (PMA), poly(vinyl chloride) (PVC), poly(dimethyl acrylamide) (PDMA), poly(ethylene oxide) (PEO), poly(oligo(ethylene glycol) methyl ether acrylate) (PEGMEA), and even poly(methyl methacrylate) (PMMA). This method employs photo-mediated hydrogen atom transfer (HAT) followed by oxidation to promote polymer degradation. This reaction is carried out under aerobic condition in the presence of iron trichloride (FeCl3) as a photocatalyst in combination with low-intensity purple light irradiation. The process can degrade up to 97% of the polymer in less than 3 h. This degradation process can be easily controlled by switching the light off, which allows for precise modulation of the degradation rate, enhancing the effectiveness of the method. Overall, this method provides a sustainable method for degrading various polymer types with low energy input.

RESUMEN

Natural photosynthesis enzymes utilize energies of several photons for challenging oxidation of water, whereas artificial photo-catalysis typically involves only single-photon excitation. Herein, a multiphoton excitation strategy is reported that combines parallel photo-excitations with a photoinduced electron transfer process for the activation of C(sp3)─H bonds, including methane. The metal-organic framework Fe3-MOF is designed to consolidate 4,4',4″-nitrilotrisbenzoic units for the photoactivation of dioxygen and trinuclear iron clusters as the HAT precursor for photoactivating alkanes. Under visible light irradiation, the dyes and iron clusters absorbed parallel photons simultaneously to reach their excited states, respectively, generating 1O2 via energy transfer and chlorine radical via ligand-to-metal charge transfer. The further excitation of organic dyes leads to the reduction of 1O2 into O2 •- through a photoinduced electron transfer, guaranteeing an extra multiphoton oxygen activation manner. The chlorine radical abstracts a hydrogen atom from alkanes, generating the carbon radical for further oxidation transformation. Accordingly, the total oxidation conversion of alkane utilizing three photoexcitation processes combines the energies of more than two photons. This new platform synergistically combines a consecutive excited photoredox organic dye and a HAT catalyst to combine the energies of more than two photons, providing a promising multiphoton catalysis strategy under energy saving, and high efficiency.

RESUMEN

Although highly appealing for rapid access of molecular complexity, multi-functionalization of alkenes that allows incorporation of more than two functional groups remains a prominent challenge. Herein, we report a novel strategy that merges dipolar cycloaddition with photoredox promoted radical ring-opening remote C(sp3)-H functionalization, thus enabling a smooth 1,2,5-trifunctionalization of unactivated alkenes. A highly regioselective [3+2] cycloaddition anchors a reaction trigger onto alkene substrates. The subsequent halogen atom transfer (XAT) selectively initiates ring-opening process, which is followed by a series of 1,5-hydrogen atom transfer (1,5-HAT) and intermolecular fluorine atom transfer (FAT) events. With this method, site-selective introduction of three different functional groups is accomplished and a broad spectrum of valuable ß-hydroxyl-ε-fluoro-nitrile products are synthesized from readily available terminal alkenes.

RESUMEN

A protocol exploiting isocyanides as carbamoylating agents for the α-C(sp3)-H functionalization of cyclic ethers has been optimized via a combined visible light-driven hydrogen atom transfer/Lewis acid-catalyzed approach. The isocyanide substrate scope revealed an exquisite functional group compatibility (18 examples, with yields up to 99 %). Both radical and polar trapping, kinetic isotopic effect and real-time NMR studies support the mechanistic hypothesis and provide insightful details for the design of new chemical processes involving the generation of oxocarbenium ions.

RESUMEN

Halogenation of aliphatic C-H bonds is a chemical transformation performed in nature by mononuclear nonheme iron dependent halogenases. The mechanism involves the formation of an iron(IV)-oxo-chloride species that abstracts the hydrogen atom from the reactive C-H bond to form a carbon-centered radical that selectively reacts with the bound chloride ligand, a process commonly referred to as halide rebound. The factors that determine the halide rebound, as opposed to the reaction with the incipient hydroxide ligand, are not clearly understood and examples of well-defined iron(IV)-oxo-halide compounds competent in C-H halogenation are scarce. In this work we have studied the reactivity of three well-defined iron(IV)-oxo complexes containing variants of the tetradentate 1-(2-pyridylmethyl)-1,4,7-triazacyclononane ligand (Pytacn). Interestingly, these compounds exhibit a change in their chemoselectivity towards the functionalization of C-H bonds under certain conditions: their reaction towards C-H bonds in the presence of a halide anionleads to exclusive oxygenation, while the addition of a superacid results in halogenation. Almost quantitative halogenation of ethylbenzene is observed when using the two systems with more sterically congested ligands and even the chlorination of strong C-H bonds such as those of cyclohexane is performed when a methyl group is present in the sixth position of the pyridine ring of the ligand. Mechanistic studies suggest that both reactions, oxygenation and halogenation, proceed through a common rate determining hydrogen atom transfer step and the presence of the acid dictates the fate of the resulting alkyl radical towards preferential halogenation over oxygenation.

Asunto(s)

RESUMEN

The development of small organic molecules that can convert light energy into chemical energy to directly promote molecular transformation is of fundamental importance in chemical science. Herein, we report a zwitterionic acridinium amidate as a catalyst for the direct functionalization of aliphatic C-H bonds. This organic zwitterion absorbs visible light to generate the corresponding amidyl radical in the form of excited-state triplet diradical with prominent reactivity for hydrogen atom transfer to facilitate C-H alkylation with a high turnover number. The experimental and theoretical investigations revealed that the noncovalent interactions between the anionic amidate nitrogen and a pertinent hydrogen-bond donor, such as hexafluoroisopropanol, are crucial for ensuring the efficient generation of catalytically active species, thereby fully eliciting the distinct reactivity of the acridinium amidate as a photoinduced direct hydrogen atom transfer catalyst.

RESUMEN

The radical Truce-Smiles rearrangement is a straightforward strategy for incorporating aryl groups into organic molecules for which asymmetric processes remains rare. By employing a readily available and non-expensive chiral auxiliary, we developed a highly efficient asymmetric photocatalytic acyl and alkyl radical Truce-Smiles rearrangement of α-substituted acrylamides using tetrabutylammonium decatungstate (TBADT) as a hydrogen atom-transfer photocatalyst, along with aldehydes or C-H containing precursors. The rearranged products exhibited excellent diastereoselectivities (7 : 1 to >98 : 2 d.r.) and chiral auxiliary was easily removed. Mechanistic studies allowed understanding the transformation in which density functional theory (DFT) calculations provided insights into the stereochemistry-determining step.

RESUMEN

Here, we report CdS quantum dot (QD) gels, a three-dimensional network of interconnected CdS QDs, as a new type of direct hydrogen atom transfer (d-HAT) photocatalyst for C-H activation. We discovered that the photoexcited CdS QD gel could generate various neutral radicals, including α-amido, heterocyclic, acyl, and benzylic radicals, from their corresponding stable molecular substrates, including amides, thio/ethers, aldehydes, and benzylic compounds. Its C-H activation ability imparts a broad substrate and reaction scope. The mechanistic study reveals that this reactivity is intrinsic to CdS materials, and the neutral radical generation did not proceed via the conventional sequential electron transfer and proton transfer pathway. Instead, the C-H bonds are activated by the photoexcited CdS QD gel via a d-HAT mechanism. This d-HAT mechanism is supported by the linear correlation between the logarithm of the C-H bond activation rate constant and the C-H bond dissociation energy (BDE) with a Brønsted slope α=0.5. Our findings expand the currently limited direct hydrogen atom transfer photocatalysis toolbox and provide new possibilities for photocatalytic C-H activation.

RESUMEN

Herein, we disclose a new strategy that rapidly and reliably incorporates bromine atoms at distal, secondary C(sp3)-H sites in aliphatic amines with an excellent and predictable site-selectivity pattern. The resulting halogenated building blocks serve as versatile linchpins to enable a series of carbon-carbon and carbon-heteroatom bond-formations at remote C(sp3) sites, thus offering a new modular and unified platform that expediates the access to advanced sp3 architectures possessing valuable nitrogen-containing saturated heterocycles of interest in medicinal chemistry settings.

RESUMEN

The Cu-O-Cu core exhibits methane-to-methanol conversion, mirroring the reactivity of the copper-containing enzyme pMMO. Herein, we computationally examined the reactivity of a biomimetic Cu-O-Cu core towards methane-to-methanol conversion. The oxygen atom of the Cu-O-Cu core abstracts hydrogen present in the C-H bond of methane. The spin density at the bridging oxygen helps to abstract hydrogen from the C-H bond. We modulated the spin density of the bridging oxygen by substituting only a single copper atom of the Cu-O-Cu core by metals (M) such as Fe, Co, and Ag. These substitutions result in bimetallic [Cu-O-M]2+ models. We observed that the energy barriers for the C-H activation step and the subsequent rebound step vary with the metal M. [Cu-O-Ag]2+ exhibits the highest reactivity for M2M conversion, while [Cu-O-Fe]2+ displays the lowest reactivity. To understand the different reactivity of these models towards M2M conversion, we employed distortion-interaction analysis, orbital analysis, spin density analysis, and quantum theory of atoms in molecules analysis. Orbital analysis reveals that all four adducts follow a hydrogen atom transfer mechanism for C-H activation. Further, spin density analysis reveals that a higher spin density on the bridging oxygen leads to a lower C-H activation barrier.

RESUMEN

Saturated heterocycles are important class of structural scaffolds in small-molecule drugs, natural products, and synthetic intermediates. Here, we disclosed a metal free, mild, and scalable functionalization of saturated heterocycles using vinylarenes as a linchpin approach. Key to success of this transformation is the employing of simple and cheap benzophenone as a hydrogen atom transfer (HAT) catalyst. This operationally robust process was used for the making of diverse functionalized saturated heterocycles. Furthermore, aldehydes, alkane, and alcohol have been functionalized under the optimized conditions. The potential pharmaceutical utility of the procedure has also been demonstrated by late-stage functionalization of bioactive natural compounds and pharmaceutical molecules. Initial mechanism studies and control experiments were performed to elucidate the mechanism of the reactions.

RESUMEN

The reaction regioselectivity of gem-difluoroalkenes is dependent on the intrinsic polarity. Thus, the reversal of the regioselectivity of the addition reaction of gem-difluoroalkenes remains a formidable challenge. Herein, we described an unprecedented reversal of regioselectivity of hydrogen atom transfer (HAT) to gem-difluoroalkenes triggered by Fe-H species for the formation of difluoroalkyl radicals. Hydrogenation of the in situ generated radicals gave difluoromethylated products. Mechanism experiments and theoretical studies revealed that the kinetic effect of the irreversible HAT process resulted in the reversal of the regioselectivity of this scenario, leading to the formation of a less stable α-difluoroalkyl radical regioisomer. On basis of this new reaction of gem-difluoroalkene, the iron-promoted hydrohalogenation of gem-difluoroalkenes for the efficient synthesis of aliphatic chlorodifluoromethyl-, bromodifluoromethyl- and iododifluoromethyl-containing compounds was developed. Particularly, this novel hydrohalogenation of gem-difluoroalkenes provided an effect and large-scale access to various iododifluoromethylated compounds of high value for synthetic application.