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Starting from a historical background that acknowledges isonitriles as a neglected class of compounds due to their unpleasant smell and hardly controlled reaction conditions with open shell species, the present concept article aims at highlighting the seeds of the modern isonitrile photochemistry. Representative essential transformations achieved via either UV light irradiation or radical initiators at high temperatures are brought into play to draw a parallel with the current literature relying on the exploitation of visible light photochemical methods. Such a comparison points out the potential of this enabling technology to further expand the scope of isonitrile chemistry and the unmet challenges which makes it a very stimulating field.
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Transition metal-catalyzed radical-based enantioconvergent reactions have become a powerful strategy to synthesize enantiopure compounds from racemic starting materials. However, existing methods primarily address precursors with central chirality, neglecting those with axial chirality. Herein, we describe the enantioconvergent reductive coupling of racemic allenes with aldehydes, facilitated by a photoredox, chromium, and cobalt triple catalysis system. This method selectively affords one product from sixteen possible regio- and stereoisomers. The protocol leverages CoIII-H mediated hydrogen atom transfer (MHAT) and Cr-catalyzed radical-polar crossover for efficient stereoablation of axial chirality and asymmetric addition, respectively. Supported by mechanistic insights from control experiments, deuterium labeling, and DFT calculations, our approach offers synthetic chemists a valuable tool for creating enantioenriched chiral homoallylic alcohols, promising to advance radical-based strategies for synthesizing complex chiral molecules.
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Herein, we describe a new strategy for the carbonylation of alkyl halides with different nucleophiles to generate valuable carbonyl derivatives under visible light irradiation. This method is mild, robust, highly selective, and proceeds under metal-free conditions to prepare a range of structurally diverse esters and amides in good to excellent yields. In addition, we highlight the application of this activation strategy for 13C isotopic incorporation. We propose that the reaction proceeds by a photoinduced reduction to afford radical anions from alkyl halides, which undergo subsequent single electron-oxidation to form a carbocationic intermediate. Carbon monoxide is trapped by the carbocation to generate an acylium cation, which can be attacked by a series of nucleophiles to give a range of carbonyl products.
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The facile generation of the α-acyloxy carboxamide radical is hereby reported for the first time, utilizing a photoredox catalyzed reaction of Passerini adducts synthesized using a 4-formyl-1,4-dihydropyridine as the carbonyl component. This radical effectively engages in a Giese reaction with a range of olefins, ultimately leading to the synthesis of novel Passerini-derived products not previously amenable to direct aldehyde-based transformations. Consequently, the resulting strategy, developed both in batch and in flow, offers a promising opportunity to expand the chemical space accessible through the Passerini reaction, virtually incorporating "impossible" aldehydes.
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Herein, we report a facile and efficient deuteration degree controllable method for the preparation of aryl deuteromethyl ethers through dual photoredox and thiol catalysis using phenols as the starting materials and inexpensive D2O and CDCl3 as the deuterium sources. All aryl d1, d2, and d3 deuteromethyl ethers can be precisely prepared with good to excellent yields and deuteration ratios. The reaction operates under mild conditions without the need for high temperatures or high loading of transition metal catalysts, and a wide range of functional groups are well tolerated.
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Photo-driven cross-coupling of o-arylenediamines and alcohols has emerged as an alternative for the synthesis of bio-active benzimidazoles. However, tackling the key problem related to efficient adsorption and activation of both coupling partners over photocatalysts towards activity enhancement remains a challenge. Here, we demonstrate an efficient interface synergy strategy by coupling exposed oxygen vacancies (VO) and Pd Lewis acid sites for benzimidazole and hydrogen (H2) coproduction over Pd-loaded TiO2 nanospheres with the highest photoredox activity compared to previous works so far. The results show that the introduction of VO optimizes the energy band structure and supplies coordinatively unsaturated sites for adsorbing and activating ethanol molecules, affording acetaldehyde active intermediates. Pd acts as a Lewis acid site, enhancing the adsorption of alkaline amine moleculesvia Lewis acid-base pair interactions and driving the condensation process. Furthermore, VO and Pd synergistically promote interfacial charge transfer and separation. This work offers new insightful guidance for the rational design of semiconductor-based photocatalysts with interface synergy at the molecular level towards the high-performance coproduction of renewable fuels and value-added feedstocks.
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In this work, we developed a visible-light-driven method for the selective synthesis of amides and N-acylureas from carboxylic acids and thioureas. This protocol was featured as avoidance of additional oxidants and transition metal catalysts, simple manipulations, low cost, broad substrate scope, and good functional group tolerance. As only oxygen serves as the oxidation reagent, this method provides a promising synthesis candidate for the formation of N-aryl amides and N-acylureas, including late-stage functionalization of complex pharmaceutical molecules and biologically active molecules.
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Two conflicting mechanisms have emerged for the direct arylation of allylic C-H bonds enabled by the combined use of thiol and photoredox catalysis. In the original report (Nature, 2015, 519, 74-77), a radical coupling step-between a radical anion of an arene and an allylic radical-is proposed to be the key C-C bond-forming step. A recent mechanistic study (J. Org. Chem. 2022, 87, 223-230) has suggested that the C-C bond formation occurs via radical anion capture by the olefin followed by an H atom transfer (HAT) event to deliver the allylic C-H arylation product. Utilizing cyclohexene-4,4,5,5-d 4 as a mechanistic probe to distinguish between otherwise indistinguishable regioisomeric allylic C-H arylation products in the reaction of cyclohexene and dicyanobenzene, we establish that the radical anion capture-HAT mechanism is not operative. Furthermore, experimental k H/k D studies and DFT calculations lend strong support to the radical coupling mechanism proceeding via irreversible HAT to form the allylic radical of cyclohexene, followed by regioselectivity-determining radical coupling (for unsymmetrical olefins) and facile decyanation.
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Porphyrins were identified some years ago as a promising, easily accessible, and tunable class of organic photoredox catalysts, but a systematic study on the effect of the electronic nature and of the position of the substituents on both the ground-state and the excited-state redox potentials of these compounds is still lacking. We prepared a set of known functionalized porphyrin derivatives containing different substituents either in one of the meso positions or at a ß-pyrrole carbon, and we determined their ground- and (singlet) excited-state redox potentials. We found that while the estimated singlet excited-state energies are essentially unaffected by the introduction of substituents, the redox potentials (both in the ground- and in the singlet excited-state) depend on the electron-withdrawing or electron-donating nature of the substituents. Thus, the presence of groups with electron-withdrawing resonance effects results in an enhancement of the reduction facility of the photocatalyst, both in the ground and in the excited state. We next prepared a second set of four previously unknown meso-substituted porphyrins, having a benzoyl group at different positions. The reduction facility of the porphyrin increases with the proximity of the substituent to the porphine core, reaching a maximum when the benzoyl substituent is introduced at a meso position.
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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.
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The absorption of light by photosensitizers has been shown to offer novel reactive pathways through electronic excited state intermediates, complementing ground state mechanisms. Such strategies have been applied in both photocatalysis and photoredox catalysis, driven by generating reactive intermediates from their long-lived excited states. One developing area is photoinduced ligand-to-metal charge transfer (LMCT) catalysis, in which coordination of a ligand to a metal center and subsequent excitation with light results in the formation of a reactive radical and a reduced metal center. This mini review concerns the foundations and recent developments in ligand-to-metal charge transfer in transition metal catalysis focusing on the organic transformations made possible through this mechanism.
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C(sp3)-rich heterocycles are privileged building blocks for pharmaceuticals and agrochemicals. Therefore, synthetic methods that provide access to novel saturated nitrogen-containing heterocycles are in high demand. Herein, we report a general synthesis of 1-azabicyclo[2.1.1]hexanes (1-aza-BCH) via a formal cycloaddition of azabicyclo[1.1.0]butanes (ABB) with styrenes under photochemical conditions. To overcome the challenging direct single electron reduction of ABBs, we designed a polar-radical-polar relay strategy that leverages a fast acid-mediated ring-opening of ABBs to form bromoazetidines, which undergo efficient debrominative radical formation to initiate the cycloaddition reaction. The reaction is applicable to a broad range of ABB-ketones and we demonstrate the 1-aza-BCH products can be further functionalised to access larger saturated, conformationally rigid heterocycles.
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Mediated electron transfer (MET) is fundamental to many biological functions, including cellular respiration, photosynthesis, and enzymatic catalysis. However, leveraging the MET process to enable the release of therapeutic gases has been largely unexplored. Herein, we report the bio-inspired activation of a series of UV-absorbing N-nitrosamide derivatives (NOA) under red light exposure, enabling the quantitative release of nitric oxide (NO) gasotransmitter via an MET process. The cornerstone of our design is the covalent linkage of a 2,4-dinitroaniline moiety, which acts as an electron mediator to the N-nitrosamide groups. This facilitates efficient electron transfer from the excited palladium(II) meso-tetraphenyltetrabenzoporphyrin (PdTPTBP) photocatalyst and the selective activation of NOA. Our approach has been validated with distinct photocatalysts and various N-nitrosamides, including those derived from carbamates, amides, and ureas. Notably, the modulation of the linker length between the electron mediator and N-nitrosamide groups serves as a regulatory mechanism for controlling NO release kinetics. Moreover, this biomimetic NO release platform demonstrates effective operation under both normoxic and hypoxic conditions, and it enables localized delivery of NO under physiological conditions, exhibiting significant anticancer efficacy within the phototherapeutic window and enhanced selectivity towards tumor cells.
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Visible light-driven photocatalytic deracemization is highly esteemed as an ideal tool for organic synthesis due to its exceptional atom economy and synthetic efficiency. Consequently, successful instances of deracemization of allenes have been established, where the activated energy of photosensitizer should surpass that of the substrates, representing an intrinsic requirement. Accordingly, this method is not applicable for axially chiral molecules with significantly high triplet energies. In this study, we present a photoredox catalytic deracemization approach that enables the efficient synthesis of valuable yet challenging-to-access axially chiral 2-azaarene-functionalized quinazolinones. The substrate scope is extensive, allowing for both 3-axis and unmet 1-axis assembly through facile oxidation of diverse central chiral 2,3-dihydroquinazolin-4(1H)-ones that can be easily prepared and achieve enantiomer enrichment via deracemization. Mechanistic studies reveal the importance of photosensitizer selection in attaining excellent chemoselectivity and highlight the indispensability of a chiral Brønsted acid in enabling highly enantioselective protonation to accomplish efficient deracemization.
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Isomerisation reactions provide streamlined routes to organic compounds which are otherwise hard to directly synthesise. The most common forms are positional, geometrical or stereochemical isomerisations which involve the relocation of a double bond or a change in relative location of groups in space. In contrast, far fewer examples of structural (or constitutional) isomerisation exist where the connectivity between atoms is altered. The development of platforms capable of such rearrangement poses a unique set of challenges because chemical bonds must be selectively cleaved, and new ones formed without overall addition or removal of atoms. Here, we show that a dual catalytic system can enable the structural isomerisation of readily available allylic alcohols into more challenging-to-synthesise α-arylated ketones via a H-atom transfer initiated semi-pinacol rearrangement. Key to our strategy is the combination of a cobalt catalyst and photocatalyst under reductive, protic conditions which allows intermediates to propagate catalytic turnover. By providing an unusual disconnection to structural motifs which are difficult to access through direct arylation, we anticipate inspiring other advanced catalytic isomerisation strategies that will further retrosynthetic logic for complex molecule synthesis.
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The selective fluorination of C(sp3)-H bonds is an attractive target, particularly for pharmaceutical and agrochemical applications. Consequently, over recent years much attention has been focused on C(sp3)-H fluorination, and several methods that are selective for benzylic C-H bonds have been reported. These protocols operate via several distinct mechanistic pathways and involve a variety of fluorine sources with distinct reactivity profiles. This review aims to give context to these transformations and strategies, highlighting the different tactics to achieve fluorination of benzylic C-H bonds.
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Radical-involved arylative cross-coupling reactions have recently emerged as an attractive strategy to access valuable aryl-substituted motifs. However, there still exist several challenges such as limited scope of radical precursors/acceptors, and lack of general asymmetric catalytic systems, especially regarding the multicomponent variants. Herein, we reported a general copper-Box system for asymmetric three-component arylative radical cross-coupling of vinylarenes and 1,3-enynes, with oxime carbonates and aryl boronic acids. The reactions proceed under practical conditions in the absence or presence of visible-light irradiation, affording chiral 1,1-diarylalkanes, benzylic alkynes and allenes with good enantioselectivities. Mechanistic studies imply that the copper/Box complexes play a dual role in both radical generation and ensuing asymmetric cross-coupling. In the cases of 1,3-enynes, visible-light irradiation could improve the activity of copper/Box complex toward the initial radical generation, enabling better efficiency match between radical formation and cross-coupling.
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Visible-light active heterogeneous organophotocatalysts have recently gained considerable interest in organic synthetic community. Ordered mesoporous polymers (OMPs) are highly promising as heterogeneous alternative to traditional precious metal/organic dyes-based photocatalysts. Herein, we report the preparation of a benzothiadiazole functionalized OMPs (BT-MPs) through a "bottom-up" strategy. High ordered periodic porosity, large surface area, excellent stability and rational energy-band structures guarantee the high catalytic activity of BT-MPs. As a result, at least six conversions, e. g., the [3+2] cycloaddition of phenols with olefins, the selective oxidation of sulfides, the C-3 thiocyanation of indole and the aminothiocyanation of ß-keto ester, could be promoted smoothly by BT-MPs. In addition, BT-MPs was readily recovered with well maintaining its photocatalytic activity and could be reused for at least eight times. This study highlights the potential of exploiting photoactive OMPs as recyclable, robust and metal-free heterogeneous photocatalysts.
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Particle size is a critical factor for improving photocatalytic reactivity of conjugated microporous polymers (CMPs) as mass transfer in the porous materials is often the rate-limiting step. However, due to the synthetic challenge of controlling the size of CMPs, the impact of particle size is yet to be investigated. To address this problem, a simple and versatile dispersion polymerization route that can synthesize dispersible CMP nanoparticles with controlled size from 15 to 180 nm is proposed. Leveraging the precise control of the size, it is demonstrated that smaller CMP nanoparticles have dramatically higher photocatalytic reactivity in various organic transformations, achieving more than 1000% enhancement in the reaction rates by decreasing the size from 180 to 15 nm. The size-dependent photocatalytic reactivity is further scrutinized using a kinetic model and transient absorption spectroscopy, revealing that only the initial 5 nm-thick surface layer of CMP nanoparticles is involved in the photocatalytic reactions because of internal mass transfer limitations. This finding substantiates the potential of small CMP nanoparticles to efficiently use photo-generated excitons and improve energy-efficiency of numerous photocatalytic reactions.
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Photocatalysis holds a pivotal position in modern organic synthesis, capable of inducing novel reactivities under mild and environmentally friendly reaction conditions. However, the merger of photocatalysis and transition-metal-catalyzed asymmetric C-H activation as an efficient and sustainable method for the construction of chiral molecules remains elusive and challenging. Herein, we develop a cobalt-catalyzed enantioselective C-H activation reaction enabled by visible-light photoredox catalysis, providing a synergistic catalytic strategy for the asymmetric dearomatization of indoles with high levels of enantioselectivity (96 % to >99 % ee). Mechanistic studies indicate that the excited photocatalyst was quenched by divalent cobalt species in the presence of Salox ligand, leading to the formation of catalytically active chiral Co(III) complex. Moreover, stoichiometric reactions of cobaltacycle intermediate with indole suggest that the irradiation of visible light also play a critical role in the dearomatization step.