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A catalytic metal-free approach for the H/D exchange in aromatic compounds using D2O as the terminal deuterating reagent has been developed. This metal-free protocol employs a triaryl carbenium as the mediator and showcases a wide applicability in the late-stage deuteration of various natural products and small-molecule drugs. Gram-scale deuteration was successfully demonstrated with ß-Estradiol, highlighting the method's practicability. Detailed mechanistic insights, supported by DFT calculations, unveiled the essential role of in-situ generated acidic species in this electrophilic aromatic substitution process. This newly developed method offers a sustainable and versatile alternative to traditional metal-catalyzed H/D exchange techniques, addressing challenges such as the use of expensive metals, impurity formation, and the necessity for residual metal removal from the final products.
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In this study, a novel approach for the tertiary α-alkylation of ketones using alkanes with electron-deficient CâH bonds is presented, employing a synergistic catalytic system combining inexpensive copper salts with aminocatalysis. This methodology addresses the limitations of traditional alkylation methods, such as the need for strong metallic bases, regioselectivity issues, and the risk of over alkylation, by providing a high reactivity and chemoselectivity without the necessity for pre-functionalized substrates. The dual catalytic strategy enables the direct functionalization of C(sp3)âH bonds, demonstrating remarkable selectivity in the presence of conventional C(sp3)âH bonds that are adjacent to heteroatoms or π systems, which are typically susceptible to single-electron transfer processes. The findings contribute to the advancement of alkylation techniques, offering a practical and efficient route for the construction of C(sp3)âC(sp3) bonds, and paving the way for further developments in the synthesis of complex organic molecules.
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The selective oxidation of benzylic C-H bonds is a pivotal transformation in organic synthesis. Undoubtedly, achieving efficient and highly selective aerobic oxidation of methylarenes to benzaldehydes has been highly challenging due to the propensity of benzaldehyde to undergo overoxidation under typical aerobic conditions. Herein, we propose an innovative approach to address this issue by leveraging electrocatalytic processes, facilitated by ion-pair mediators [Ph3C]+[B(C6F5)4]-. By harnessing the power of electrochemistry, we successfully demonstrated the effectiveness of our strategy, which enables the selective oxidation of benzylic C-H bonds in benzylic molecules and toluene derivatives. Notably, our approach exhibited high efficiency, excellent selectivity, and compatibility with various functional groups, underscoring the broad applicability of our methodology.
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A new bioconjugation reagent containing silicon has been developed for the selective reaction with thiols. The inclusion of silicon significantly improves chemoselectivity and suppresses retro processes, thereby exceeding the capabilities of traditional reagents. The method is versatile and compatible with a broad range of thiols and unsaturated carbonyl compounds and yields moderate to high results. These reactions can be conducted under biocompatible conditions, thereby making them suitable for protein bioconjugation. The resulting conjugates display good stability in the presence of various biomolecules, which suggests their potential application for the synthesis of antibody-drug conjugates. Furthermore, the presence of a silicon moiety within the conjugated products opens up new avenues for drug release and bridging inorganics with other disciplines. This new class of silicon-containing thiol-specific bioconjugation reagents has significant implications for researchers working in bioanalytical science and medicinal chemistry and leads to innovative opportunities for advancing the field of bioconjugation research and medicinal chemistry.
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Inmunoconjugados , Silicio , Compuestos de Sulfhidrilo/química , Indicadores y Reactivos , Proteínas/químicaRESUMEN
Inspired by the high affinity of copper with DNA and RNA, a uracil-copper catalytic system was developed to promote ring-opening allylation of cyclopropanols with allylic alcohols under water-tolerant conditions. A new C-OH bond-breaking model can well resolve the trade-off between the need for acidic activators for C(allyl)-OH bond cleavage and the demand for strong basic conditions for generating homoenolates. Therefore, Morita-Baylis-Hillman alcohols, rather than their pre-activated versions, could be incorporated directly into dehydrative cross-coupling with cyclopropanols delivering water as the only by-product. A variety of functionalized δ,ε-unsaturated ketones were obtained in good-to-high yield with high E-selectivity.
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ConspectusThe pursuit of novel and eco-friendly methods in organic synthesis is gaining prominence, with a strong emphasis on green transformations using renewable and sustainable resources. Among these environmentally conscious approaches, water-compatible reactions stand out for their many advantages. Water, as a solvent, offers unmatched abundance, cost-efficiency, and environmental compatibility compared to organic solvents. Its use eliminates the need for complex protection and deprotection steps for reactive functional groups in multistep synthesis and enables the use of water-soluble substrates like proteins and carbohydrates. Water-compatible reactions also provide opportunities to combine with enzymes, resulting in chemoenzymatic transformations that can increase efficiency. Additionally, these reactions facilitate site-specific modification and the bioconjugation of biomolecules, leading to bioconjugate therapeutics.Over nearly three decades, our research group has been dedicated to developing innovative water-compatible methodologies and concepts. This Account provides a comprehensive overview of our contributions since 1994. Our central strategy revolves around integrating green chemistry principles into our methods, focusing on (i) developing reactions that can operate under mild conditions, including room temperature, atmospheric pressure, and physiological pH; (ii) designing atom-economical reactions that minimize waste production; (iii) replacing toxic and flammable organic solvents with eco-friendly alternatives like water and ethanol; and (iv) reducing reliance on metals or halogenated compounds in specific reactions.In this Account, we detail our achievements in developing efficient methodologies in aqueous media, highlighting their scope, limitations, asymmetric control, and applications for synthesizing complex molecules and functionalizing peptides and proteins. Mechanistic investigations underlying these developments are also discussed when applicable. Furthermore, we offer insights into the reasoning behind our work and address future opportunities and challenges in this area of research. We hope that this Account will inspire continued interest and foster new breakthroughs. By exploring innovative and broadly applicable strategies that expand the water-compatible synthetic toolbox, we aim to pave the way for the truly green and sustainable synthesis of complex molecules and pharmaceuticals.
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Developing efficient and straightforward strategies to rapidly construct structurally distinct and diverse organic molecules is one of the most fundamental tasks in organic synthesis, drug discovery and materials science. In recent years, divergent synthesis of organic functional molecules from the same starting materials has attracted significant attention and has been recognized as an efficient and powerful strategy. To achieve this objective, the proper adjustment of reaction conditions, such as catalysts, solvents, ligands, etc., is required. In this review, we summarized the recent efforts in chemo-, regio- and stereodivergent reactions involving acyclic and cyclic systems catalyzed by palladium complexes. Meanwhile, the reaction types, including carbonylative reactions, coupling reactions and cycloaddition reactions, as well as the probable mechanism have also been highlighted in detail.
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Oxidative amination for the installation of nitrogen functional molecules from nitrogen nucleophiles has always been a very challenging topic in organic synthesis. Here we report a novel conversion of different aldehydes with secondary amines for the synthesis of diversified α-amino ketones. This method can be achieved through oxidative rearrangement of an in situ-generated enamine intermediate promoted by commercially available sodium percarbonate. Furthermore, this one-pot process is also suitable for the functional modification of complex molecules.
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A dehydrative cross-coupling of unactivated allylic alcohols with sulfinic acids was achieved under catalyst-free conditions. This reaction proceeded via allyl sulfination and concomitant allyl sulfinate-sulfone rearrangement. Various allylic sulfones could be obtained in good to excellent yields with water as the only byproduct. This study expands the synthetic toolbox for constructing allylic sulfone molecules.
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A novel organophotoredox/DABCO catalytic system for the fluoroalkylation of activated allylic acetates via radical-radical coupling is described. The method offers mild reaction conditions, high selectivity, and broad substrate compatibility and enabled diverse bioactive molecules, FDA-approved drugs, and amino acid derivatives to be incorporated into transformation. This study expands the synthetic toolbox for the construction of fluorine-containing molecules.
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Site-specific modification of thiol-containing biomolecules has been recognized as a versatile and powerful strategy for probing our biological systems and discovering novel therapeutics. The addition of lipophilic silicon moiety opens up new avenues for multi-disciplinary research with broad applications in both the medicinal and material sciences. However, adhering to the strict biocompatibility requirements, and achieving the introduction of labile silicon handle and high chemo-selectivity have been formidable. In this paper, we report silicon-based conjugating reagents including ß-trialkylsilyl and silyl ether-tethered alkynones that selectively react with thiols under physiological conditions. The pH-neutral, metal-free and additive-free reaction yields stable products with broad substrate compatibility and full retention of silicon handles in most cases. Besides simple aliphatic and aromatic thiols, this approach is applicable in the labeling of thiols present in proteins, sugars and payloads, thereby expanding the toolbox of thiol conjugation.
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We have developed an efficient method that employs organophotoredox-catalyzed relay Grob fragmentation to facilitate the smooth ring-opening allylation of cyclic alcohols in an environmentally friendly manner. This protocol directly incorporates a wide spectrum of cyclic alcohols and activated allylic acetates into the cross-coupling reaction, eliminating the need for metal catalysts. The process yields a variety of distally unsaturated ketones with good to excellent outcomes and stereoselectivity, while acetic acid is the sole byproduct.
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Rare earth metals exhibit high catalytic activity and selectivity in various organic reactions due to their unique electronic properties. Among them, praseodymium has shown high catalytic activity under mild reaction conditions compared with transitional metals. Here, we report a strategy of Pr-catalyzed aerobic dehydrogenative aromatization of saturated N-heterocycles to produce 7 classes of products with a broad substrate scope.
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Metales de Tierras Raras , Elementos de Transición , Metales de Tierras Raras/química , CatálisisRESUMEN
Pd-catalyzed double Heck reaction allows regioselective 1,1-diarylation of unactivated aliphatic alkenes. When two different aryl bromides are used, the second aryl rings are added trans to aliphatic chains in the main olefinic isomers, consistent with a mechanism of two consecutive Heck arylations at the terminal carbons.
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Alquenos , Estructura Molecular , Catálisis , Isomerismo , EstereoisomerismoRESUMEN
Amine-targeting reactions that work under biocompatible conditions or in water are green processes that are extremely useful for the synthesis of functional materials and biotherapeutics. Unfortunately, despite the usefulness of this reaction, there are very few good amine-specific click methods reported thus far. Here, we report an amine-specific click reagent using alkynone ß-trifluoroborates as the electrophiles. These boron-containing alkynyl reagents exhibit extremely high chemoselectivity toward amines even in the presence of thiols. The resulting oxaboracycle products are bench-stable, displaying the reactivities of both organoborates and enaminones. Intrinsic advantages of this methodology include benign reaction conditions, operational simplicity, remarkable product stability, and excellent chemoselectivity, which satisfy the criteria of click chemistry and demonstrate the high potential in bioconjugation. Hence, this water-based chemical approach is also applicable to the modification of native amino acids, peptides, and proteins. Ultimately, the essential role of water during the reaction was elucidated.
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Aminas , Proteínas , Aminas/química , Indicadores y Reactivos , Proteínas/química , Péptidos , AguaRESUMEN
Ionic liquid (IL)-based gels (ionogels) have received considerable attention due to their unique advantages in ionic conductivity and their biphasic liquid-solid phase property. In ionogels, the negligibly volatile ionic liquid is retained in the interconnected 3D pore structure. On the basis of these physical features as well as the chemical properties of well-chosen ILs, there is emerging interest in the anti-bacterial and biocompatibility aspects. In this review, the recent achievements of ionogels for biomedical applications are summarized and discussed. Following a brief introduction of the various types of ILs and their key physicochemical and biological properties, the design strategies and fabrication methods of ionogels are presented by means of different confining networks. These sophisticated ionogels with diverse functions, aimed at biomedical applications, are further classified into several active domains, including wearable strain sensors, therapeutic delivery systems, wound healing and biochemical detections. Finally, the challenges and possible strategies for the design of future ionogels by integrating materials science with a biological interface are proposed.
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Líquidos Iónicos , Conductividad Eléctrica , Ciencia de los MaterialesRESUMEN
A Pd/Ca catalytic system to promote the unsymmetrical bis-allylation of malononitrile was developed by selecting conjugated dienes and allylic alcohols as allylic reagents. This catalytic system suppressed the competitive symmetrical bis-allylation process and guaranteed the desired unsymmetrical bis-allylation with high chemoselectivity. A wide range of conjugated dienes and allylic alcohols were tolerated well in this transformation, and diverse 1,6-dienes were obtained with high efficiency.
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A transition-metal-free strategy regarding an iodine-sodium percarbonate catalysis to achieve the ortho-aminomethylation of phenols in aqueous media has been developed. This method can effectively broaden a wide range of phenols, tolerate sensitive functional groups, and achieve the late-stage functionalization of ten functional molecules that contain phenolic structures.
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Yodo , Elementos de Transición , Fenoles/química , CatálisisRESUMEN
Alkenes and their derivatives are featured widely in a variety of natural products, pharmaceuticals, and advanced materials. Significant efforts have been made toward the development of new and practical methods to access this important class of compounds by selectively activating the alkenyl C(sp2)-H bonds in recent years. In this comprehensive review, we describe the state-of-the-art strategies for the direct functionalization of alkenyl sp2 C-H and C-F bonds until June 2022. Moreover, metal-free, photoredox, and electrochemical strategies are also covered. For clarity, this review has been divided into two parts; the first part focuses on currently available alkenyl sp2 C-H functionalization methods using different alkene derivatives as the starting materials, and the second part describes the alkenyl sp2 C-F bond functionalization using easily accessible gem-difluoroalkenes as the starting material. This review includes the scope, limitations, mechanistic studies, stereoselective control (using directing groups as well as metal-migration strategies), and their applications to complex molecule synthesis where appropriate. Overall, this comprehensive review aims to document the considerable advancements, current status, and emerging work by critically summarizing the contributions of researchers working in this fascinating area and is expected to stimulate novel, innovative, and broadly applicable strategies for alkenyl sp2 C-H and C-F bond functionalizations in the coming years.
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Alquenos , Alquenos/químicaRESUMEN
A transition-metal-free catalytic system was designed to address the dehydrative cross-coupling of unactivated primary/secondary alcohols with amines/amides under environmentally benign conditions. Mg2+ and counteranion (PF6-) worked synergistically to realize C-OH bond cleavage and concomitant C-N bond formation. A wide range of allylic alcohols and amines/amides were tolerated well in this transformation, which allowed C-N bond construction with high efficiency.