Applications In Organic Synthesis Research Articles

A Decennial Update on the Applications of Trifluroacetic Acid

Abstract: Since its discovery at the beginning of the 20th century, trifluoroacetic acid, commonly known as TFA, has seen extensive application in organic synthesis both as a solvent and as a catalyst/ reagent. TFA can be used to facilitate a wide variety of chemical transformations, including rearrangements, functional group deprotections, condensations, hydroarylations and trifluoroalkylations, among others. The decennial mini-review examines key TFA synthetic applications from the middle of 2013 to the present, providing the organic chemistry research community with an opportunity to delve deeply into the numerous and varied applications of this strong acid, water-miscible, and low boiling point reagent.

Nanomaterials functionalized acidic ionic organosilica as highly active catalyst in the selective synthesis of benzimidazole via dehydrogenative coupling of diamines and alcohols

An acidic tungstate-based zwitterionic organosilica drived simple self-condensation of tungstic acid and zwitterionic organosilane (PMO-IL-WO42−), was remarkably demonstrated to be highly efficient and environmentally friendly catalyst for directly selective synthesis of benzimidazoles from benzyl alcohols under atmpshpheric air pressure and without any additional oxidant. The one-pot synthesis of benzimidazoles from benzyl alcohols and 1,2-phenylenediamine was efficiently achieved via direct dehydrogenative reaction using a low amount of recoverable PMO-IL-WO42− nanocatalyst in water under ambient conditions with a conversion efficiency of more than 90%. Enhancements in yield and selectivity of benzimidazole formation were observed when water was utilized as the solvent. Furthermore, the PMO-IL-WO42− nanocatalyst exhibited exceptional stability, demonstrating the ability to be effortlessly separated and reused for at least eight reaction cycles without any noticeable loss in activity or product selectivity. This method supports an eco-friendly atom economy and provides a sustainable approach to accessing benzimidazoles directly from benzyl alcohols under mild conditions, demonstrating its potential for practical applications in organic synthesis.

A Novel Efficient and Biodegradable Natural Catalyst and Bio Based Solvents for the Green One Pot Three Component Synthesis of Tetrahydrobenzo[B]pyran and 3,4-Dihydropyrano[C]chromenes

This study presents a novel and efficient method for synthesizing Tetrahydrobenzo[b]pyran and 3,4-Dihydropyrano[c]chromene derivatives using honey as a highly efficient homogeneous catalyst. Through a one-pot three-component condensation of aromatic aldehydes with malononitrile and dimedone or 4-hydroxycoumarin, excellent yields were achieved under environmentally friendly conditions. The utilization of honey, a non-toxic and biodegradable catalyst, underscores the method's significance in green chemistry. The abstract highlights the method's advantages, including high yields, short reaction times, simple work-up, and its potential for applications in the green pharmaceutical and chemical industries. Additionally, the intricate role of honey as a catalyst in chemical reactions is explored, shedding light on its mechanism and potential applications in organic synthesis and other chemical processes. This research introduces a promising and environmentally friendly approach for the green synthesis of biologically active heterocyclic compounds using a natural, biodegradable catalyst, contributing significantly to the advancement of green chemistry practices.

Fluoroalkoxylating Reagents in Organic Synthesis: Recent Advances

AbstractThe fluoroalkoxy groups (ORf) are widely used motifs in pharmaceutical and agrochemical fields due to their unique physicochemical properties including higher lipophilicity and increased metabolic stability. Thus, the high value of ORf‐containing derivatives has stimulated the development of fluoroalkoxylation reactions. In this review, we highlight the recent progress of various trifluoroalkoxylating reagents and their applications in organic synthesis in the past five years.

Recent Advances in the Domino Annulation Reaction of Quinone Imines.

Quinone imines are important derivatives of quinones with a wide range of applications in organic synthesis and the pharmaceutical industry. The attack of nucleophilic reagents on quinone imines tends to lead to aromatization of the quinone skeleton, resulting in both the high reactivity and the unique reactivity of quinone imines. The extreme value of quinone imines in the construction of nitrogen- or oxygen-containing heterocycles has attracted widespread attention, and remarkable advances have been reported recently. This review provides an overview of the application of quinone imines in the synthesis of cyclic compounds via the domino annulation reaction.

Organometallic Chirality Sensing via "Click"-Like η6-Arene Coordination with an Achiral Cp*Ru(II) Piano Stool Complex.

Piano stool complexes have been studied over many years and found widespread applications in organic synthesis, catalysis, materials and drug development. We now report the first examples of quantitative chiroptical molecular recognition of chiral compounds through click-like η6-arene coordination with readily available half sandwich complexes. This conceptually new approach to chirality sensing is based on irreversible acetonitrile displacement of [Cp*Ru(CH3CN)3]PF6 by an aromatic target molecule, a process that is fast and complete within a few minutes at room temperature. The metal coordination coincides with characteristic circular dichroism inductions that can be easily correlated to the absolute configuration and enantiomeric ratio of the bound molecule. A relay assay that decouples the determination of the enantiomeric composition and of the total sample amount by a practical CD/UV measurement protocol was developed and successfully tested. The introduction of piano stool complexes to the chiroptical sensing realm is mechanistically unique and extends the scope of currently known methods with small-molecule probes that require the presence of amino, alcohol, carboxylate or other privileged functional groups for binding of the target compound. A broad application range including pharmaceutically relevant multifunctional molecules and the use in chromatography-free asymmetric reaction analysis are also demonstrated.

Organometallic Chirality Sensing via “Click”‐Like η6‐Arene Coordination with an Achiral Cp*Ru(II) Piano Stool Complex

AbstractPiano stool complexes have been studied over many years and found widespread applications in organic synthesis, catalysis, materials and drug development. We now report the first examples of quantitative chiroptical molecular recognition of chiral compounds through click‐like η6‐arene coordination with readily available half sandwich complexes. This conceptually new approach to chirality sensing is based on irreversible acetonitrile displacement of [Cp*Ru(CH3CN)3]PF6 by an aromatic target molecule, a process that is fast and complete within a few minutes at room temperature. The metal coordination coincides with characteristic circular dichroism inductions that can be easily correlated to the absolute configuration and enantiomeric ratio of the bound molecule. A relay assay that decouples the determination of the enantiomeric composition and of the total sample amount by a practical CD/UV measurement protocol was developed and successfully tested. The introduction of piano stool complexes to the chiroptical sensing realm is mechanistically unique and extends the scope of currently known methods with small‐molecule probes that require the presence of amino, alcohol, carboxylate or other privileged functional groups for binding of the target compound. A broad application range including pharmaceutically relevant multifunctional molecules and the use in chromatography‐free asymmetric reaction analysis are also demonstrated.

Electrochemical Oxidative 1,2-Dithiocyanation: Access to Functionalized Alkenes and Alkynes.

Reported herein is the 1,2-dithiocyanation of alkenes and alkynes via an efficient and facile electrochemical method. This approach not only showed a broad substrate scope and good functional-group compatibility but also avoided stoichiometric oxidants. Different from previous reports, various internal alkynes could be tolerated to provide tetra-substituted alkenes. Further gram-scale-up experiments and synthetic transformation demonstrated a potential application in organic synthesis. This process underwent a radical pathway, as evidenced by our mechanistic studies.

Synthesis of Pyrano[2,3-d]Pyrimidine Diones Catalyzed by Cobalt-Doped Iron Tartrate Nanomaterial: A Sustainable and Efficient Approach

This study presents a novel and environmentally sustainable approach for the one-pot multicomponent green synthesis of pyrano[2,3-d]pyrimidine dione derivatives. The devised procedure involves a three-component condensation of aldehydes, malononitrile, and barbituric acid, employing a nanomaterial catalyst in the form of cobalt-doped iron tartrate. This catalyst, characterized by its nanoscale dimensions, demonstrates exceptional reusability and water solubility, contributing to its eco-friendly profile. The synthesis is conducted under reflux conditions, optimizing the reaction efficiency. Key attributes of the proposed protocol include the use of a non-toxic, cost-effective, and readily available catalyst. The high atom economy of the reaction signifies minimal waste generation, enhancing the sustainability of the synthetic process. Additionally, the reaction features a short duration, aligning with the principles of efficiency and resource conservation. Notably, the utilization of water as the solvent further enhances the green approach, minimizing the environmental impact. This innovative synthesis protocol not only addresses the growing demand for environmentally conscious methodologies but also showcases the potential for scalable and practical applications in organic synthesis. The integration of a reusable nanomaterial catalyst, coupled with the adoption of water as a solvent, positions this approach as a promising advancement in the pursuit of sustainable and green chemical practices. The study provides valuable insights into the development of efficient and environmentally benign synthetic routes for the production of pyrano[2,3-d]pyrimidine dione derivatives, paving the way for the exploration of greener alternatives in the realm of organic chemistry.

A Review on the Development of Polymer Supported Heterogeneous Palladium Materials for Organic Synthesis and Electrochemical Applications

Abstract:: This comprehensive review explores the advancements in catalytic transformation, focusing on the use of heterogeneous catalytic systems with a particular emphasis on polymeric-supported palladium (Pd) complexes. This study explores the limitations associated with conventional homogeneous reagents, emphasizes the transition to eco-friendly catalytic systems, and emphasizes the importance of Pd nanoparticles. These nanoparticles are particularly noteworthy for their distinctive properties, including elevated catalytic activity, making them promising for various applications in organic synthesis. The review thoroughly examines the design and synthesis of heterogeneous catalysts, emphasizing the crucial selection of safe and recyclable supports to augment the longevity and reusability of metallic catalysts. Diverse polymer varieties, including polystyrene (PS), polyethylene (PE), polyacrylate derivatives, polyethylene glycol (PEG), and grafted polymers, are investigated as viable supports for Pd complexes. The authors intricately describe the synthesis techniques for these polymer-supported Pd catalysts and furnish illustrative examples showcasing their effectiveness in organic transformation. This comprehensive review additionally highlights the synthesis of polymer-supported palladium (Pd) materials and discusses their applications in electrochemistry. The focus extends to the electrocatalytic properties of Pdbased polymeric nanomaterials, showcasing their effectiveness in glucose sensing, hydrogen peroxide detection, and the sensing of other biological analytes. Furthermore, the catalytic capabilities of Pd nanoparticles in various electrochemical applications, including wastewater treatment and electrochemical capacitors, are explored. Integrating polymer-supported Pd materials into these electrochemical processes underscores their versatility and potential contributions to advancements in catalysis and electrochemical sensing. Catalytic applications featuring polymer-supported palladium complexes with polymeric ligands in organic synthesis processes use the Sonogashira reaction, Suzuki-Miyaura coupling, Heck reaction, Catalytic asymmetric transformations, etc. The subsequent section of the paper focuses on the creation of polymeric palladium complexes, achieved by the complexation of polymeric ligands with palladium precursors. It delves into noteworthy examples of catalytic processes employing polymer-supported palladium complexes featuring polymeric ligands, emphasizing distinct polymers, such as PS, PE, polyacrylate derivatives, PEG, and grafting polymers. The review concludes by exploring catalytic asymmetric transformations using chiral palladium complexes immobilized on polymer supports and discusses various chiral ligands and their immobilization on polymer supports, emphasizing their application in asymmetric allylic alkylation. The review furnishes a comprehensive summary of recent advancements, challenges, and prospective avenues in catalytic oxidation facilitated by polymer- supported palladium catalysts with electrochemical applications.

Electrochemical E-Selective Semireductive Dicarboxylation of Aryl Alkynes with CO2.

Herein, we report an electrochemical protocol for the dicarboxylation of aryl alkynes using CO2. With a graphite rod as the cathode and Al as the sacrificial anode, a series of valuable butenedioic acids are obtained in moderate to excellent yields with an E/Z ratio up to 50:1. This method features high E-selectivity, high step and atom economy, easy scalability, and a nice substrate scope, which renders it appealing for promising applications in organic synthesis and materials chemistry.

Competing Mechanisms in Palladium-Catalyzed Alkoxycarbonylation of Styrene.

Palladium-catalyzed carbonylation is a versatile method for the synthesis of various aldehydes, esters, lactones, or lactams. Alkoxycarbonylation of alkenes with carbon monoxide and alcohol produces either saturated or unsaturated esters as a result of two distinct catalytic cycles. The existing literature presents an inconsistent account of the procedures favoring oxidative carbonylation products. In this study, we have monitored the intermediates featured in both catalytic cycles of the methoxycarbonylation of styrene PhCH=CH2 as a model substrate, including all short-lived intermediates, using mass spectrometry. Comparing the reaction kinetics of the intermediates in both cycles in the same reaction mixture shows that the reaction proceeding via alkoxy intermediate [PdII]-OR, which gives rise to the unsaturated product PhCH=CHCO2Me, is faster. However, with an advancing reaction time, the gradually changing reaction conditions begin to favor the catalytic cycle dominated by palladium hydride [PdII]-H and alkyl intermediates, affording the saturated products PhCH2CH2CO2Me and PhCH(CO2Me)CH3 preferentially. The role of the oxidant proved to be crucial: using p-benzoquinone results in a gradual decrease of the pH during the reaction, swaying the system from oxidative conditions toward the palladium hydride cycle. By contrast, copper(II) acetate as an oxidant guards the pH within the 5-7 range and facilitates the formation of the alkoxy palladium complex [PdII]-OR, which favors the oxidative reaction producing PhCH=CHCO2Me with high selectivity. Hence, it is the oxidant, rather than the catalyst, that controls the reaction outcome by a mechanistic switch. Unraveling these principles broadens the scope for developing alkoxycarbonylation reactions and their application in organic synthesis.

Transition‐Metal Catalyzed C−H Alkylation Using Epoxides as Alkylating Reagents

AbstractThe alkylation of arenes is one of the most fundamental transformations in synthetic chemistry and the transition‐metal‐catalyzed direct C−H alkylation represents a straightforward and attractive approach from both atom and step‐economy perspectives. Epoxides, the smallest three‐membered saturated O‐heterocycles that can be easily prepared in racemic or enantioenriched forms, are highly useful building blocks for the synthesis of complex organic molecules. Owing to their inherent high ring‐strain, epoxides readily undergo ring‐opening reactions and have been used as alkylating reagents for C−H alkylation catalyzed by transition metals. This review summarizes recent advances in utilizing epoxides as alkylating reagents in transition‐metal‐catalyzed C−H alkylation as well as their synthetic applications in organic synthesis.

Characterization of elusive rhamnosyl dioxanium ions and their application in complex oligosaccharide synthesis

Attaining complete anomeric control is still one of the biggest challenges in carbohydrate chemistry. Glycosyl cations such as oxocarbenium and dioxanium ions are key intermediates of glycosylation reactions. Characterizing these highly-reactive intermediates and understanding their glycosylation mechanisms are essential to the stereoselective synthesis of complex carbohydrates. Although C-2 acyl neighbouring-group participation has been well-studied, the reactive intermediates in more remote participation remain elusive and are challenging to study. Herein, we report a workflow that is utilized to characterize rhamnosyl 1,3-bridged dioxanium ions derived from C-3 p-anisoyl esterified donors. First, we use a combination of quantum-chemical calculations and infrared ion spectroscopy to determine the structure of the cationic glycosylation intermediate in the gas-phase. In addition, we establish the structure and exchange kinetics of highly-reactive, low-abundance species in the solution-phase using chemical exchange saturation transfer, exchange spectroscopy, correlation spectroscopy, heteronuclear single-quantum correlation, and heteronuclear multiple-bond correlation nuclear magnetic resonance spectroscopy. Finally, we apply C-3 acyl neighbouring-group participation to the synthesis of complex bacterial oligosaccharides. This combined approach of finding answers to fundamental physical-chemical questions and their application in organic synthesis provides a robust basis for elucidating highly-reactive intermediates in glycosylation reactions.

Electrocatalytic dehalogenation in the applications of organic synthesis and environmental degradation

AbstractElectrocatalytic dehalogenation technology is a promising approach for the synthesis of chemicals (such as pesticides and pharmaceutical intermediates) and the disposal of halogenated organic pollutants. Compared with the traditional chemical reduction technology, the electrocatalytic reduction dehalogenation method has the advantages of high efficiency, controllable operation, and reduced secondary pollution. This review systematically consolidates the recent advances in the electrocatalytic dehalogenation in the application of organic synthesis and environmental degradation, focusing on the involved mechanisms, and influences factors (e.g., electrocatalysts, solution environment, and reaction conditions) on the performance of electrocatalytic dehalogenation. Furthermore, the latest characterization and analytical methods and the industrial application of electrocatalytic dehalogenation technology are summarized. Lastly, the existing challenges and perspectives are proposed for efficient electrocatalytic dehalogenation.

Synergistic Photoredox and Electrochemical Catalysis in Organic Synthesis and Late‐Stage Functionalizations

AbstractThis review delves into the innovative field of interfacial photoelectrochemical (iPEC) and photoelectrochemical (PEC) catalysis, the dynamic synthesis methodologies that seamlessly integrates electrochemical and photoredox catalysis for efficient and environmentally friendly reactions. Utilizing minute quantities of photocatalysts, visible light becomes a powerful tool, generating transient excited states to catalyze a spectrum of reactions through single‐electron oxidation or reduction events. The review categorizes recent advancements, highlighting applications in organic synthesis, late‐stage modifications, and the distinctive features of photoelectrochemical methodology. Despite being in its early stages, this synergistic approach holds great promise for propelling organic synthesis forward, with potential applications in large‐scale synthesis and diverse late‐stage functionalizations, including asymmetric catalysis and bioconjugation strategies for biomolecule modifications.

Harnessing the Power of C–H Functionalization Chemistry to Accelerate Drug Discovery

AbstractThe field of C–H functionalization chemistry has experienced rapid growth in the past twenty years, with increasingly powerful applications in organic synthesis. Recognizing the potential of this emerging field to impact drug discovery, a dedicated effort was established in our laboratories more than ten years ago, with the goal of facilitating the application of C–H functionalization chemistries to active medicinal-chemistry programs. Our approach centered around the strategy of late-stage functionalization (LSF) wherein C–H functionalization chemistry is employed in a systematic and targeted manner to generate high-value analogues from advanced drug leads. To successfully realize this approach, we developed broadly useful LSF chemistry platforms and workflows that increased the success rates of the C–H functionalization chemistries and accelerated access to new derivatives. The LSF strategy, when properly applied, enabled a rapid synthesis of molecules designed to address specific medicinal-chemistry issues. Several case studies are presented, along with descriptions of the group’s platforms and workflows.1 Introduction2 Building an LSF Chemistry Toolbox2.1 C–H Borylation2.2 Minisci Platforms2.3 Automated Direct-Metalation Platform3 Building an LSF Workflow4 LSF Application Case Studies4.1 BTK Inhibitor Program4.2 GPR40 Agonist Program5 Conclusions

Recent Advances in the Preparation of Air Stable Organozinc Pivalates and their Applications in Organic Synthesis

AbstractThis review discusses various methods for the preparation of air and water‐stable organozinc pivalates containing aryl, heteroaryl, alkyl, alkenyl, benzyl and alkynyl scaffolds achieved via i) selective metalation (DoM) in the presence of a directing group (DG) in the aromatic core, ii) direct oxidative Zn metal insertion/or X/M exchange reaction followed by transmetalation with Zn(Opiv)2, which are then further functionalized by Negishi cross‐coupling reactions, or trapping with different aryl, heteroaryl, alkenyl, alkynyl electrophiles used by transition metal catalysts (Pd, Co, Ni, Cu). Selective deprotonation of aryl or heteroaryl derivatives can be performed using LDA, TMP−Mg and TMP−Zn reagents in the presence of a directing group on the aromatic system. Different organozinc reagents based on aromatic and non‐aromatic structures with electron‐rich and electron‐deficient substituents undergo transition metal‐catalyzed C(sp2)−C(sp2), C(sp2)−C(sp) and C(sp2)−C(sp3) types of cross‐coupling reactions with aryl and heteroaryl halides and diaryl disulfides under mild conditions with the sustainable catalytic process. The literature report shows that the polyfunctionalized nitrogen, oxygen and sulfur‐based bioactive pharmaceutical scaffolds, natural products and target organic molecules are accessible using highly air and moisture‐stable organozinc pivalates under sustainable coupling reaction conditions. Importantly, the sensitive functional groups are tolerable, and the commercially available substrates and inexpensive low toxic reagents can be employed with organozinc pivalates. In this context, this review article provides a detailed summary of the numerous synthetic strategies and practical methods for the preparation of aryl, alkenyl, benzyl and alkynyl organozinc reagents that can be isolated in the pure solid form. Additionally, some recently published examples demonstrating their catalytic application in organic synthesis are discussed.

A Journey of the Development of Privileged Difluorocarbene Reagents TMSCF2X (X = Br, F, Cl) for Organic Synthesis.

ConspectusAs fluorine has played an increasingly important role in modulating the physical, chemical, and biological properties of organic molecules, the selective introduction of fluorine atom(s) or fluorinated moieties into target molecules has become a powerful tool in the development of new pharmaceuticals, agrochemicals, and functional materials. In this context, the difluoromethylene (CF2) and difluoromethyl (CF2H) groups are of special interest because of their ability to serve as bioisosteres of ethereal oxygen atoms and hydroxyl (OH) and thiol (SH) groups, respectively. Difluorocarbene is one of the most versatile reactive intermediates to incorporate CF2 and CF2H groups; however, before 2006, most of the previously known difluorocarbene reagents suffered from several drawbacks such as using ozone-depleting substances (ODSs), difficult-to-handle reagents, or harsh reaction conditions or having narrow substrate scope and/or low yields. Moreover, the reactivity of difluorocarbene generated from different precursors (reagents) was often unpredictable, since the difluorocarbene generation conditions (activation modes) of various difluorocarbene precursors are different, and these conditions may mismatch those required for subsequent difluorocarbene-involved transformations. Therefore, the development of new environmentally friendly and versatile difluorocarbene reagents, as well as the investigation of the mechanistic insights into difluorocarbene-involved reactions, has been highly desirable.In this Account, we summarize our contributions to the development of new difluorocarbene reagents and their applications in organic synthesis since 2006. We have developed seven new difluorocarbene reagents, including 2-chloro-2,2-difluoroacetophenone (1), chlorodifluoromethyl phenyl sulfone (2), S-difluoromethyl-S-phenyl-N-tosylsulfoximine (3), difluoromethyltri(n-butyl)ammonium chloride (4), (chlorodifluoromethyl)trimethylsilane (TMSCF2Cl, 5), (bromodifluoromethyl)trimethylsilane (TMSCF2Br, 6), and (trifluoromethyl)trimethylsilane (TMSCF3, 7). In this journey, we realized the key factor for an ideal difluorocarbene reagent that can be used for a broad range of reactions, that is, the reagent should allow various activation modes for the generation of difluorocarbene species, such as under basic/acidic/neutral conditions, at wide range of temperatures, and in different solvents, which are compatible with a wide range of difluorocarbene-involved transformations. Among all known difluorocarbene reagents, silanes TMSCF2X (X = Br, F, Cl) have stood out as privileged ones, which paves a new avenue for further developing difluorocarbene chemistry. In particular, TMSCF2Br was recognized as an "all-rounder": TMSCF2Br can be applied in almost all common difluorocarbene-involved reactions, and more importantly, TMSCF2Br also enables many other novel transformations that other difluorocarbene reagents cannot achieve, thanks to its unique structure and rich activation modes of releasing difluorocarbene under different reaction conditions. It can be expected that with the commercial availability of TMSCF2X reagents (X = Br, F, Cl) now, the development of difluorocarbene chemistry will be accelerated in the years to come.

Enantioselective sulfur(VI) fluoride exchange reaction of iminosulfur oxydifluorides.

Linkage chemistry and functional molecules derived from the stereogenic sulfur(VI) centre have important applications in organic synthesis, bioconjugation, drug discovery, agrochemicals and polymeric materials. However, existing approaches for the preparation of optically active S(VI)-centred compounds heavily rely on synthetic chiral S(IV) pools, and the reported linkers of S(VI) lack stereocontrol. A modular assembly method, involving sequential ligand exchange at the S(VI) centre with precise control of enantioselectivity, is appealing but remains elusive. Here we report an asymmetric three-dimensional sulfur(VI) fluoride exchange (3D-SuFEx) reaction based on thionyl tetrafluoride gas (SOF4). A key step involves the chiral ligand-induced enantioselective defluorinative substitution of iminosulfur oxydifluorides using organolithium reagents. The resulting optically active sulfonimidoyl fluorides allow for further stereospecific fluoride-exchange by various nucleophiles, thereby establishing a modular platform for the asymmetric SuFEx ligation and the divergent synthesis of optically active S(VI) functional molecules.