Carbon-heteroatom Bond-forming Reactions Research Articles

Molecular Editing of Toluene by Sequential meta-C-H/Benzylic C-N Deaminative Functionalizations.

An approach to synthesizing structurally diverse toluene derivatives via sequential meta-C-H and benzylic C-N deaminative functionalization was developed by using a recyclable bifunctional directing template. The functionalized Katritzky salt intermediates are shown to be engaged in a wide range of carbon-carbon and carbon-heteroatom bond formation reactions. The synthetic utility of the strategy was demonstrated by late-stage functionalization of toloxatone.

Isocyanide-based Multicomponent Reactions (IMCRs) in Water or Aqueous Biphasic Systems.

Isocyanide is an intriguing one-carbon synthon that is frequently employed in a variety of carbon-carbon and carbon-heteroatom bond-forming reactions. Isocyanide-based multicomponent reactions (IMCRs) are effective synthetic tools in organic synthesis for the preparation of complex heterocyclic molecules. The IMCRs in water have become an attractive research direction, enabling simultaneous growth of both IMCRs and green solvents towards ideal organic synthesis. The goal of this review is to provide a general overview of IMCRs in water or biphasic aqueous systems for accessing various organic molecules, as well as an examination of their benefits and mechanistic insights. High atom economies, mild reaction conditions, high yields, and catalyst-free processes are crucial features of these IMCRs in water or biphasic aqueous systems.

Advances in Nickel-Catalyzed O-Arylation of Aliphatic Alcohols and Phenols with (Hetero)aryl Electrophiles

AbstractTransition-metal catalysis has been consequential in enabling carbon–heteroatom bond-forming reactions. Recent breakthroughs in Ni-catalyzed cross-couplings have offered competitive and, in some cases, superior reactivity to Pd- or Cu-based processes. Amidst the ongoing renaissance in this field, the Ni-catalyzed C–O cross-coupling of alcohols and (hetero)aryl (pseudo)halides has surfaced as an effective strategy for the synthesis of (hetero)aryl ethers. Methodologies to achieve such transformations tend to rely on one of three catalytic approaches: (i) thermal conditions often accompanied by ancillary ligand design tailored for Ni catalysis; (ii) the synergistic combination of photoredox and Ni catalysis; or (iii) electrochemically driven Ni catalysis. In some instances, these protocols have provided access to expanded C–O cross-coupling substrate scope, including the use of inexpensive and abundant electrophile coupling partners (e.g., (hetero)aryl chlorides). This Short Review aims to summarize recent progress in the development of Ni-catalyzed O-arylations of primary, secondary, and tertiary aliphatic alcohols, as well as phenols, with (hetero)aryl electrophiles.1 Introduction2 Thermally Promoted Ni C–O Cross-Coupling2.1 Primary and Secondary Aliphatic Alcohols2.2 Tertiary Aliphatic Alcohols2.3 Phenols3 Photochemically Promoted Ni C–O Cross-Coupling3.1 Primary and Secondary Aliphatic Alcohols3.2 Phenols4 Electrochemically Promoted Ni C–O Cross-Coupling4.1 Primary and Secondary Aliphatic Alcohols5 Conclusions and Outlook

Mechanochemistry-Amended Barbier Reaction as an Expedient Alternative to Grignard Synthesis.

Organomagnesium halides (Grignard reagents) are essential carbanionic building blocks widely used in carbon-carbon and carbon-heteroatom bond-forming reactions with various electrophiles. In the Barbier variant of the Grignard synthesis, the generation of air- and moisture-sensitive Grignard reagents occurs concurrently with their reaction with an electrophile. Although operationally simpler, the classic Barbier approach suffers from low yields due to multiple side reactions, thereby limiting the scope of its application. Here, we report a mechanochemical adaptation of the Mg-mediated Barbier reaction, which overcomes these limitations and facilitates the coupling of versatile organic halides (e.g., allylic, vinylic, aromatic, aliphatic) with a diverse range of electrophilic substrates (e.g., aromatic aldehydes, ketones, esters, amides, O-benzoyl hydroxylamine, chlorosilane, borate ester) to assemble C-C, C-N, C-Si, and C-B bonds. The mechanochemical approach has the advantage of being essentially solvent-free, operationally simple, immune to air, and surprisingly tolerant to water and some weak Brønsted acids. Notably, solid ammonium chloride was found to improve yields in the reactions of ketones. Mechanistic studies have clarified the role of mechanochemistry in the process, indicating the generation of transient organometallics facilitated by improved mass transfer and activation of the surface of magnesium metal.

Cu-Mediated Thianthrenation and Phenoxathiination of Arylborons.

Great success in synthetic chemistry is motivated by the development of novel and reactive linchpins for carbon-carbon and carbon-heteroatom bond formation reactions, which has dramatically altered chemists' approach to building molecules. Herein, we report the ready synthesis of aryl sulfonium salts, a versatile electrophilic linchpin, via a novel Cu-mediated thianthrenation and phenoxathiination of commercially available arylborons with thianthrene and phenoxathiine, providing a series of aryl sulfonium salts in high efficiency. More importantly, by leveraging the sequential Ir-catalyzed C-H borylation and Cu-mediated thianthrenation of arylborons, the formal thianthrenation of arenes is also achieved. The Ir-catalyzed C-H borylation with undirected arenes normally occurred at the less steric hindrance position, thus providing a complementary method for thianthrenation of arenes in comparison with electrophilic thianthrenation. This process is capable of late-stage functionalization of a series of pharmaceuticals, which might find wide synthetic applications in both industry and academic sectors.

Ball Milling in Organic Transformations

Abstract: In organic synthesis, mechanochemical approaches have received increased attention because of their broad applications in green methodologies. By utilization of mechanical forces on the various reactants, there is a certain increase of their surface area and also areas of contact, which usually make reaction pathways more available through a greater number of effective collisions. Mechanical energy can be produced and transferred through ball mills, one of the highest necessary devices for green organic solid-state reactions. In the last few decades, various challenging organic transformations have been published using ball milling in different fields of organic synthesis. Ball milling has received tremendous attention in numerous organic synthesis since it allows for reactions to occur at ambient temperature in the absence of any solvent under mild conditions which are compatible for a green process. The carbon-carbon and carbon–heteroatom bond formation reactions and also synthesis of heterocyclic compounds are of ample importance in both academia and pharmaceutical industry. This review will highlight the recent developments of amidation reactions, asymmetric synthesis, various heterocyclic compounds synthesis, crosscoupling reactions, C–H bond activation for C–C and carbon–heteroatom bond formation reactions under the ballmilling conditions.

Reactive orbital energy theory serving a theoretical foundation for the electronic theory of organic chemistry.

It is established that the reactive orbital energy theory (ROET) theoretically reproduces the rule-based electronic theory diagrams of organic chemistry by a comparative study on the charge transfer natures of typical organic carbon-carbon and carbon-heteroatom bond formation reactions: aldol, Mannich, α-aminooxylation, and isogyric reactions. The ROET, which is an expansion of the reaction electronic theories (e.g., the frontier orbital theory) in terms of orbital energies, elucidates the reactive orbitals driving reactions and the charge transferability indices of the reactions. Performing the ROET analyses of these reactions shows that the charge transfer directions given in the rule-based diagrams of the electronic theory are reproduced even for the functional groups of charge transfer destinations in all but only two processes for 38 reaction processes. The ROET analyses also make clear the detailed orbital-based pictures of these bond formation reactions: that is, the use of the out-of-plane antibonding π orbitals in acidic conditions (enol-mode) and in-plane antibonding π orbitals in basic conditions (enolate-mode), which explain the experimentally assumed mechanisms such as the π-bond formations in acidic conditions and σ-bond formations at α-carbons in basic conditions. Furthermore, the ROET analyses explicate that the methyl group initially accepts electrons and then donates them to the bond formations in the target reactions. It is, consequently, suggested that the ROET serves a theoretical foundation for the electronic theory of organic chemistry.

Benign-Metal-Catalyzed Carbon–Carbon and Carbon–Hetero­atom Bond Formation

AbstractCarbon–carbon and carbon–heteroatom bond-formation reactions catalyzed by benign and inexpensive metals are of much interest in organic synthesis, as these reactions provide green and cost-effective routes. This account summarizes our recent contributions to the construction of carbon–carbon and carbon–heteroatom bonds by using benign-metal catalysts. A number of carbon–heteroatom bond formations, including C–N, C–O, C–S, C–Se, C–Te, and C–P bond formations, are discussed. Mechanistic insights into several reactions are also reported1 Introduction2 C–C Bond Formation3 C–N and C–O Bond Formation4 Carbon–Chalcogen (C–S, C–Se, C–Te) and C–P Bond Formation5 Conclusions

Diverse synthesis of α-tertiary amines and tertiary alcohols via desymmetric reduction of malonic esters

Amines and alcohols with a fully substituted α-carbon are structures of great value in organic synthesis and drug discovery. While conventional methods towards these motifs often rely on enantioselective carbon-carbon or carbon-heteroatom bond formation reactions, a desymmetric method is developed here by selectively hydrosilylating one of the esters of easily accessible α-substituted α-amino- and -oxymalonic esters. The desymmetrization is enabled by a suite of dinuclear zinc catalysts with pipecolinol-derived tetradentate ligands and can accommodate a diverse panel of heteroatom substituents, including secondary amides, tertiary amines, and ethers of different sizes. The polyfunctionalized reduction products, in return, have provided expeditious approaches to enantioenriched nitrogen- and oxygen-containing molecules, including dipeptides, vitamin analogs, and natural metabolites.

Synthesis of bioactive scaffolds catalyzed by agro-waste-based solvent medium

Abstract The backbone of synthetic organic chemistry is the formation of carbon–carbon and carbon–heteroatom bonds. Scientists are actively working to develop new methods of bond-forming reactions because it is one of the most useful tools for the development of structurally diverse molecular entities. On the other hand, scientists are constantly discovering chemical processes to make them more sustainable in order to avoid the ever-increasing chemical emission associated with hazards to the environment. Thus, the development of greener catalytic reactions demonstrated a massive uptick in the ability to carry out carbon–carbon and carbon–heteroatom bond-forming reactions under environmentally friendly and simple reaction conditions. Various approaches are demonstrated, namely, solvent-free, microwave irradiation, ionic liquids, ball milling, ultrasound, one-pot, and aqueous-mediated methods under green chemistry protocol. Agro-waste is the postharvest part or agricultural residues derived from various agricultural activities, which has diverse scope and applications. The use of this agro-waste is an eco-friendly and cost-effective process of waste management. Appropriate and optimal utilization of these waste by-products is one of the major challenges in the present days. The recent trend around the globe is to transform waste into wealth concepts to achieve various applications. Agro-waste-derived ashes and extracted medium are successfully studied recently as a heterogeneous- or homogenous-based catalyst in various organic transformations. Agro-waste-derived catalysts are easily available, cost-effective, simple to prepare, nontoxic, easy to handle, biodegradable, and more environmentally benign. This article focuses more on a few instances of agro-waste-based homogeneous and heterogeneous organic synthesis, especially those used in the construction of bioactive molecule synthesis via C–C and C–X bond formation reactions are discussed. The compiled literature in this article is based on keywords used in the search engine on “agro-waste-based catalyst for organic transformations”, and review articles published on this topic, future scope, and summary are discussed.

Microwave-assisted Organo-catalyzed C-C and C-X (Heteroatom) Bondforming Reactions: An Overview

: Organocatalysis is a term used to describe small organic molecules that exclusively include carbon, hydrogen, oxygen, nitrogen, sulphur, and phosphorus atoms that are used to speed up chemical reactions. The researchers demonstrated a large area of applications in various organic transformations catalysed by the organocatalysts due to their lower moisture sensitivity in air, easy abundance, less polluting nature, noninterference with the final product, and costeffectiveness. This highlights high demand and direct benefits in pharmaceutical intermediate and fine chemical manufacturing compared to other conventional transition metal and enzyme catalysts. This review article intends to compile literature-reported applications of the microwave accelerated organocatalyzed carbon-carbon and carbon-heteroatom bond formation reactions.

Ultrasound-promoted Organic Synthesis - A Recent Update

Abstract: Ultrasonication, nowadays, is well-regarded as an effective green tool in implementing a plethora of organic transformations. The last decade has seen quite useful applications of ultrasound irradiation in synthetic organic chemistry. Ultrasound has already come out as a unique technique in green chemistry practice for its inherent properties of minimizing wastes and reducing energy and time, thereby increasing the product yields with higher purities under milder reaction conditions. The present review summarizes ultrasound-promoted useful organic transformations involving both carbon-carbon and carbon-heteroatom (N, O, S) bond-forming reactions in the absence or presence of varying catalytic systems, reported during the period 2016-2020.

Access to diverse organosulfur compounds via arynes: a comprehensive review on Kobayashi's aryne precursor.

Arynes are highly reactive transient intermediates having enormous applications in organic synthesis. In the last three decades aryne chemistry has shown incredible developments in carbon-carbon and carbon-heteroatom bond formation reactions. After the discovery of Kobayashi's protocol for the generation of aryne intermediates in a mild way, this field of chemistry witnessed rapid growth in synthetic organic chemistry. One aspect of development in this field involves C-S bond formation under mild conditions which has a tremendous scope for the synthesis of various important organosulfur building blocks.

Advances in Carbon–Element Bond Construction under Chan–Lam Cross-Coupling Conditions: A Second Decade

AbstractCopper-mediated carbon–heteroatom bond-forming reactions involving a wide range of substrates have been in the spotlight for many organic chemists. This review highlights developments between 2010 and 2019 in both stoichiometric and catalytic copper-mediated reactions, and also examples of nickel-mediated reactions, under modified Chan–Lam cross-coupling conditions using various nucleophiles; examples include chemo- and regioselective N-arylations or O-arylations. The utilization of various nucleophiles as coupling partners together with reaction optimization (including the choice of copper source, ligands, base, and other additives), limitations, scope, and mechanisms are examined; these have benefitted the development of efficient and milder methods. The synthesis of medicinally valuable or pharmaceutically important nitrogen heterocycles, including isotope-labeled compounds, is also included. Chan–Lam coupling reaction can now form twelve different C–element bonds, making it one of the most diverse and mild reactions known in organic chemistry.1 Introduction2 Construction of C–N and C–O Bonds2.1 C–N Bond Formation2.1.1 Original Discovery via Stoichiometric Copper-Mediated C–N Bond Formation2.1.2 Copper-Catalyzed C–N Bond Formation2.1.3 Coupling with Azides, Sulfoximines, and Sulfonediimines as Nitrogen­ Nucleophiles2.1.4 Coupling with N,N-Dialkylhydroxylamines2.1.5 Enolate Coupling with sp3-Carbon Nucleophiles2.1.6 Nickel-Catalyzed Chan–Lam Coupling2.1.7 Coupling with Amino Acids2.1.8 Coupling with Alkylboron Reagents2.1.9 Coupling with Electron-Deficient Heteroarylamines2.1.10 Selective C–N Bond Formation for the Synthesis of Heterocycle-Containing Compounds2.1.11 Using Sulfonato-imino Copper(II) Complexes2.2 C–O Bond Formation2.2.1 Coupling with (Hetero)arylboron Reagents2.2.2 Coupling with Alkyl- and Alkenylboron Reagents3 C–Element (Element = S, P, C, F, Cl, Br, I, Se, Te, At) Bond Forma tion under Modified Chan–Lam Conditions4 Conclusions

Metal-Catalyzed Transformations of Cyclopropanols via Homoenolates

Abstract Metal homoenolates represent uniquely useful organometallic intermediates in synthetic chemistry, allowing umpolung synthesis of β-functionalized carbonyl compounds. While siloxycyclopropanes had been established as reliable precursors to homoenolates, often stoichiometric, for diverse carbon–carbon bond forming reactions, unprotected cyclopropanols have emerged as alternative and attractive precursors to homoenolates, often catalytically generated, in carbon–carbon and carbon–heteroatom bond-forming reactions. This review article provides an overview of the development of such homoenolate transformations, as classified with respect to the metals involved in the cyclopropane ring opening.

Catch It If You Can: Copper-Catalyzed (Transfer) Hydrogenation Reactions and Coupling Reactions by Intercepting Reactive Intermediates Thereof

The key reactive intermediate of copper(I)-catalyzed alkyne semihydrogenations is a vinylcopper(I) complex. This intermediate can be exploited as a starting point for a variety of trapping reactions. In this manner, an alkyne semihydrogenation can be turned into a dihydrogen­-mediated coupling reaction. Therefore, the development of copper-catalyzed (transfer) hydrogenation reactions is closely intertwined with the corresponding reductive trapping reactions. This short review highlights and conceptualizes the results in this area so far, with H2-mediated carbon–carbon and carbon–heteroatom bond-forming reactions emerging under both a transfer hydrogenation setting as well as with the direct use of H2. In all cases, highly selective catalysts are required that give rise to atom-economic multicomponent coupling reactions with rapidly rising molecular complexity. The coupling reactions are put into perspective by presenting the corresponding (transfer) hydrogenation processes first.1 Introduction: H2-Mediated C–C Bond-Forming Reactions2 Accessing Copper(I) Hydride Complexes as Key Reagents for Coupling Reactions; Requirements for Successful Trapping Reactions3 Homogeneous Copper-Catalyzed Transfer Hydrogenations4 Trapping of Reactive Intermediates of Alkyne Transfer Semi­hydrogenation Reactions: First Steps Towards Hydrogenative Alkyne Functionalizations5 Copper(I)-Catalyzed Alkyne Semihydrogenations6 Copper(I)-Catalyzed H2-Mediated Alkyne Functionalizations; Trapping of Reactive Intermediates from Catalytic Hydrogenations6.1 A Detour: Copper(I)-Catalyzed Allylic Reductions, Catalytic Generation of Hydride Nucleophiles from H26.2 Trapping with Allylic Electrophiles: A Copper(I)-Catalyzed Hydro­allylation Reaction of Alkynes6.3 Trapping with Aryl Iodides7 Conclusion

Chiral <italic>N</italic>,<italic>N</italic>ʹ-dioxide and their metal complexes in asymmetric catalysis

Chirality is a fundamental property of nature. Chiral compounds are closely related to life science, human health, material science, and so on. Asymmetric catalysis is one of the most efficient and important synthetic methodologies to obtain chiral compounds, which meets the requirement of green chemistry. Metal-catalyzed asymmetric reactions attract much attention in the past few years, and thousands of chiral ligands have been synthesized, however, widely applicable, so-called privileged chiral ligands are still very limited. Therefore, the design and synthesis of highly efficient and selective chiral ligands becomes the most important and challenging goal. Our group is committed to asymmetric catalysis and develope a novel type of C 2-symmetric chiral ligand of N , N ʹ-dioxide amide compounds which is easily synthesized from cheap chiral amino acids and amines. Such conformationally flexible privileged ligands break through the notion of the rigid feature of previously privileged ligands. Naturally, it would guide the creation of new ideal chiral ligands and catalysts. N , N ʹ-dioxides are not only used as bifunctional organocatalysts, but also provide an arsenal of chiral metal complexes upon coordination with a variety of metal salts, such as alkaline-earth metal salts, transition metal salts and rare-earth metal salts. This powerful catalyst system has been proved to be highly effective for more than fifty types of asymmetric reactions with wide substrate generality under mild conditions, including carbon-carbon bond formation, and carbon-heteroatom bond formation reactions. The concerns of controlling chemo-, regio-, and stereoselectivity of involved reactions are well addressed. Some new and challengling asymmetric reactions are realized, for intances, the first asymmetric Roskamp reaction is achieved with a N , N ʹ-dioxide/Sc(III) complex at low catalyst loading, which updates the comment about β-keto esters in text of Organic Chemistry , Oxford, and the reaction is amended as “Roskamp-Feng reaction” in Elsevier’s Organic Synthesis Based on Name Reactions . The asymmetric amination of ketones with α-diazoesters shed light on the diversity of diazo chemistry. N , N ʹ-dioxide/La(III) complex catalyzed sulfa-Michael reaction exhibits very strong chiral amplification effect. N , N ʹ-dioxide/Ni(II) complex acts as both chiral Lewis catalyst and metal-carbene promotor in Doyle-Kirmse reaction, [ 2 , 3 ] -Stevens rearrangement and Sommelet-Hauser rearrangement of a new type of designed α-diazo pyrazoleamides. Such the creation of catalytic systems and catalytic asymmetric methods provide simple, efficient, precise, green access to several biologically active drug molecules and natural products, such as Paroxetine, Pregabalin, Thiazesim, KAE609 and so on. Now, N , N ʹ-dioxides have become commercially available chiral ligands and have been successfully applied by many research groups and companies. The above original and systematic research achievements make important contribution to the chirality science.

Boron Has More Surprises

Download : Download high-res image (124KB) Download : Download full-size image Dr. Anup Bhunia is an Alexander von Humboldt postdoctoral fellow working at the Westfalische Wilhelms-Universitat Munster in the lab of Prof. Armido Studer. He received his BSc in chemistry from Midnapore College, his MSc from the Indian Institute of Technology, and his PhD from the CSIR-National Chemical Laboratory under the guidance of Prof. Akkattu T. Biju. His graduate work entailed transition-metal-free carbon–carbon and carbon–heteroatom bond-forming reactions using N-heterocyclic carbene catalysis and aryne chemistry. His postdoctoral research has centered on the development of new reagents for stereo- and regioselective functionalizations of alkenes through metal catalysis or free-radical reactions.

Design of Carbon-carbon and Carbon-heteroatom Bond Formation Reactions under Green Conditions

:The development of C-C and C-heteroatom (C-N, C-O and C-P) bond reactions is a field of significant interest and has received momentous attention in modern organic chemistry. These reactions have been exploited in the synthesis of pharmaceuticals, agrochemicals and molecules of interest in materials science. With the increasing awareness of global warming and the use of renewable energies, it is of paramount importance to reduce the usage of hazardous chemicals in both industrial and academic research and to achieve a healthier environment through green practices. Green chemistry is a rapidly emerging approach that shows us a path for the sustainable growth of future science and technologies. In the recent past, healthy growth has been recorded in a number of organic reactions in aqueous media, which are environment-friendly and energy conserving. This review documents the literature on the development of green methodologies involving the design of C-C, C-O, C-N and C-P bond formations of coupling and condensed reactions. It emphasizes the exceptional practices and important advances achieved using alternative green tools, such as microwave (MW), high-speed ball milling (HSBM) and ultrasound irradiation techniques, and a variety of reusable catalysts and green solvents, with attention to water.

Lactonization as a general route to β-C(sp3)–H functionalization

Summary ParagraphFunctionalization of the β-C–H of aliphatic acids is emerging as a valuable synthetic disconnection that complements a wide range of conjugate addition reactions1–5. Despite efforts on β-C–H functionalizations for carbon-carbon (C-C) and carbon-heteroatom (C-Y) bond-forming reactions, these bear numerous decisive limitations, especially for industrial-scale applications, including the lack of mono-selectivity, use of expensive oxidants, and limited scope6–13. Notably, the majority of these reactions are incompatible with free aliphatic acids without exogenous directing groups. Considering the challenge of developing C–H activation reactions, it is not surprising that achieving different transformations requires independent catalyst design and directing group optimizations in each case. Here, we report a Pd-catalyzed β-C(sp3)–H lactonization of aliphatic acids enabled by a mono-N-protected β-amino acid ligand. The highly strained and reactive β-lactone products are versatile linchpins for the mono-selective installation of diverse alkyl, alkenyl, aryl, alkynyl, fluoro, hydroxyl, and amino groups at the β position of the parent acid, thus providing a route to myriad carboxylic acids. The use of inexpensive tert-butyl hydrogen peroxide (TBHP) as the oxidant to promote the desired selective reductive elimination from the Pd(IV) center, as well as the ease of product purification without column chromatography renders this reaction amenable to ton-scale manufacturing.