Carbon-heteroatom Bond Formation Research Articles

Determination of the pKa Value of a Brønsted Acid by 19F NMR Spectroscopy.

Brønsted acids, such as phosphoric acids derived from chiral 1,1'-bi-2-naphthol (BINOL), are important catalysts in the formation of carbon-carbon and carbon-heteroatom bonds, for example. The catalytic activity of these Brønsted acids is strongly linked to their acidity, and as such, the evaluation of compounds to determine pKa values provides insight into their catalytic activity. Herein, a 19F{1H} NMR methodology is detailed to determine the pKa of a fluorinated binaphthyl-derived phosphinic acid, rac-1, in acetonitrile and in the presence of a fluorinated sulfonamide reference compound (2-4). The approach was tested initially using 2 and 3, with the ΔpKa (0.08) in strong agreement with previously reported values (6.6 for 2 and 6.68/6.73 for 3). Sigmoidal curves of normalised chemical shift change (Δδ) against equivalents of the base phosphazene P1-tBu added overlapped for 2 and 3, but in the case of rac-1 and either 2, 3 or 4, there was significant separation. A variety of different approaches for determining the ΔpKa were compared. Values of pKa determined when the normalised Δδ was 90% were optimal for 2 and 3, whereas a normalised Δδ of 75% was optimal for 4, resulting in the pKa of rac-1 being determined to be 8.47-8.71.

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.

Visible light induced cooperative catalysis by 4CzIPN and Mg(NO3)2·6H2O to furnish C-P functionalization of alkenes and indoles

Carbon-carbon or carbon-heteroatom bond formation from simple substrates using photoredox-Lewis acid dual catalytic systems is an intriguing area of research. Herein, an expedient photocatalytic strategy for selective C-P bond formation by employing 4CzIPN-Mg(NO3)2·6H2O mediated cooperative catalysis is reported. Following this versatile protocol, various organo-phosphorus compounds like phosphorylated oxindoles, malononitriles, malonates, coumarin esters, and indoles were effectively synthesized. This visible-light-promoted transition-metal-free method originated from the synergistic interaction of 4CzIPN-Mg(NO3)2·6H2O and substrates. Control experiments and other mechanistic studies were carried out to understand this cooperative photocatalytic process.

Electrochemical synthesis of heterocyclic compounds via carbon–heteroatom bond formation: direct and indirect electrolysis

Abstract Electrochemical organic synthesis has attracted attention as an environmentally friendly method for constructing heterocyclic compounds via carbon–heteroatom bond formation. Herein, we describe the representative examples of electrochemical reactions to produce heterocycles and discuss them according to whether they involve direct or indirect electrolysis.

Regioconvergent Nucleophilic Substitutions with Morita-Baylis-Hillman Fluorides.

Lithium iodide enables regioconvergent C-F bond functionalization of isomeric Morita-Baylis-Hillman fluorides with carbon, sulfur, and nitrogen nucleophiles. The defluorinative carbon-carbon and carbon-heteroatom bond formations give multifunctional compounds in excellent yields and with good to high diastereoselectivities at room temperature. The possibility of catalytic enantioselective allylation is also discussed.

Site-Selective Distal C(sp3)-H Bromination of Aliphatic Amines as a Gateway for Forging Nitrogen-Containing sp3 Architectures.

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

Regioselective Palladium-Catalyzed Chain-Growth Allylic Amination Polymerization of Vinyl Aziridines.

Organometallic-mediated chain growth polymerization of readily accessible chemical building blocks is responsible for important commercial and technological advances in polymer science, but the incorporation of heteroatoms into the polymer backbone through these mechanisms remains a challenge. Transition metal π-allyl complexes are well-developed organometallic intermediates for carbon-heteroatom bond formation in small-molecule catalysis yet remain underexplored in polymer science. Here, we developed a regioselective palladium-phosphoramidite-catalyzed chain-growth allylic amination polymerization of vinyl aziridines for the synthesis of novel nitrogen-rich polymers via ambiphilic π-allyl complexes. The polymerization accessed a linear microstructure with four carbons between each nitrogen, which is challenging to achieve through other chain-growth polymerization approaches. The highly regioselective allylic amination polymerization demonstrated the characteristics of a controlled polymerization and was able to achieve molar masses exceeding 20 kg mol-1 with low dispersities (D̵ < 1.3). The identification of the polymer structure and well-defined chain ends were supported by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and chain extension experiments demonstrate opportunities for building more complex materials from this method. A Hammett study was performed to understand the role of the catalyst and monomer structure on regioselectivity, and the data supported a mechanism wherein regioselectivity was primarily controlled by the ligand-metal complex. Postpolymerization desulfonylation provided access to a novel polyamine that demonstrated broad anticancer activity in vitro, which highlights the benefits of unlocking novel polyamine microstructures through regioselective chain-growth allylic amination polymerization.

C–heteroatom coupling with electron-rich aryls enabled by nickel catalysis and light

Nickel photoredox catalysis has resulted in a rich development of transition-metal-catalysed transformations for carbon–heteroatom bond formation. By harnessing light energy, the transition metal can attain oxidation states that are difficult to achieve through thermal chemistry in a catalytic manifold. For example, nickel photoredox reactions have been reported for both the synthesis of anilines and aryl ethers from aryl(pseudo)halides. However, oxidative addition to simple nickel systems is often sluggish in the absence of special, electron-rich ligands, leading to catalyst decomposition. Electron-rich aryl electrophiles therefore currently fall outside the scope of many transformations in the field. Here we provide a conceptual solution to this problem and demonstrate nickel-catalysed C–heteroatom bond-forming reactions of arylthianthrenium salts, including amination, oxygenation, sulfuration and halogenation. Because the redox properties of arylthianthrenium salts are primarily dictated by the thianthrenium, oxidative addition of highly electron-rich aryl donors can be unlocked using simple NiCl2 under light irradiation to form the desired C‒heteroatom bonds.

Generation and Application of Aryl Radicals Under Photoinduced Conditions.

Photoinduced aryl radical generation is a powerful strategy in organic synthesis that facilitates the formation of diverse carbon-carbon and carbon-heteroatom bonds. The synthetic applications of photoinduced aryl radical formation in the synthesis of complex organic compounds, including natural products, physiologically significant molecules, and functional materials, have received immense attention. An overview of current developments in photoinduced aryl radical production methods and their uses in organic synthesis is given in this article. A generalized idea of how to choose the reagents and approach for the generation of aryl radicals is described, along with photoinduced techniques and associated mechanistic insights. Overall, this article offers a critical assessment of the mechanistic results as well as the selection of reaction parameters for specific reagents in the context of radical cascades, cross-coupling reactions, aryl radical functionalization, and selective C-H functionalization of aryl substrates.

Recent advances in dual photoredox/nickel catalyzed alkene carbofunctionalised reactions.

Alkene carbofunctionalization reactions have great potential for synthesizing complex molecules and constructing complex structures in natural products and medicinal chemistry. Recently, dual photoredox/nickel catalysis has emerged as a novel strategy for alkene carbofunctionalization. Nickel offers numerous advantages over other transition metals, such as cost-effectiveness, abundance, and low toxicity, and moreover, it has many oxidation states. Nickel catalysts exhibit excellent catalytic activity in dual photoredox/transition metal catalysis, facilitating the formation of carbon-carbon or carbon-heteroatom bonds in organic transformations. This review highlights the latest advancements in dual photoredox/nickel-catalyzed alkene carbofunctionalizations and includes the literature published from 2020 to 2024.

Recent Advances in Monofluorinated Carbenes, Carbenoids, Ylides, and Related Species.

The synthesis of monofluorinated compounds is of great interest because of the vast applications of organofluorine compounds. Recently, the introduction of monofluorocarbene synthons has emerged as an important strategy for the synthesis of fluorine-containing products. In contrast to direct fluorination, in which C-F bonds are formed, the use of monofluorinated carbenes and related reactive species involves C-C or C-X bond formation while delivering valuable fluorine atoms into the target structure. Owing to increased knowledge on carbon-carbon and carbon-heteroatom bond formations, monofluorinated carbenes have enormous potential for the synthesis of organofluorine compounds, which, in our opinion, has not yet been fully exploited. This review summarizes the recent advances in the synthetic applications of monofluorinated carbenes, carbenoids, ylides, and related species.

Transition-Metal-Catalyzed Addition of Organosulfur Compounds to Alkynes and Alkenes: Catalysis and Catalyst Poisons.

The addition of heteroatom compounds to alkynes and alkenes is an atom-efficient method of carbon-heteroatom bond formation and is widely used as a fundamental synthetic method for the construction of functional molecules. Nevertheless, examples of transition-metal-catalyzed addition reactions of group 16 heteroatom compounds to carbon-carbon unsaturated bonds have been limited due to the widespread belief that organic sulfur and selenium compounds are representative catalyst poisons. In recent decades, however, several seminal catalytic reactions of sulfur compounds have been developed, providing important insights into catalysis and poisons. Therefore, in this paper, we focus on the transition-metal-catalyzed addition of organosulfur compounds to alkynes and alkenes, gain comprehensive insights into the catalysis and catalyst poisons, and propose concepts for the development of transition-metal-catalyzed reactions of group 16 heteroatom compounds.

Green Chemistry Approach toward the Regioselective Synthesis of α,α-Disubstituted Allylic Amines.

Molybdenum-catalyzed allylic substitution reactions are known to provide direct and practical ways to construct new carbon-carbon bonds and privileged compounds. However, due to the lack of reports on carbon-heteroatom bond formation as a common deficiency, these reactions still face a great challenge. Described herein is a robust and convenient molybdenum-catalyzed regioselective allylic amination of tertiary allylic carbonates with an amine as the heteroatom nucleophile. Both aromatic and aliphatic amines react with various tertiary allylic alcohol derivatives to deliver the desired α,α-disubstituted allylic amines in high yield with complete regioselectivity. In addition, ethanol as the green solvent, a recyclable catalyst system through simple centrifugation techniques, and simple handling procedures make the current approach green, economic, and sustainable.

Recent Advances in Copper-Catalyzed Carbon Chalcogenides Cross- Coupling Reactions.

Cu-catalyzed carbon-heteroatom bond formation is a powerful tool in the field of organic synthesis. In the past two decades, numerous Cu-based catalytic systems are developed in both homogeneous and heterogeneous forms. Important developmentshave been reported on Cubased catalytic systems in the field of C-Chalcogenide cross-coupling in the last few decades. Where homogeneous Cu/L-based catalytic systems are found to perform reactions with high selectivity, heterogeneous supported-Cu and Cu-based nanoparticles are found to perform the reactions under sustainable conditions and high recyclability of catalytic systems. This present overview mainly focuses on the recent advances and applications in this fast-growing research field with an emphasis on copper-catalyzed cross-coupling generations of carbon-chalcogenide (S/Se/Te) bonds.

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.

Recent Advances in Carbon-Nitrogen/Carbon-Oxygen Bond Formation Under Transition-Metal-Free Conditions.

Carbon-heteroatom bond formation under transition-metal free conditions provides a powerful synthetic alternative for the efficient synthesis of valuable molecules. In particular, C-N and C-O bonds are two important types of carbon-heteroatom bonds. Thus, continuous efforts have been deployed to develop novel C-N/C-O bond formation methodologies involving various catalysts or promoters under TM-free conditions, which enables the synthesis of various functional molecules comprising C-N/C-O bonds in a facile and sustainable manner. Considering the significance of C-N/C-O bond construction in organic synthesis and materials science, this review aims to comprehensively present selected examples on the construction of C-N (including amination and amidation) and C-O (including etherification and hydroxylation) bonds without transition metals. Besides, the involved promoters/catalysts, substrate scope, potential application and possible reaction mechanisms are also systematically discussed.

Stereoselective C–O silylation and stannylation of alkenyl acetates

Facile formation of carbon-heteroatom bonds is a long-standing objective in synthetic organic chemistry. However, direct cross-coupling with readily accessible alkenyl acetates via inert C‒O bond-cleavage for the carbon-heteroatom bond construction remains challenging. Here we report a practical preparation of stereoselective tri- and tetrasubstituted alkenyl silanes and stannanes by performing cobalt-catalyzed C‒O silylation and stannylation of alkenyl acetates using silylzinc pivalate and stannylzinc chloride as the nucleophiles. This protocol features a complete control of chemoselectivity, stereoselectivity, as well as excellent functional group compatibility. The resulting alkenyl silanes and stannanes show high reactivities in arylation and alkenylation by Hiyama and Stille reactions. The synthetic utility is further illustrated by the facile late-stage modifications of natural products and drug-like molecules. Mechanistic studies suggest that the reaction might involve a chelation-assisted oxidative insertion of cobalt species to C‒O bond. We anticipate that our findings should prove instrumental for potential applications of this technology to organic syntheses and drug discoveries in medicinal chemistry.

Diphenyl Diselenide-Assisted Radical Addition Reaction of Diphenyl Disulfide to Unsaturated Bonds upon Photoirradiation.

The addition reaction of interelement compounds with heteroatom-heteroatom single bonds to unsaturated bonds under photoirradiation is an important method for the efficient and atom-economical construction of carbon-heteroatom bonds. However, in practice, the desired addition reaction is sometimes unable to proceed as expected due to the low efficiency of the desired addition reactions or the preferential polymerization of unsaturated compounds. In this study, by combining an interelement compound with homologous heteroatom compounds as a catalyst, we succeeded in suppressing the polymerization of the unsaturated compounds and in attaining a highly selective carbon-heteroatom bond formation through the desired addition reaction. In this paper, we have examined in detail whether such a "catalytic radical reaction" proceeds for unsaturated compounds and found that the dithiolation of some unsaturated compounds (i.e., vinylic ethers, styrenes, and isocyanides) could proceed with the assistance of (PhSe)2 under light. The developed methods in this study are expected to have strong implications in the fields of radical chemistry, heteroatom chemistry, synthetic organic chemistry, and catalyst chemistry as atom-economical methods for carbon-heteroatom bond formation.

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.

Self-sufficient P450-reductase chimeras for biocatalysis.

In recent years, cytochromes P450 have emerged as powerful, versatile biocatalysts for the site-selective functionalization of small molecules. Catalyzing an impressive range of chemical transformations, these enzymes have been widely used to effect C-H oxidation, biaryl coupling, and carbon-heteroatom bond formation, among many other reactions. However, the majority of P450s are multi-protein systems that employ secondary redox partners in key steps of the catalytic cycle, which limits their broader applicability. In response, the discovery of self-sufficient P450s, such as P450BM3 and P450RhF, has provided a template for the construction of artificial, self-sufficient P450-reductase fusions. In this chapter, we describe a procedure for the design, assembly, and application of two engineered, self-sufficient P450s of Streptomyces origin via fusion with an exogenous reductase domain. In particular, we generated artificial chimeras of P450s PtmO5 and TleB by linking them covalently with the reductase domain of P450RhF. Upon verification of their activities, both enzymes were employed in preparative-scale biocatalytic reactions. This approach can feasibly be applied to any P450 of interest, thereby laying the groundwork for the production of self-sufficient P450s for diverse chemical applications.