Coupling Partners Research Articles

Triskelion-shaped Hexabenzocoronenes: Synthesis and Characterization of tris-substituted HBC derivatives.

The synthesis of unprecedented triskelion-shaped hexa-peri-hexabenzocoronenes with C3, C3h or D3h symmertry is reported. We present a new, five step synthetic access to tris-iodinated HBC derivatives carrying different solubilizing moieties (tert-butyl and mesityl), which serve as suitable building blocks for further functionalization. These molecules can undergo Sonogashira cross coupling reactions to obtain a series of seven ethynyl tris-substituted HBCs. The coupling partners range from carbon-based aromatic scaffolds (tBu-benzene, naphthalene, phenanthrene) to ligands for metal complexes (bipyridine, phenanthroline, terpyridine, acetylacetone). The optoelectronic properties were investigated by UV/vis absorption spectroscopy resulting in a significant batho-chromic shift of the absorption maximum compared to the iodinated starting material. Semiempirical calculations were used to determine the conformation and symmetry of the compounds.

Strained Ion Pair Interactions-Driven Anion-Assisted Concerted Addition of Ketoximes/Aldoximes and Hydroxamic Acids to Glycals.

Oximes and hydroxylamides are notable for their role as coupling partners in organic synthesis. However, their direct application as acceptors in O-glycosylation with glycal donors remains largely unexplored. Herein, we introduce a novel 2-deoxy glycosylation method for synthesizing N-O linked glycosides facilitated by sterically strained 2,4,6-tri-tert-butylpyridinium salts. This approach offers a broad substrate range, high tolerance for functional groups, and easy scalability, resulting in glycosyl oximes and glycosyloxyamines with exclusive α-selectivity and excellent yields. The effectiveness of this method is showcased through functionalization of glycosylated products, late-stage modification of bioactive drug molecules, and disaccharide synthesis. This innovative strategy offers an alternative route and holds promise for wide-ranging applications in the construction of bioactive N-O-linked glycosides in the future. The unique catalytic mechanism by the sterically hindered pyridinium salt has been studied via 1H NMR, IR, UV-vis, and fluorescence studies.

Recent Advances in C-O Bond Cleavage of Aryl, Vinyl, and Benzylic Ethers.

Transition metal-catalyzed cross-coupling with aryl halides has revolutionized the way of diversifying aromatic compounds. Aryl ethers are attractive alternatives to aromatic halides as coupling partners considering the accessibility and potential environmental benefits. The last two decades have witnessed a striking success in the field of C-O bond activation of aryl ethers, including the construction of C-C bond and C-X bond, as well as reductive deoxygenation. Here, we present a comprehensive review of C-O bond activation in the context of aryl, vinyl, and benzylic ethers. This review elaborates on the current state-of-the-art methods, categorized by different catalytic systems, including transition metal catalysis, photoredox catalysis, and other innovative approaches. The newly developed methods allow C-O bond activation under mild conditions with exceptional functional group tolerance, potentially enabling the late-stage functionalization of pharmaceuticals. The limitations and future perspectives of the methods are also presented.

Coupling of unactivated alkyl electrophiles using frustrated ion pairs

Cross-electrophile coupling reactions have evolved into a major strategy for rapidly assembling important organic molecules1. Two readily accessible electrophiles are coupled to form new C–C bonds, providing a key advantage over traditional cross-coupling strategies that require the preformation of reactive organometallic species. Yet, the formation of C(sp3)–C(sp3) bonds that form the core of nearly all organic compounds remains highly challenging with current approaches, calling for the design of innovative new strategies. Here we report a distinct, transition-metal-free platform to form such bonds without the need for activating or stabilizing groups on the coupling partners. The reaction is enabled by an unusual single-electron transfer in a frustrated ion pair, and it can couple fragments containing functional groups that would be challenging in related transition-metal-catalysed processes. Moreover, we could further leverage this new mechanistic manifold in the design of other reactions, showing the broad potential of this type of reactivity. We anticipate that our results will provide a framework for further exploration of this reactivity pattern to tackle challenging problems in organic synthesis.

Light-assisted functionalization of aryl radicals towards metal-free cross-coupling.

The many synthetic possibilities that arise when using radical intermediates, in place of their polar counterparts, make contemporary radical chemistry research an exhilarating field. The introduction of photocatalysis has helped tame aryl radicals, leading to a resurgence of interest in their chemistry, and an expansion of viable coupling partners and attainable transformations. These methods are more selective and safer than classical approaches, and they utilize new radical precursors. Given the importance of sustainability in current organic synthesis and our interest in light-assisted metal-free transformations, this Review focuses on recent advances in the use of aryl radicals in photoinduced cross-couplings that do not rely on metals for the crucial bond-forming event, and it is structured according to the key step that the aryl radicals engage in.

Rhodium(III)-Catalyzed Regioselective C-H Alkenylation and Alkylation of Menadione Analogues with β-Trifluoromethyl Enones.

Menadione and its structural analogues are important motifs present in various bioactive natural products and drugs with a wide range of biological activities. In addition, β-trifluoromethyl enone has been employed as an efficient fluorinated building block for the synthesis of CF3-containing organic scaffolds. Herein, we report both C-H alkenylation and C-H alkylation reactions using β-CF3 enones as coupling partners with amino-substituted menadiones under Rh(III) catalysis. While β-CF3 enones have been studied in C-H alkylation reactions, we herein for the first time disclose the Rh (III)-catalyzed C-H alkenylation reaction of β-CF3 enones. The presence of an oxidant was crucial for the alkenylation reaction with β-CF3 enone. Meanwhile, the alkylation reaction proceeds via redox-neutral conditions.

Solvent-Controlled Rh(III)-Catalyzed Mono- and Dual Functionalization of Quinolyl Aldoximes with Diazo Compounds.

A solvent-controlled Rh(III)-catalyzed mono- and dual-C-H bond activation/carbene migratory insertion with diazo compounds as a single coupling partner was demonstrated. The reaction proceeded under mild conditions, yielding products in good to excellent yields. These results are significant for the development of the domino multiple functionalization of C(sp2)-H bonds via a carbenoid insertion approach.

Demonstrating Synergistic Activity of Magnetic Iron Oxide Nano Photocatalyst for C-H Activation in Heterogeneous Phase.

This report describes a dual catalytic approach for the versatile C-H arylation of arenes under photo-excitation at room temperature. The cooperative catalysis utilizes iron oxide magnetic nanoparticles (which mostly contain Fe3O4 along with some γ-Fe2O3) as the potential photocatalyst, which merges with the Pd-catalyzed C-H activation cycle for the reductive generation of aryl radical from aryl diazonium salt, revealing its photocatalytic activities. The method is applicable to a wide range of aryl coupling partners and different directing groups, demonstrating excellent productivity, nice co-operativity and recyclability. Adequate control experiments and mechanistic studies assisted in establishing the radical-based reaction mechanism for the C-H arylation occurring in the heterogeneous phase.

Diaryliodonium Salt‐Mediated Radical Transformation of Indoles with Alcohols for the Synthesis of Unsymmetrical Bis(indolyl)methanes

AbstractA method for the synthesis of unsymmetrical bis(indolyl)methanes (BIMs) using simple indoles and readily available alcohols as the coupling partners under both heat and 390–400 nm light conditions was developed. Detailed research of the mechanism demonstrated that the diaryliodonium salt‐mediated transformation undergoes a nucleophilic hydroxymethyl radical formation process. Moreover, the diaryliodonium salt‐mediated method is also applicable for synthesizing symmetrical BIMs.

Friedel-Crafts Reactivity with Sulfondiimidoyl Fluorides for the Synthesis of Heteroaryl Sulfondiimines.

Sulfur functional groups are ubiquitous in molecules used in the pharmaceutical and agrochemical industries, and within these collections sulfones hold a prominent position. The double aza-analogues of sulfones, sulfondiimines, offer significant potential in discovery chemistry but to date their applications have been limited by the lack of convenient synthetic routes. The existing methods mainly rely on imination of low-valent-sulfur intermediates, or the combination of pre-formed organometallic reagents and electrophilic S(VI)-functionalities. Herein, we describe a Friedel-Crafts-type reaction of sulfondiimidoyl fluorides with (hetero)aryls. This new SuFEx reactivity benefits from broad functional group tolerance, mild reaction conditions, and does not require the use of pre-formed organometallic reagents. The efficient use of unprotected indoles and pyrroles, as well as furan, thiophene and carbocyclic aromatics, further demonstrates the advantages of these reactions. We show that the reactivity of the sulfondiimidoyl fluorides can be tuned by switching the N-substituents, allowing an expansion of the range of coupling partners. The utility of the transformation is exemplified by the synthesis of the sulfondiimine analogue of the HIV-I reverse transcriptase-inhibitor L-737,126.

Friedel–Crafts Reactivity with Sulfondiimidoyl Fluorides for the Synthesis of Heteroaryl Sulfondiimines

AbstractSulfur functional groups are ubiquitous in molecules used in the pharmaceutical and agrochemical industries, and within these collections sulfones hold a prominent position. The double aza‐analogues of sulfones, sulfondiimines, offer significant potential in discovery chemistry but to date their applications have been limited by the lack of convenient synthetic routes. The existing methods mainly rely on imination of low‐valent‐sulfur intermediates, or the combination of pre‐formed organometallic reagents and electrophilic S(VI)‐functionalities. Herein, we describe a Friedel–Crafts‐type reaction of sulfondiimidoyl fluorides with (hetero)aryls. This new SuFEx reactivity benefits from broad functional group tolerance, mild reaction conditions, and does not require the use of pre‐formed organometallic reagents. The efficient use of unprotected indoles and pyrroles, as well as furan, thiophene and carbocyclic aromatics, further demonstrates the advantages of these reactions. We show that the reactivity of the sulfondiimidoyl fluorides can be tuned by switching the N‐substituents, allowing an expansion of the range of coupling partners. The utility of the transformation is exemplified by the synthesis of the sulfondiimine analogue of the HIV‐I reverse transcriptase‐inhibitor L‐737,126.

Unveiling the Novel Mechanistic Insights and Role of Base in Zn‐Catalyzed Csp–Csp2 Cross‐Coupling Reaction

ABSTRACTA detailed mechanistic investigation of the Zn (II)‐catalyzed Csp–Csp2 (Sonogashira‐type) cross‐coupling reaction is reported herein, using the Density Functional Theory method. The present study unveiled an unconventional non‐redox mechanism for Zn‐catalyzed cross‐coupling reaction, where the oxidation state of Zn remains intact throughout the catalytic cycle. Our study further revealed the significant role of the base in controlling the feasibility of cross‐coupling reactions that are catalyzed by electron‐deficient metal centers. Our study indicates that K3PO4 acts as an ancillary ligand (Lewis base) for the electron‐deficient Zn (II) catalytic center rather than as a proton abstractor for the nucleophilic coupling partner (phenylacetylene) in this reaction. The active catalyst was identified to be a four‐coordinate bis‐DMEDA Zn (II) complex. The mechanism proceeds via the initial activation of the nucleophilic coupling partner (phenylacetylene), followed by the electrophilic coupling partner (organic halide) activation liberating the cross‐coupled product by a concerted nucleophilic substitution pathway. The turn‐over limiting step was identified to be the activation of the electrophilic coupling partner. The activation barrier obtained for the reaction, 31.0 kcal/mol concords well with experimental temperature requirements (125°C). The coordination by base is found to stabilize the rate‐determining intermediates and transition states involved in the reaction. The mechanistic insights gained from this study could aid in the rational design and development of sustainable cross‐coupling reactions using zinc as the catalyst.

Base-Promoted Coupling of HFIP in Cu-Catalyzed Asymmetric Ring Opening of Cyclic Diaryliodoniums.

We report a Cu-catalyzed asymmetric ring-opening reaction of cyclic diaryliodoniums with 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), enabling the construction of axially chiral biaryl compounds containing HFIP ether. HFIP is highly polar and exceptionally stable; thus, it is commonly used as a solvent due to its poor nucleophilicity. However, its use as a nucleophilic reagent has been rare. In this study, we successfully employed HFIP as a nucleophilic coupling partner in a Cu-catalyzed asymmetric ring-opening experiment of cyclic diaryliodoniums.

The Azide-Wittig Reaction.

The introduction of heteroatoms into conjugated organic molecules is an important strategy to tune their reactivity and physical properties. In this realm triazabutadienes (TBDs) of the general from R2C=N-N=NR' are an interesting class of compounds, however, general synthetic protocols for their generation are limited. Based on the serendipitous finding that the sterically encumbered azide Mes*N3 (Mes*=2,4,6-tBu3C6H2) reacted with PMe3 in the presence of an aromatic aldehyde to form a TBD, we now report on the "Azide-Wittig" reaction. This azide-Wittig reaction is shown to be a versatile tool for the synthesis of a variety of TBDs, tolerating a wide range of aldehydes and organic azides as coupling partners. The preference for azide-Wittig, rather than aza-Wittig reactivity was rationalized using computational methods. This study shows how kinetic control can significantly alter the reaction pathway, thereby switching from an aza-Wittig to an azide-Wittig regime.

Enantioselective [2π + 2σ] Photocycloaddition Enabled by Brønsted Acid Catalyzed Chromophore Activation.

Bicyclo[2.1.1]hexanes have emerged as valuable scaffolds for the design of new pharmaceutical and agrochemical active ingredients. These structures can be efficiently synthesized via [2π + 2σ] photocycloadditions; however, control over the absolute stereochemistry of these strain-releasing reactions has remained challenging. Herein, we demonstrate that Brønsted acid catalyzed chromophore activation of C-acyl imidazoles enables highly enantioselective [2π + 2σ] photocycloadditions. Because this approach is agnostic to the identity of the coupling partner, the same strategy can be used to synthesize several other medicinally relevant strained small-ring structures.

Cleavage of the Robust Silicon–Fluorine σ‐Bond Allows Silicon–Carbon Bond Formation: Synthetic Strategies Toward Ortho‐Silyl Aryl Phosphonates

AbstractA straightforward, mild, and transition‐metal‐free three‐component coupling reaction involving arynes, phosphites, and silyl fluorides was developed through Si−F bond activation. Although the Si−F bond is one of the strongest bonds, Si−C bond formation via Si−F bond cleavage with the assistance of bidentate silicon and phosphonium Lewis acids has been successfully achieved. This unprecedented strategy provides a facile approach for synthesizing ortho‐silyl‐substituted aryl phosphonates. Notably, this method allows the use of not only dialkylarylsilyl fluorides and diarylalkylsilyl fluorides but also triarylsilyl fluorides as coupling partners, which is uncommon in the field of arylsilane synthesis. Furthermore, a variety of ortho‐silyl‐substituted aryl phosphonates were produced in moderate to good yields with broad functional group tolerance. Additionally, the versatility of ortho‐silyl‐substituted aryl phosphonates was demonstrated by the elaboration of the products into a range of silicon‐containing compounds.

Cleavage of the Robust Silicon-Fluorine σ-Bond Allows Silicon-Carbon Bond Formation: Synthetic Strategies Toward Ortho-Silyl Aryl Phosphonates.

A straightforward, mild, and transition-metal-free three-component coupling reaction involving arynes, phosphites, and silyl fluorides was developed through Si-F bond activation. Although the Si-F bond is one of the strongest bonds, Si-C bond formation via Si-F bond cleavage with the assistance of bidentate silicon and phosphonium Lewis acids has been successfully achieved. This unprecedented strategy provides a facile approach for synthesizing ortho-silyl-substituted aryl phosphonates. Notably, this method allows the use of not only dialkylarylsilyl fluorides and diarylalkylsilyl fluorides but also triarylsilyl fluorides as coupling partners, which is uncommon in the field of arylsilane synthesis. Furthermore, a variety of ortho-silyl-substituted aryl phosphonates were produced in moderate to good yields with broad functional group tolerance. Additionally, the versatility of ortho-silyl-substituted aryl phosphonates was demonstrated by the elaboration of the products into a range of silicon-containing compounds.

A Linear and Stereoselective Approach for the Synthesis of Dapoxetine from Benzaldehyde

Abstract: In addition to providing a succinct pathway for the stereoselective synthesis of dapoxetine, a potent SSRI employed in the treatment of premature ejaculation, this study highlights the strategic use of Ellman's sulfinamide as a chiral auxiliary. The key method involves the diastereoselective allylation of (S,E)-N-Benzylidenesulfinamide, resulting in the desired S-configuration critical for the pharmacological activity of dapoxetine. The utilization of readily available benzaldehyde as the starting material and 1-naphthol as a late-stage coupling partner contributes to the economic feasibility of the synthesis. Especially, the linear synthetic approach adopted in this study employs simplified and more efficient protocols for various transformations, culminating in an overall yield of 26%. This research not only presents a practical synthetic route for dapoxetine, but also underscores the importance of cost-effective and streamlined methodologies in drug development processes.

Nitrobenzene and Aniline‐Mediated Direct Olefination of Methyl Substituted N‐Heteroarenes With Benzylic Alcohols

AbstractMetal‐free, strong‐base‐free, and solvent‐free synthesis of alkenyl heteroarenes through PhNO2/PhNH2 mediated direct olefination of methyl substituted N‐heteroarenes with benzylic alcohols was described. Detailed mechanistic studies indicated that in situ formed imine was the active intermediate for the olefination. PhNO2 protected benzylic alcohols from overoxidation, and PhNH2 not only acted as the coupling partner for the formation of intermediate imine, but also provides an alkaline condition for the generation of enamine salt. Gram scale reaction and the synthesis of three pharmaceutically relevant conjugated olefins were also successful using this methodology.

Synthesis of α-Quaternary Amides via Cp*Co(III)-Catalyzed Sequential C-H Bond Addition to 1,3-Dienes and Isocyanates.

The synthesis of sterically congested amides was accomplished via Cp*Co(III)-catalyzed sequential C-H bond addition to 1,3-dienes followed by aminocarbonylation with isocyanates, a coupling partner that had never been utilized in sequential C-H bond addition reactions. A variety of C-H bond reactants, internally substituted dienes, and aromatic isocyanates provided secondary amide products incorporating α-all-carbon quaternary centers. The conversion of the amide products to other useful compound classes was also demonstrated.