Aryl Nucleophiles Research Articles

Mechanistic Facets of the Competition between Cross-Coupling and Homocoupling in Supporting Ligand-Free Iron-Mediated Aryl–Aryl Bond Formations

In the context of cross-coupling chemistry, the competition between the cross-coupling path itself and the oxidative homocoupling of the nucleophile is a classic issue. In that case, the electrophilic partner acts as a sacrificial oxidant. We investigate in this report the factors governing the cross- versus homocoupling distribution using aryl nucleophiles ArMgBr and (hetero)aryl electrophiles Ar′Cl in the presence of an iron catalyst. When electron-deficient electrophiles are used, a key transient heteroleptic [Ar2Ar′FeII]− complex is formed. DFT calculations show that an asynchronous two-electron reductive elimination follows, which governs the selective evolution of the system toward either a cross- or homocoupling product. Proficiency of the cross-coupling reductive elimination strongly depends on both π-accepting and σ-donating effects of the FeII-ligated Ar′ ring. The reactivity trends discussed in this article rely on two-electron elementary steps, which are in contrast with the usually described tendencies in iron-mediated oxidative homocouplings which involve single-electron transfers. The results are probed by paramagnetic 1H NMR spectroscopy, experimental kinetics data, and DFT calculations.

Tunable Gold-catalyzed Reactions of Propargyl Alcohols and Aryl Nucleophiles.

Gold‐catalyzed transformations of 1,3‐diarylpropargyl alcohols and various aryl nucleophiles were studied. Selective tunable synthetic methods were developed for 1,1,3‐triarylallenes, diaryl‐indenes and tetraaryl‐allyl target products by C3 nucleophilic substitution and subsequent intra‐ or intermolecular hydroarylation, respectively. The reactions were scoped with regards to gold(I)/(III) catalysts, solvent, temperature, and electronic and steric effects of both the diarylpropargyl alcohol and the aryl nucleophiles. High yields of triaryl‐allenes and diaryl‐indenes by gold(III) catalysis were observed. Depending on the choice of aryl nucleophile and control of reaction temperature, different product ratios have been obtained. Alternatively, tetraaryl‐allyl target products were formed by a sequential one‐pot tandem process from appropriate propargyl substrates and two different aryl nucleophiles. Corresponding halo‐arylation products (I and Br; up to 95 % 2‐halo‐diaryl‐indenes) were obtained in a one‐pot manner in the presence of the respective N‐halosuccinimides (NIS, NBS).

Diarylation of N- and O-nucleophiles through a metal-free cascade reaction

Diarylation of N- and O-nucleophiles through a metal-free cascade reaction

Bifunctional Polyene Cyclizations: Synthetic Studies on Pimarane Natural Products.

Polyene cyclizations generate molecular complexity from a linear polyene in a single step. While methods to initiate these cyclizations have been continuously expanded and improved over the years, the majority of polyene substrates are still limited to simple alkyl‐substituted alkenes. In this study, we took advantage of the unique reactivity of higher‐functionalized bifunctional alkenes. The realization of a polyene tetracyclization of a dual nucleophilic aryl enol ether involving a transannular endo‐termination step enabled the total synthesis of the tricyclic diterpenoid pimara‐15‐en‐3α‐8α‐diol. The highly flexible and modular route allowed for the preparation of a diverse library of cyclization precursors specifically designed for the total synthesis of the tetracyclic nor‐diterpenoid norflickinflimiod C. The tetracyclization of three diversely substituted allenes enabled access to complex pentacyclic products and provided a detailed insight into the underlying reaction pathways.

Indium(III)-Catalyzed Stereoselective Synthesis of Tricyclic Frameworks by Cascade Cycloisomerization Reactions of Aryl 1,5-Enynes.

The indium(III)-catalyzed cascade cycloisomerization reaction of 1,5-enynes with pendant aryl nucleophiles is reported. The reaction proceeds in cascade under mild reaction conditions, using InI3 (5 mol %) as a catalyst with a range of 1,5-enynes furnished with aryl groups (phenyl and phenol) at alkene (E and Z isomers) and with terminal and internal alkynes. Using 1-bromo-1,5-enynes, a one-pot sequential indium-catalyzed cycloisomerization and palladium-catalyzed cross-coupling with triorganoindium reagents were developed. The double cyclization is stereospecific and operates via a biomimetic cascade cation-olefin through 1,5-enyne cyclization (6-endo-dig) and subsequent C-C hydroarylation or C-O phenoxycyclization. Density functional theory (DFT) computational studies on 1,5-enynyl aryl ethers support a two-step mechanism where the first stereoselective 1,5-enyne cyclization produces a nonclassical carbocation intermediate that evolves to the tricyclic reaction product through a SEAr mechanism. Using this approach, a variety of tricyclic heterocycles such as benzo[b]chromenes, phenanthridines, xanthenes, and spiroheterocyclic compounds are efficiently synthesized with high atom economy.

Enantioselective α-Arylation of Primary Alcohols under Sequential One-Pot Catalysis

Secondary benzylic alcohols and diarylmethanols are common structural motifs of biologically active and medicinally relevant compounds. Here we report their enantioselective synthesis by α-arylation of primary aliphatic and benzylic alcohols under sequential catalysis integrating a Ru-catalyzed hydrogen transfer oxidation and a Ru-catalyzed nucleophilic addition. The method can be applied to various alcohols and aryl nucleophiles tolerating a range of functional groups, including secondary alcohols, ketones, alkenes, esters, NH amides, tertiary amines, aryl halides, and heterocycles.

Transition-Metal-Free Coupling of Polyfluorinated Arenes and Functionalized, Masked Aryl Nucleophiles.

A chemoselective C(sp2)−C(sp2) coupling of sufficiently electron‐deficient fluorinated arenes and functionalized N‐aryl‐N’‐silyldiazenes as masked aryl nucleophiles is reported. The fluoride‐promoted transformation involves the in situ generation of the aryl nucleophile decorated with various sensitive functional groups followed by a stepwise nucleophilic aromatic substitution (SNAr). These reactions typically proceed at room temperature within minutes. This catalytic process allows for the functionalization of both coupling partners, furnishing highly fluorinated biaryls in good yields.

A general copper-catalyzed radical C(sp3)−C(sp2) cross-coupling to access 1,1-diarylalkanes under ambient conditions

Abstract A general copper-catalyzed C(sp3)−C(sp2) cross-coupling of (hetero)benzyl bromides with the air- and moisture-stable aryl nucleophiles has been developed, providing a facile access to pharmaceutically useful 1,1-di(hetero)arylalkane and 1-aryl-1-heteroarylalkane scaffolds. Critical to the success is the utilization of a proline-based N,N,P-ligand to enhance the reducing capability of copper, thus easily converting benzyl bromides to the corresponding radical species via a single-electron transfer process under ambient conditions. The reaction features a broad substrate scope, covering (hetero)arylboronate esters, oxadiazoles, and benzo[d]oxazoles, as well as primary and secondary (hetero)benzyl bromides with excellent functional group tolerance.

Homogeneous Catalyzed Aryl–Aryl Cross-Couplings in Flow

AbstractAryl–aryl cross-coupling reactions are important reactions for the production of various biaryl compounds. This short review covers the various aryl–aryl cross-coupling reactions carried out in flow, focusing on the metal species of the aryl nucleophiles used in the cross-coupling reactions.1 Introduction2 Suzuki–Miyaura Coupling (B)3 Migita–Kosugi–Stille Coupling (Sn)4 Negishi Coupling (Zn)5 Kumada–Tamao–Corriu Coupling (Mg)6 Murahashi Coupling (Li)7 Conclusion

Biaryl Construction Based on Nickel-Catalyzed C–O Bond Activation

AbstractNickel-catalyzed carbon–oxygen bond activation is one of the most powerful strategies for the direct construction of various biaryl compounds. Under nickel catalysis, efficiently produced and naturally abundant arenol-based electrophiles can be activated and coupled with different aryl nucleophiles, including nucleophiles containing magnesium, zinc, boron, etc., to produce biaryl structural units. This Account summarizes recent progress on biaryl synthesis via nickel-catalyzed C–O bond activation.1 Introduction2 Coupling of Arenols and Arenol Derivatives with Aryl Magnesium Reagents3 Coupling of Arenols and Arenol Derivatives with Aryl Zinc Reagents4 Coupling of Arenols and Arenol Derivatives with Aryl Boron Reagents5 Others6 Conclusion

Recent Advances in Enantioselective Direct C–H Addition to Carbonyls and Michael Acceptors

Abstract Enantioselective C-H addition is one of the most straightforward and efficient approaches towards the synthesis of optically active molecules from readily available arenes. The most significant feature of these reactions is that the nucleophilic aryl metal species is generated catalytically in situvia C–H bond activation. These reactions typically proceed without requirement of either strongly basic or acidic conditions, thus with good functional group compatibility. In this review, recent progress on transition-metal-catalyzed enantioselective direct C-H addition to polar unsaturated bonds is summarized. The intramolecular C-H additions to carbonyls enabled by Ir(I) or Rh(III) catalyst provided an access to chiral alcohol scaffolds with high efficiency. Planar chiral 1,2-substituted ferrocenes were afforded by C-H addition of ferrocenes to acrylates by an Ir/chiral diene catalyst. In addition, the asymmetric hydroarylation reactions of Michael acceptors including acrylates, α, β-unsaturated esters and nitroolefins were also described. Moreover, the enantioselective conjugate additions of aromatic and benzylic C-H bonds to α, β-unsaturated ketones catalyzed by Cp*M(III)/chiral acid hybrid catalyst (M = Rh, Co) were presented. These enantioselective C-H additions provided a straightforward access to structurally diverse and valuable chiral fragments. Meanwhile, the reaction mechanisms are also introduced.

Hydroarylation of N‐Allenyl Derivatives Catalyzed by Copper**

An additive‐free copper catalytic system was used to perform the addition of (hetero)aryl nucleophiles to N‐allenyl derivatives. This intermolecular C–C bond formation occurs with both complete regio‐ and stereoselectivity to afford the linear (E) allylic product with moderate to excellent yields. This atom economical method is the first example of hydroarylation of allenes catalyzed by copper.

Diboron-Based Delayed Fluorescent Emitters with Orange-to-Red Emission and Superior Organic Light-Emitting Diode Efficiency.

For the application of organic light-emitting diodes (OLEDs) in lighting and panels, the basic requirement is to include a full spectrum color range. Compared with the development of blue and green luminophores in thermally activated delayed fluorescence (TADF) technology, the progress of orange-to-red materials is slow and needs further investigation. In this study, three diboron compound-based materials, dPhADBA, dmAcDBA, and SpAcDBA, were designed and synthesized by nucleophilic arylation of three amine donors on 9,10-diboraanthracene (DBA) in a two-step reaction. With increasing electron-donating ability, they show orange-to-red emission with TADF characteristics. The electroluminescence of these diboron compounds exhibits emissions λmax at 613, 583, and 567 nm for dPhADBA, dmAcDBA, and SpAcDBA, respectively. It is noteworthy that the rod-like D-A-D structures can achieve high horizontal ratios (84-86%) and outstanding device performance for orange-to-red TADF OLEDs: the highest external quantum efficiencies for dPhADBA, dmAcDBA, and SpAcDBA are 11.1 ± 0.5, 24.9 ± 0.5, and 30.0 ± 0.8%, respectively. Therefore, these diboron-based molecules offer a promising avenue for the design of orange-to-red TADF emitters and the development of highly efficient orange-to-red OLEDs.

A Transannular Polyene Tetracyclization for Rapid Construction of the Pimarane Framework.

Polyene cyclizations are one of the most powerful and fascinating chemical transformations to rapidly generate molecular complexity. However, cyclizations employing heteroatom‐substituted polyenes are rare. Described here is the tetracyclization of a dual nucleophilic aryl enol ether involving an unprecedented transannular endo‐termination step. In this transformation, five stereocenters, two of which are quaternary, four carbon–carbon bonds, and four six‐membered rings are formed from a readily available cyclization precursor. The realization of this cyclization enabled short synthetic access to the tricyclic diterpenoid pimara‐15‐en‐3α‐8α‐diol.

Silylation of Aryl Chlorides by Bimetallic Catalysis of Palladium and Gold on Alloy Nanoparticles

AbstractSupported palladium‐gold alloy‐catalyzed cross‐coupling of aryl chlorides and hydrosilanes enabled the selective formation of aryl‐silicon bonds. Whereas a monometallic palladium catalyst predominantly promoted the hydrodechlorination of aryl chlorides and gold nanoparticles showed no catalytic activity, gold‐rich palladium‐gold alloy nanoparticles efficiently catalyzed the title reaction to give arylsilanes with high selectivity. A wide array of aryl chlorides and hydrosilanes participated in the heterogeneously‐catalyzed reaction to furnish the corresponding arylsilanes in 34–80% yields. A detailed mechanistic investigation revealed that palladium and gold atoms on the surface of alloy nanoparticles independently functioned as active sites for the formation of aryl nucleophiles and silyl electrophiles, respectively, which indicates that palladium and gold atoms on alloy nanoparticles work together to enable the selective formation of aryl‐silicon bonds.magnified image

Autocatalytic Carbonyl Arylation through In Situ Release of Aryl Nucleophiles from N-Aryl-N'-Silyldiazenes.

A method for the catalytic generation of functionalized aryl alkali metals is reported. These highly reactive intermediates are liberated from silyl‐protected aryl‐substituted diazenes by the action of Lewis basic alkali metal silanolates, resulting in desilylation and loss of N2. Catalytic quantities of these Lewis bases initiate the transfer of the aryl nucleophile from the diazene to carbonyl and carboxyl compounds with superb functional‐group tolerance. The aryl alkali metal can be decorated with electrophilic substituents such as methoxycarbonyl or cyano as well as halogen groups. The synthesis of a previously unknown cyclophane‐like [4]arene macrocycle from a 1,3‐bisdiazene combined with a 1,4‐dialdehyde underlines the potential of the approach.

Evolution of Ate‐Organoiron(II) Species towards Lower Oxidation States: Role of the Steric and Electronic Factors

Ate-iron(II) species such as [Ar3 FeII ]- (Ar=aryl) are key intermediates in Fe-catalyzed couplings between aryl nucleophiles and organic electrophiles. They can be active species in the catalytic cycle, or lead to Fe0 and FeI oxidation states, which can themselves be catalytically active or lead to unwished organic byproducts. Analysis of the reactivity of the intermediates obtained by step-by-step displacement of the mesityl groups in high-spin [Mes3 FeII ]- by less hindered phenyl ligands was performed, and uncovered the crucial role of both steric and electronic parameters in the formation of the Fe0 and FeI oxidation states. The formation of quaternized [Ar4 FeII MgBr(THF)]- intermediates allows the bielectronic reductive elimination energy required for the formation of Fe0 to be reduced. Similarly, the small steric pressure of the aryl groups in [Ar3 FeII ]- enables the formation of aryl-bridged [{FeII (Ar)2 }2 (μ-Ar)2 ]2- species, which afford the FeI oxidation state by bimetallic reductive elimination. These results are supported by 1 H NMR, EPR, and 57 Fe Mössbauer spectroscopies, as well as by DFT calculations.

Scandium(III) Triflate as a Lewis Acid Catalyst of Oxime Ligation

Imine-forming reactions are widely applicable in bioconjugation owing to their high chemoselectivity. The ligation of a ketone or aldehyde with an aminooxy functional group to form a physiologically stable oxime bond is often used to link complex and precious biomolecules. Although the reaction proceeds modestly in acidic solution, the abundance of protonated carbonyl species at pH 7 limits its utility in many biological applications. The use of nucleophilic aryl amines, such as aniline or a phenylenediamine, allows a high population of protonated Schiff base to undergo transimination to the oxime product. Although this method affords significant enhancements at low pH, reactions can still be sluggish at neutral pH, especially with ketones such as acetophenone that are commonly used in bioconjugation. Here, we employ scandium(iii) trifluromethanesulfonate (triflate) (Sc(OTf)3), a uniquely water-stable Lewis acid, as a co-catalyst with ortho-phenylenediamine in the oxime ligation to yield up to an order of magnitude rate enhancement over the catalysts when applied individually.

Nucleophilic Arylation of Halopurines Facilitated by Brønsted Acid in Fluoroalcohol.

Various aryl-substituted purine derivatives were synthesized through the direct arylation of halopurines with aromatic compounds, facilitated by the combination of triflic acid and fluoroalcohol. This metal-free method is complementary to conventional coupling reactions using metal catalysts and reagents for the syntheses of aryl-substituted purine analogues.

Palladium-catalysed C−H glycosylation for synthesis of C-aryl glycosides

C-aryl glycosides are widely found in nature and play important roles in drug design. Despite the significant progress made over the past few decades, efficient and stereoselective synthesis of complex C-aryl glycosides remains challenging, lagging far behind the state of the art of the synthesis of O- or N-glycosides. Here, we report a simple and powerful bioinspired strategy for the stereoselective synthesis of C-aryl glycosides via palladium-catalysed ortho-directed C(sp2)−H functionalization of arenes and heteroarenes with easily accessible glycosyl chloride donors. The catalytic palladacycle intermediate generated via C−H palladation provides a soft aryl nucleophile that can react with glycosyl oxocarbenium ion partners with high efficiency and excellent stereocontrol. The method can be applied to a wide range of arene and heteroarene substrates, glycosyl chloride donors and auxiliary groups. It can simplify the synthesis of a variety of complex C-aryl glycosides and offers a tool for late-stage modification of drug molecules. C-aryl glycosides are present in many natural products and of interest in drug design, but their chemical synthesis is challenging. This work reports an efficient and diastereoselective ortho-directed C−H glycosylation of arenes and heteroarenes with glycosyl chloride using a palladium catalyst.