Aryl Halides Research Articles

Electrochemical Nickel‐Catalyzed Hydrogenation

AbstractOlefin hydrogenation is one of the most important transformations in organic synthesis. Electrochemical transition metal‐catalyzed hydrogenation is an attractive approach to replace the dangerous hydrogen gas with electrons and protons. However, this reaction poses major challenges due to rapid hydrogen evolution reaction (HER) of metal‐hydride species that outcompetes alkene hydrogenation step, and facile deposition of the metal catalyst at the electrode that stalls reaction. Here we report an economical and efficient strategy to achieve high selectivity for hydrogenation reactivity over the well‐established HER. Using an inexpensive and bench‐stable nickel salt as the catalyst, this mild reaction features outstanding substrate generality and functional group compatibility, and distinct chemoselectivity. In addition, hydrodebromination of alkyl and aryl bromides could be realized using the same reaction system with a different ligand, and high chemoselectivity between hydrogenation and hydrodebromination could be achieved through ligand selection. The practicability of our method has been demonstrated by the success of large‐scale synthesis using catalytic amount of electrolyte and a minimal amount of solvent. Cyclic voltammetry and kinetic studies were performed, which support a NiII/0 catalytic cycle and the pre‐coordination of the substrate to the nickel center.

Electrochemical Nickel-Catalyzed Hydrogenation.

Olefin hydrogenation is one of the most important transformations in organic synthesis. Electrochemical transition metal-catalyzed hydrogenation is an attractive approach to replace the dangerous hydrogen gas with electrons and protons. However, this reaction poses major challenges due to rapid hydrogen evolution reaction (HER) of metal-hydride species that outcompetes alkene hydrogenation step, and facile deposition of the metal catalyst at the electrode that stalls reaction. Here we report an economical and efficient strategy to achieve high selectivity for hydrogenation reactivity over the well-established HER. Using an inexpensive and bench-stable nickel salt as the catalyst, this mild reaction features outstanding substrate generality and functional group compatibility, and distinct chemoselectivity. In addition, hydrodebromination of alkyl and aryl bromides could be realized using the same reaction system with a different ligand, and high chemoselectivity between hydrogenation and hydrodebromination could be achieved through ligand selection. The practicability of our method has been demonstrated by the success of large-scale synthesis using catalytic amount of electrolyte and a minimal amount of solvent. Cyclic voltammetry and kinetic studies were performed, which support a NiII/0 catalytic cycle and the pre-coordination of the substrate to the nickel center.

Ligand‐Free Copper(0)‐Catalyzed C−S Ullmann‐Type Cross‐Coupling Reaction: S‐Arylation of 5,4‐Disubstituted 2,4‐Dihydro‐3H‐1,2,4‐triazole‐3‐thiones

AbstractWe investigated the S‐arylation of 5,4‐disubstituted 2,4‐dihydro‐3H‐1,2,4‐triazole‐3‐thiones under ligand‐free Cu(0) catalysis employing Ullmann‐type reaction conditions. We determined optimal reaction conditions and assessed the impact of substituents in the arylating agent on the reaction progress. Notably, the presence of an electron‐withdrawing group (EWG) in the aryl halide facilitated the reaction even without a catalyst. In particular, an EWG in the para position of the aromatic ring exerted a directing effect on the leaving group, regardless of the halogen present.

Direct Ortho C–H Arylation of Benzamides/Benzoic Acids with Aryl Iodide Catalyzed by a Pyridine-2-carboimine Pd Complex Immobilized on Amine-Functionalized Magnetic Nanoparticles

Direct Ortho C–H Arylation of Benzamides/Benzoic Acids with Aryl Iodide Catalyzed by a Pyridine-2-carboimine Pd Complex Immobilized on Amine-Functionalized Magnetic Nanoparticles

Remote Boryl and Alkenyl Radical Migration of Olefin-Bearing Aryl Bromides

Remote Boryl and Alkenyl Radical Migration of Olefin-Bearing Aryl Bromides

Electronic Effects in a Green Protocol for (Hetero)Aryl-S Coupling.

Aryl and heteroaryl iodides have been efficiently converted into the corresponding thioacetates in cyclopentyl methyl ether (CPME), a green solvent, under Cu catalysis. The chemoselectivity of the reaction is mainly controlled by electronic factors, enabling the conversion of both electron-rich and electron-deficient substrates into the corresponding thioacetates in good to excellent yields. The products can be easily deprotected to the corresponding thiolates to carry out additional synthetic transformations in situ. Surprisingly, despite CPME's relatively low dielectric constant, the reaction rate significantly increased when conducted under microwave irradiation conditions. This synthetic methodology exhibits a remarkable tolerance to functional groups, mild reaction conditions, and a wide substrate scope, utilizing a safe and inexpensive CuI pre-catalyst in the green solvent CPME. A non-aqueous workup allowing for the complete recovery of both catalyst and solvent makes this approach an environmentally sustainable protocol for C(sp2) sulfur functionalization. Additionally, the reaction shows selective cross-coupling with iodides in competition with chlorides and bromides, allowing its use in multistep syntheses. To demonstrate the potential of this methodology, it was applied to the high-yield synthesis of a photochromic dithienylethene, where a selective synthesis had not been reported before.

Silver Surface-Assisted Dehydrobrominative Cross-Coupling between Identical Aryl Bromides.

Cross-coupling reactions represent an indispensable tool in chemical synthesis. An intriguing challenge in this field is to achieve selective cross-coupling between two precursors with similar reactivity or, to the limit, the identical molecules. Here we report an unexpected dehydrobrominative cross-coupling between 1,3,5-tris(2-bromophenyl)benzene molecules on silver surfaces. Using scanning tunneling microscopy, we examine the reaction process at the single-molecular level, quantify the selectivity of the dehydrobrominative cross-coupling, and reveal the modulation of selectivity by substrate lattice-related catalytic activity or molecular assembly effect. Theoretical calculations indicate that the dehydrobrominative cross-coupling proceeds via regioselective C-H bond activation of debrominated TBPB and subsequent highly selective C-C coupling of the radical-based intermediates. The reaction kinetics plays an important role in the selectivity for the cross-coupling. This work not only expands the toolbox for chemical synthesis but also provides important mechanistic insights into the selectivity of coupling reactions on the surface.

Universal inter-molecular radical transfer reactions on metal surfaces.

On-surface synthesis provides tools to prepare low-dimensional supramolecular structures. Traditionally, reactive radicals are a class of single-electron species, serving as exceptional electron-withdrawing groups. On metal surfaces, however, such species are affected by conduction band screening effects that may even quench their unpaired electron characteristics. As a result, radicals are expected to be less active, and reactions catalyzed by surface-stabilized radicals are rarely reported. Herein, we describe a class of inter-molecular radical transfer reactions on metal surfaces. With the assistance of aryl halide precursors, the coupling of terminal alkynes is steered from non-dehydrogenated to dehydrogenated products, resulting in alkynyl-Ag-alkynyl bonds. Dehalogenated molecules are fully passivated by detached hydrogen atoms. The reaction mechanism is unraveled by various surface-sensitive technologies and density functional theory calculations. Moreover, we reveal the universality of this mechanism on metal surfaces. Our studies enrich the on-surface synthesis toolbox and develop a pathway for producing low-dimensional organic materials.

Scalable Synthesis of Cinnamylamines Via the Heck Reaction: Application in the Synthesis of Abamine, Naftifine and Reboxetine

AbstractFollowing an extensive screening of reaction parameters such as the nature and amount of bases, Pd pre‐catalysts, ligands, additives, solvents and temperature range, we succeeded in developing a Heck reaction using N‐Boc‐allylamine and commercially available aryl bromides, capable of delivering a wide range of Boc‐protected trans‐cinnamylamines with 75–85 % regio‐ and stereoselectivity over other isomers. Optimisation of the Boc‐deprotection step and its work‐up procedure allowed for all minor isomers and impurities to be purged thus isolating pure trans‐cinnamylamines typically in 55–65 % yield without need for chromatography. We have successfully performed this chemistry in up to 5 g scale and demonstrated its usefulness by applying it to the synthesis of abamine, naftifine hydrochloride and a formal synthesis reboxetine mesylate.

Arenethiolate-Catalyzed 1,5-HAT of Aryl Halides: Synthesis of γ-Spirolactams.

γ-Spirolactam is a privileged building block that is found in a wide range of natural products and bioactive compounds. Herein, we report an arenethiolate-catalyzed 1,5-HAT of aryl halides to obtain γ-spirolactams through a SET reduction/intramolecular 1,5-HAT/cyclization/HAT process. This protocol features metal-free conditions and a broad substrate scope, furnishing the γ-spirolactams in moderate to excellent yields. Notably, aryl bromides, aryl chlorides and even aryl fluorides are well tolerated in this transformation. A mechanism involving arenethiolate as a SET catalyst is proposed based on DFT calculation.

Catalytic 2-Ethylhexanoic Acid Promotes Mild Miyaura Borylations.

The Miyaura borylation of aryl and heteroaryl chlorides and bromides using a combination of potassium carbonate and 5 mol % 2-ethylhexanoic acid at 25 °C is reported. The in situ generation of a catalytic amount of potassium 2-ethylhexanoate under these conditions avoids the need for special handling of stoichiometric quantities of hygroscopic potassium 2-ethylhexanoate during the reaction setup as well as difficulties in removing the resulting carboxylic acid during product isolation.

Iron-Catalyzed C-H Oxygenation Using Perchlorate Enabled by Secondary Sphere Hydrogen Bonds.

Perchlorate (ClO4-) is a groundwater pollutant that is challenging to remediate. We report a strategy to use Fe(II) tris(2-pyridylmethyl)amine (TPA) complexes featuring appended aniline hydrogen bonds (H-bonds) to promote ClO4- reduction. These complexes facilitate oxygen atom transfer from ClO4- to PPh3 and C-H oxygenation reactions of organic substrates. Catalytic reactions using 15 mol % afforded excellent yields for oxygenation of anthracene and cyclic alkyl aromatics, and this methodology tolerates aryl halides as well as heterocycles containing either O, S, or N.

C(5)—H arylation of 1-substituted 1,2,4-triazoles with aryl halides under Pd/NHC catalysis

C(5)—H arylation of 1-substituted 1,2,4-triazoles with aryl halides under Pd/NHC catalysis

Efficient heck and Suzuki-Miyaura cross-coupling reactions catalyzed by heterogeneous Pd NPs-decorated porous MOF catalysts under mild conditions

Carbon-carbon coupling reactions are extremely interesting for a variety of applications, including pharmaceuticals and biologically active compounds. In this study, we investigated the utilization of functionalized MIL-101 porous MOF for stabilizing palladium nanoparticles (NPs) and examined their catalytic performance in the cross-coupling reaction of aryl halides with phenylboronic acid and methyl acrylate under mild conditions. To achieve this, MIL-101(Al) was synthesized using a solvothermal method, followed by functionalization with environmentally friendly l-Cysteine (CYS). Subsequently, the MIL-101(Al)-CYS compound was immersed in an ethanolic solution of palladium and stirred overnight. The catalyst exhibited remarkable efficiency (over 90 %) in Suzuki and Heck cross-coupling reactions, demonstrating excellent activity and recyclability. The reactions were conducted in polyethylene glycol 200 (PEG 200), a green reaction medium, at temperatures of 70 °C and 60 °C, with Pd loadings of 0.22 and 0.08 mol%, respectively. MOF-based catalysts, owing to their highly tunable structures and porosity, hold great promise as heterogeneous catalysts in organic reactions.

Enantioselective domino alkyl arylation of vinyl phosphonates by combining photoredox and nickel catalysis

A nickel/photoredox mediated asymmetric domino alkyl arylation of vinyl phosphonates to generate a diverse array of enantioenriched α-aryl phosphonates is disclosed. This asymmetric three-component difunctionalization couples aryl halides and alkyl bromides with vinyl phosphonates, exhibiting excellent chemo- and regioselectivity under mild reaction conditions. The method avoids the need for pre-formed organometallics and phosphorus halides. Mechanistic and DFT studies suggest that photoexcited [4CzIPN]* oxidizes diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (HEH) to generate the [4CzIPN]•–, which then reduces the alkyl bromide to form alkyl radicals that undergo Giese addition to the vinyl phosphonate. At the same time, Ni0 oxidatively adds the aryl bromide followed by enantiodetermining oxidative radical trapping of the phosphonate-based radical by the tetrahedral NiII center followed by reductive elimination. Independent gradient model based on Hirshfeld partition (IGMH) analysis suggests that the orientation of the phosphonate group (P=O…π interaction) is expected to play an essential role in controlling the enantioselectivity.

Gold-Catalyzed C(sp3)-C(sp2) Suzuki-Miyaura Coupling Reaction.

A gold-catalyzed C(sp3)-C(sp2) Suzuki-Miyaura coupling reaction facilitated by ligand-enabled Au(I)/Au(III) redox catalysis was developed. The cross-coupling of alkyl organometallics was first realized in the redox catalytic cycle in gold chemistry, without the use of external oxidants. This gold-catalyzed C(sp3)-C(sp2) coupling reaction allows a variety of alkyl chain and useful methyl trifluoroborates to react with aryl and vinyl iodides under very mild conditions, which provides a new reactivity pattern for challenging couplings with alkyl organometallics.

Solid-state nickel(0)-mediated Yamamoto coupling enabled by mechanochemistry

Abstract Herein, we report the first solid-state protocol for nickel(0)-mediated Yamamoto-coupling reactions using ball milling. A variety of aryl halides reacted efficiently in the presence of bis(cyclooctadiene)nickel(0) [Ni(cod)2] and 4,4'-di-tert-butyl-2,2'-bipyridyl under solid-state mechanochemical conditions, affording the corresponding biaryls in high yields. Considering that potentially harmful and high-boiling organic solvents are not required, the present study provides a more convenient, environmentally friendly, and sustainable alternative to conventional solution-based Yamamoto coupling. Solid-state Yamamoto-coupling polymerization and the development of a catalytic variant are also described.

Ni-catalyzed enantioconvergent deoxygenative reductive cross-coupling of unactivated alkyl alcohols and aryl bromides

Transition metal-catalyzed enantioconvergent cross-coupling of an alkyl precursor presents a promising method for producing enantioenriched C(sp3) molecules. Because alkyl alcohol is a ubiquitous and abundant family of feedstock in nature, the direct reductive coupling of alkyl alcohol and aryl halide enables efficient access to valuable compounds. Although several strategies have been developed to overcome the high bond dissociation energy of the C − O bond, the asymmetric pattern remains unknown. In this report, we describe the realization of an enantioconvergent deoxygenative reductive cross-coupling of unactivated alkyl alcohol (β-hydroxy ketone) and aryl bromide in the presence of an NHC activating agent. The approach can accommodate substituents of various sizes and functional groups, and its synthetic potency is demonstrated through a gram scale reaction and derivatizations into other compound families. Finally, we apply our convergent method to the efficient asymmetric synthesis of four β-aryl ketones that are natural products or bioactive compounds.

Non-Directed C-H Arylation of Anisole Derivatives via Pd/S,O-Ligand Catalysis.

Non-directed C-H arylation is one of the most efficient methods to synthesize biaryl compounds without the need of the prefuctionalization of starting materials, or the installment and removal of directing groups on the substrate. A direct C-H arylation of simple arenes as limiting reactants remains a challenge. Here we disclose a non-directed C-H arylation of anisole derivatives as limiting reagents with aryl iodides under mild reaction conditions. The arylated products are obtained in synthetically useful yields and the arylation of bioactive molecules is also demonstrated. Key to the success of this methodology is the use of a one-step synthesized S,O-ligand.

Room-Temperature Copper-Catalyzed Etherification of Aryl Bromides.

We disclose the development of a Cu-catalyzed C-O coupling method utilizing a new N1,N2-diarylbenzene-1,2-diamine ligand, L8. Under optimized reaction conditions, structurally diverse aryl and heteroaryl bromides underwent efficient coupling with a variety of alcohols at room temperature using an L8-based catalyst. Notably, the L8-derived catalyst exhibited enhanced activity when compared to the L4-based system previously disclosed for C-N coupling, namely the ability to functionalize aryl bromides containing acidic functional groups. Mechanistic studies demonstrate that C-O coupling utilizing L8 ⋅ Cu involves rate-limiting alkoxide transmetallation, resulting in a mechanism of C-O bond formation that is distinct from previously described Pd-, Cu-, or Ni-based systems. This lower energy pathway leads to rapid C-O bond formation; a 7-fold increase relative to what is seen with other ligands. The results presented in this report overcome limitations in previously described C-O coupling methods and introduce a new ligand that we anticipate may be useful in other Cu-catalyzed C-heteroatom bond-forming reactions.