Aryl Halides Research Articles

N-heterocyclic carbene switchable radical or benzyne meditated arylation of thiols using DMF/KOtBu

A mild, metal and photoredox-free direct arylation of alkyl and aryl thiols with aryl iodides using a DMF/KOtBu system has been developed. In the absence of an N-heterocyclic carbene (NHC) additive, the reaction proceeds via a benzyne intermediate and was suitable for the substitution of thiols with phenyl, while the presence of an NHC or phenanthroline derivative improves regioselectivity for the reaction of substituted aryl iodides via a radical pathway. This protocol features inexpensive materials and good substrate scope, and could be useful in the arylation of aryl and alkyl thiols.

Ru(II)‐Catalyzed Ortho C−H Arylation of Heterocyclic Biaryls

Ru(II)‐Pheox complexes are known catalysts for carbene insertion reactions. Herein we teach them a new trick: how to perform ortho C−H arylation processes! Our operationally simple protocol tolerates structurally diverse directing groups and both aryl iodides and diaryliodonium salts as group transfers.

Poly(arylene ether)s via Cu(II)-Catalysis.

Poly(arylene ether)s (PAEs) are a versatile class of thermoplastic materials with commercial importance. Currently their synthesis relies predominantly on either nucleophilic or electrophilic aromatic substitution reactions, severely limiting the scope of available PAEs. Herein, we report the copper(II)-catalyzed polycondensation of electronically unactivated aryl bromides with bisphenols to afford a wide range of new PAEs. These PAEs are characterized by their thermal and mechanical properties. Functional PAEs were produced that have reversible acid- and redox-triggered chromophores incorporated into the backbone, which illustrates the utility of these methods.

Cross‐Electrophile Couplings (XECs) between Similar Electrophile Reagents

Comprehensive SummaryCross‐electrophile couplings (XEC), a crucial subset of cross‐coupling reactions, center on the formation of robust C—C bonds through the union of two electrophiles. Usually, such reactions have primarily been catalyzed by transition metals. However, with the steady advancements in photochemical and electrochemical technologies, XEC reactions have significantly progressed and broadened their scope, allowing for the utilization of a wider array of tolerable functional groups, thus revealing vast application prospects. This review aims to systematically summarize the current prevalent types of electrophiles and delve into their specific application examples within XEC reactions involving electrophiles with identical functional groups. Specifically, XECs between the same type of halides have received considerable attention, whereas carboxylic acids and alcohols are still in the early stages of investigation. Furthermore, certain other common electrophiles remain unexplored in this context. Moreover, this review underscores the remarkable contributions of photochemistry and electrochemistry in the field of XEC reactions, aiming to provide valuable insights and inspiration for researchers. Also, this review hopes to spark further interest in XEC reactions, thereby fueling the continuous development and advancement of this exciting area of research. Key ScientistsSince the 1960s, advancements in the XEC reaction have been substantial, driven primarily by the application of transition metal catalysts. In this area, many distinguished scientists have contributed their wisdom and efforts. Particularly noteworthy is that, during the systematic study of XEC reactions with the identical functional groups, in 2016, MacMillan achieved a photocatalytic XEC reaction between aryl bromides and alkyl bromides; in 2020, Weix successfully realized a nickel‐catalyzed XEC reaction between aryl chlorides and alkyl chlorides. Concurrently, contributions from researchers such as Mei, Wolf, Sevov, Lin, Shen, Browne, Zhang, and Qiu have expanded the scope of XEC reactions to various halides. By 2022, MacMillan and Baran achieved a significant milestone in the XEC between carboxylic acids, further broadening the scope of research in this area. Also, advancements in the XEC of alcohols have been noted, with researchers including Weix, Lian, Tu, and Stahl conducting pioneering work and successfully executing the XEC of protective groups. It is foreseen that the ongoing research endeavors will primarily concentrate on the expansion of diverse electrophiles.

Safe Utilization of In Situ Generated HCN Gas from Oxyma and DIC: One‐Pot Conversion of Aryl Bromide to Aryl Nitrile in the Presence of Pd Catalyst

AbstractHerein, we have first time attempted to use of in situ generated HCN gas from oxyma (ethyl cyano(hydroxyimino) acetate) and DIC (diisopropylcarbodiimide) in the synthesis of aryl/heteroaryl nitriles from aryl/heteroaryl bromides. This protocol is safe to handle, efficient, and environmentally friendly. Subsequently, this established protocol was used for the conversion of a wide range of substrates into corresponding benzonitriles in moderate to high yields (35%–85%).

Functional Hexafluoroisopropyl Group Used in the Construction of Biologically Important Pyrimidine Derivatives.

A series of versatile 4-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)pyridine intermediates have been developed to efficiently produce biaryls, amines, ethers, and thioethers. These hydrolysis-stable ether intermediates exhibit reactivity toward electron-donating groups and nucleophiles in cross-coupling and nucleophilic substitution reactions while surpassing the stability of corresponding aryl halides. In comparison to conventional coupling methods, this protocol offers an alternative pathway for accessing natural product and drug-like compounds without the need for metal catalysts. With assistance of this approach, we successfully obtained a potent P-glycoprotein inhibitor 4k (YS-370), a potent epidermal growth factor receptor inhibitor 4l (YS-363), and a promising lysine-specific demethylase 1 inhibitor 5g.

Enantioselective Synthesis of Benzylic Boronic Esters via Photoredox/Nickel-Catalyzed Multicomponent Cross-Couplings.

As a class of versatile building blocks, chiral benzylic boronic esters are important intermediates employed in modern organic chemistry. We describe herein the first stereoconvergent multicomponent cross-coupling reaction of vinyl boronates, alkyltrifluoroborates, and aryl halides through a dual photoredox/nickel catalysis methodology. This synergistic platform permitted the benign construction of various enantioenriched benzylic boronic esters with broad substrate tolerance and moderate to excellent enantioselectivity (up to 98:2 er) from commercially available starting materials. Moreover, experimental and computational studies shed light on the nickel catalytic transformation and the origin of the enantioselectivity.

Copper Catalysts Anchored on Cysteine-Functionalized Polydopamine-Coated Magnetite Particles: A Versatile Platform for Enhanced Coupling Reactions.

Cysteine plays a crucial role in the development of an efficient copper-catalyst system, where its thiol group serves as a strong anchoring site for metal coordination. By immobilizing copper onto cysteine-modified, polydopamine-coated magnetite particles, this advanced catalytic platform exhibits exceptional stability and catalytic activity. Chemical modification of the polydopamine (PDA) surface with cysteine enhances copper salt immobilization, leading to the formation of the Fe3O4@PDA-Cys@Cu platform. This system was evaluated in palladium-free, copper-catalyzed Sonogashira coupling reactions, effectively catalyzing the coupling of terminal acetylenes with aryl halides. Additionally, the Fe3O4@PDA-Cys@Cu platform was employed in click reactions, confirming the enhanced catalytic efficiency due to increased copper content. The reusability of the platform was further investigated, demonstrating improved performance, especially in recyclability tests in click reaction, making it a promising candidate for sustainable heterogeneous catalysis.

Remote Migratory Reductive Arylation of Unactivated Alkenes Enabled by Electrochemical Nickel Catalysis.

Transition metal-catalyzed cross-coupling reaction between organometallic reagents and electrophiles is a potent method for constructing C(sp2)-C(sp3) bonds. Given the characters of organometallic reagents, cross-reductive coupling is emerging as an alternative strategy. The resurgence of electrochemistry offers an ideal method for electrochemical reductive of cross-coupling electrophiles. Inspired by the mechanism of electrochemical metal hydride, our study proposed that Ni-H electrochemically catalyze the hydroarylation coupling of unactivated alkenes with aryl halides. 1,1-Diarylalkanes can be produced effectively. This method have advantages including mild conditions, excellent regioselectivity, and satisfactory yields.

Reductive C(sp2)–Si Cross‐Couplings by Catalytic Sodium‐Bromine Exchange

The metal‐halogen exchange reaction constitutes one of the most important preparative routes towards polar organometallic reagents such as aryllithium or Grignard reagents. However, despite extensive developments over the past eight decades, this fundamental organometallic elementary step has only been exploited stoichiometrically. Against this background, we demonstrate that the sodium‐bromine exchange reaction can be implemented in a catalytic setting as a mean to activate C(sp2)–Br bonds in a transition metal‐free manner en route to the regioselective and general preparation of (hetero)aryl silanes. Simply treating structurally diverse (hetero)aryl bromides with N‐tert‐butyl‐N’‐silyldiazenes (tBu–N=N–Si) as silylating reagents and inexpensive sodium alkoxides as catalytic promoters yields a range of aromatic organosilicon compounds under ambient conditions. Mechanistic studies provide solid evidence for the involvement of tert‐butyl sodium as the C(sp2)–Br metalating agent.

Reductive C(sp2)–Si Cross‐Couplings by Catalytic Sodium‐Bromine Exchange

The metal‐halogen exchange reaction constitutes one of the most important preparative routes towards polar organometallic reagents such as aryllithium or Grignard reagents. However, despite extensive developments over the past eight decades, this fundamental organometallic elementary step has only been exploited stoichiometrically. Against this background, we demonstrate that the sodium‐bromine exchange reaction can be implemented in a catalytic setting as a mean to activate C(sp2)–Br bonds in a transition metal‐free manner en route to the regioselective and general preparation of (hetero)aryl silanes. Simply treating structurally diverse (hetero)aryl bromides with N‐tert‐butyl‐N’‐silyldiazenes (tBu–N=N–Si) as silylating reagents and inexpensive sodium alkoxides as catalytic promoters yields a range of aromatic organosilicon compounds under ambient conditions. Mechanistic studies provide solid evidence for the involvement of tert‐butyl sodium as the C(sp2)–Br metalating agent.

Ligand-Free Iron-Catalyzed Carbonylation of Aryl Iodides with Alkenyl Boronic Acids: Access to α,β-Unsaturated Ketones.

The application of earth-abundant and low-toxicity iron catalysts as replacements for palladium in carbonylative coupling reactions remains challenging and largely unexplored. Reported here is a highly efficient iron-catalyzed carbonylation of aryl iodides with alkenyl boronic acids under ligand-free conditions, enabling the synthesis of α,β-unsaturated ketones even at atmospheric CO pressure. The broad applicability, including its effectiveness with α-branched enones and biologically active molecules, along with high yields and selectivity, underlines the general applicability of this catalytic system.

Arylthianthrenium Salts for Triplet Energy Transfer Catalysis.

Sigma bond cleavage through electronically excited states allows synthetically useful transformations with two radical species. Direct excitation of simple aryl halides to form both aryl and halogen radicals necessitates UV-C light, so undesired side reactions are often observed and specific equipment is required. Moreover, only aryl halides with extended π systems and comparatively low triplet energy are applicable to synthetically useful energy transfer catalysis. Here we show the conceptual advantages of arylthianthrenium salts (ArTTs) for energy transfer catalysis with high energy efficiency compared to conventional aryl (pseudo)halides and their utility in arylation reactions of ethylene. The fundamental advance is enabled by the low triplet energy of ArTTs that may originate in large part from the electronic interplay between the distinct sulfur atoms in the tricyclic thianthrene scaffold, which is not accessible in either simple (pseudo)halides or other conventional sulfonium salts.

Synthesis of [6,5,5]Ring‐Fused Tricyclic Triazoles by Copper‐Promoted Double Cyclization

AbstractRing‐fused 1,2,3‐triazoles are important biologically active compounds and synthetic intermediates. Known methods for their synthesis are limited mostly to triazoles fused to six‐membered or larger rings. Herein we disclose a synthetic approach to triazoles fused to five‐membered rings based on copper(I)‐promoted double cyclization consisting of azide‐alkyne cycloaddition, followed by cross coupling to aryl iodides.

Base-free aqueous Suzuki–Miyaura coupling reaction using recoverable bi-functional Pd supported nanocatalyst

A solid base catalyst comprising pyridine-palladium polyorganosiloxane framework was synthesized via a grafting method. The resulting organic–inorganic hybrid palladium nanomaterial was characterized by 13C CP-MAS NMR, 29Si CP-MAS NMR, XRD, EDX, TEM, TGA, and the BET measurements. The hybrid palladium nanomaterial exhibited high catalytic activity for the Suzuki–Miyaura cross-coupling reaction between aryl chlorides and phenylboronic acid under base-free and aerobic conditions. A maximum turnover number (TON) of 3150, with a 0.2 mol% Pd loading and a reaction temperature of 80 °C in aqueous solution. The catalyst demonstrated remarkable stability, maintaining its activity even after six cycles of reuse without significant loss of activity. TEM images showed that the catalyst retained its structure and high-order mesostructure after several uses. ICP-AES also confirmed the absence of palladium contamination in the final products. Leaching test studies further confirmed the true heterogeneous nature of the developed catalytic system.

Visible-Light-Induced α-Arylation of Ketones with (Hetero)aryl Halides.

An enamine-mediated photoredox catalyzed C(sp2)-C(sp3) cross-coupling of dual radical precursors for the arylation of ketone is presented in this Letter. These reactions led to the formation of an enamine by using pyrrolidine to functionalize the C(sp3)-H bond in ketone substrates, which could be smoothly converted to α-arylated ketones with inert aryl bromides and even aryl chlorides in moderate to good yields under mild reaction conditions. The photocatalytically induced C(sp2)-C(sp3) cross-coupling between unactivated noncyclic ketones and aryl halides was achieved, and multiple carbonyl α-arylated backbones containing various natural products and drug molecules were successfully constructed.

Halogenase-Assisted Alkyne/Aryl Bromide Sonogashira Coupling for Ribosomally Synthesized Peptides.

We describe the enzymatic bromination of ribosomally synthesized peptides and develop protocols for Sonogashira coupling of peptidic aryl bromides with a panel of alkynes. Using this workflow, entirely new chemical handles are introduced onto ribosomal peptides, including but not limited to terminal alkynes, which enable further diversification via alkyne-azide click chemistry. Regiospecific enzymatic installation of the aryl bromide circumvents genetic code expansion and passivation of other reactive handles on the peptide chain, representing the applicability of biocatalysts in peptide modification chemistry.

Activation and C-C Coupling of Aryl Iodides via Bismuth Photocatalysis.

Within the emerging field of bismuth redox catalysis, the catalytic formation of C-C bonds using aryl halides would be highly desirable; yet such a process remains a synthetic challenge. Herein, we present a chemoselective bismuth-photocatalyzed activation and subsequent coupling of (hetero)aryl iodides with pyrrole derivatives to access C(sp2)-C(sp2) linkages through C-H functionalization. This unique reactivity is the result of the bismuth complex featuring two redox state-dependent interactions with light, which 1) activates the Bi(I) complex for oxidative addition via MLCT, and 2) promotes the homolytic cleavage of aryl Bi(III) intermediates through a LLCT process.

Unraveling the Origin of Elemental Chemical Shift and the Role of Atomic Hydrogen in a Surface Ullmann Coupling System.

The Ullmann coupling of aryl halides is a powerful method in the on-surface synthesis of functional materials. Understanding its basic aspects and influencing factors can aid in the use of this tool for the fabrication of intriguing structures. In this study, we unveil (1) the origin of the shift in the elemental binding energy (BE) and (2) the functions of atomic hydrogen (AH) in a typical Ullmann coupling system using combined spectroscopy and microscopy techniques. During debromination of the aryl halide precursor, the work function (WF) alteration is correlated with the surface Br amount. The WF change instead of C-Ag formation is proposed to play a dominant role in the shift of the molecular C 1s BE. AH dosing onto organometallic chains leads to chain decomposition and surface Br removal. In contrast, AH dosing onto covalent poly(para-phenylene) (PPP) chains results in superhydrogenation in addition to Br removal. The C 1s BE shift is attributed to both WF change and superhydrogenation effects. Thermal annealing restores the PPP chains by eliminating superhydrogenation, which causes the C 1s BE to shift to a high BE. This study provides deep insights into the mechanisms of Ullmann coupling on surfaces, highlighting the significant role of WF alterations and AH treatments in these processes.

Palladium-Catalyzed α-Arylation of Cycloalkanones with Sterically Hindered Bromoazines under Neat Conditions

AbstractThe palladium-catalyzed cross-coupling of cycloalkanones with a range of heteroaryl bromides is described herein. The transformation proceeds best with third-generation tris-tBu-phosphine Pd pre-catalyst in neat cycloalkanones. Careful screening of the reaction conditions revealed K3PO4 as an effective weak and mild base thereby tolerating base-sensitive functional groups such as acetals or nitrogen protecting groups. Moderate to good yields were achieved for a series of 29 examples with various degrees of structural complexity. Importantly, these optimized conditions allow the α-(hetero)aryl cross-coupling of ortho-substituted (hetero)aryl bromide substrates with different cyclo­alkanones that typically failed to react efficiently under previously reported conditions.