Coupling Of Aryl Bromides Research Articles

Access to Functionalized Indenes via Palladium‐Catalyzed Homolytic Cleavage of a Furan C−O Bond

AbstractA photoinduced palladium‐catalyzed ring‐opening hydroarylation of furans to form functionalized indenes was achieved via an intramolecular reductive coupling of aryl bromide with furan using silane as the reductant. Deuterium tracking and DFT analysis revealed a reasonable reaction pathway involving: 1) the homolytic cleavage of the furan C−O bond induced by the α‐allyl radical; 2) a 1,6‐H atom transfer from carbon to oxygen.

A Nickel/Organoboron-Catalyzed Coupling of Aryl Bromides with Sodium Sulfinates: The Synthesis of Sulfones under Visible Light.

An efficient cross-coupling of aryl bromides with sodium sulfinates, using an organoboron photocatalyst with nickel, is described herein. Under the irradiation of white light, this dually catalytic system enables the synthesis of a series of sulfone compounds in moderate to good yields. A broad range of functional groups and heteroaromatic compounds is tolerated under these reaction conditions. The use of an organoboron photocatalyst highlights a sustainable alternative to iridium or ruthenium complexes. These findings contribute to the field of photochemistry and provide a greener approach to sulfone synthesis.

Nickel‐Catalyzed Sonogashira Couplings: Extending the Reaction Scope to Aryl Bromides and Chlorides

AbstractThe alkyne motif is present in several naturally occurring molecules and specialty chemicals. The Sonogashira reaction is recognized as one of the most exploited methods for the synthesis of substituted alkynes. While palladium catalysts have been traditionally employed, recent efforts have been directed towards developing alternatives based on Earth‐abundant metals such as nickel. However, nickel‐catalyzed Sonogashira couplings still present important substrate limitations. While more reactive aryl iodides have been well documented, the coupling of more challenging yet cost‐effective aryl bromides and chlorides lags significantly behind. Herein, we present a method for the nickel‐catalyzed Sonogashira coupling of aryl bromides and chlorides, whose discovery was accelerated thanks to high‐throughput experimentation. Fine‐tuning of the bipyridine ligand was essential to activate chemoselectively C(sp2)−Br or C(sp2)−Cl bonds. A wide range of functionally diverse alkynes, including examples of active ingredients and their intermediates, were accessed in a single step and with yields up to 98%. The developed methodology is expected to be widely adopted by academia and industry, marking a step forward in the field of base metal catalysis.

Ni/photoredox-catalyzed coupling of aryl bromides and methylenecyclopropanes via selective distal bond cleavage

A series of 1,1-dibenzylethylene derivatives were obtained in moderate-to-good yields via double coupling of aryl bromides and methylenecyclopropanes via Ni/photoredox catalysis. The critical roles of nickel in this reaction were disclosed.

Anthracene-based covalent organic framework supported palladium nanoparticles for visible-light-mediated Suzuki–Miyaura cross-coupling

Anthracene-based covalent organic framework (COF) anchoring Pd nanoparticles photocatalyzed Suzuki–Miyaura coupling of arylbromides and arylboronic acids in water under blue LED irradiation at room temperature.

Enhancing the Catalytic Activity of Pd Nanocrystals towards Suzuki Cross‐Coupling by g‐C3N4 Photosensitization

AbstractDeveloping renewable means of activating molecules over traditional catalysts for C−C bond formation is desirable for industrial applications. Herein, we report a strategy to improve the efficiency of Pd nanoparticles (NPs) for the Suzuki cross‐coupling reactions by visible‐light irradiation using g‐C3N4 nanosheets (NSs) as photosensitizer. Pd NPs mounted on g‐C3N4 become electron‐rich under visible‐light due to generation of excited electrons in g‐C3N4 and thereby accelerate the rate‐determining step. Remarkable photocatalytic activity was accomplished utilizing Pd/g‐C3N4 for the Suzuki cross‐coupling reaction in environmentally benign aqueous settings under room temperature conditions. The activity remarkably improves (~2.5 times) upon light irradiation, yielding one of the highest known turnover frequencies (TOF) of 1858 h−1 and confirming the photosensitizer role of g‐C3N4. The TOF for coupling of aryl bromides is also significantly high (~356 h−1). We establish that the low‐energy/long‐lived excitons preferencially transfer to Pd, paving a way for rational designing photocatalysts for various C−C coupling reactions.

Nickel/Photoredox-Catalyzed Decarboxylative Coupling of Aryl Bromides with N-Protected Glycine as an Aminomethyl Source

AbstractBenzylamines are important scaffolds that are ubiquitously found in various bioactive molecules. Among the benzylamine derivatives, primary benzylamines (ArCH2NH2) are regarded as valuable building blocks for pharmaceuticals. Herein, we report decarboxylative aminomethylation of aryl bromides with N-protected glycine under nickel/photoredox-catalyzed conditions. The corresponding products can be easily deprotected under acidic conditions to give primary benzylamines.

Enabling Deoxygenative C(sp2)-C(sp3) Cross-Coupling for Parallel Medicinal Chemistry.

Herein we report the development of an automated deoxygenative C(sp2)-C(sp3) coupling of aryl bromide with alcohols to enable parallel medicinal chemistry. Alcohols are among the most diverse and abundant building blocks, but their usage as alkyl precursors has been limited. Although metallaphotoredox deoxygenative coupling is becoming a promising strategy to form C(sp2)-C(sp3) bond, the reaction setup limits its widespread application in library synthesis. To achieve high throughput and consistency, an automated workflow involving solid-dosing and liquid-handling robots has been developed. We have successfully demonstrated this high-throughput protocol is robust and consistent across three automation platforms. Furthermore, guided by cheminformatic analysis, we examined alcohols with comprehensive chemical space coverage and established a meaningful scope for medicinal chemistry applications. By accessing the rich diversity of alcohols, this automated protocol has the potential to substantially increase the impact of C(sp2)-C(sp3) cross-coupling in drug discovery.

Cover Feature: Pincer‐Type Mesoionic Carbene Nickel(II) Complexes: Synthesis, Properties, Reactions, and Catalytic Application to the Suzuki–Miyaura Coupling Reaction of Aryl Bromides (Eur. J. Inorg. Chem. 10/2022)

The Cover Feature shows an image of the final product of an elaborately designed pincer complex derived from triazolylidene, which has emerged through a long series of steps from the earth′s abundant nickel mines. The complex has interesting properties provided by the ligand with strong σ-donor and π-acceptor abilities, and bulky substituents. It is also active in the Suzuki-Miyaura coupling of aryl bromides. The crystals are called annabergite and are known to be a landmark in nickel mining. Like this crystal, the complex is expected to become one of the landmarks for the development of organonickel chemistry. More information can be found in the Research Article by K. Matsubara and co-workers.

Nickel-catalysed cross-electrophile coupling of aryl bromides and primary alkyl bromides.

The structure of primary alkylated arenes plays an important role in the molecular action of drugs and natural products. The nickel/spiro-bidentate-pyox catalysed cross-electrophile coupling of aryl bromides and primary alkyl bromides was developed for the formation of the Csp2–Csp3 bond, which provided an efficient method for the synthesis of primary alkylated arenes. The reactions could tolerate functional groups such as ester, aldehyde, ketone, ether, benzyl, and imide.

Investigations into mechanism and origin of regioselectivity in the metallaphotoredox-catalyzed α-arylation of N-alkylbenzamides.

A mechanistic study on the α-arylation of N-alkylbenzamides catalyzed by a dual nickel/photoredox system using aryl bromides is reported herein. This study elucidates the origins of site-selectivity of the transformation, which is controlled by the generation of a hydrogen atom transfer (HAT) agent by a photocatalyst and bromide ions in solution. Tetrabutylammonium bromide was identified as a crucial additive and source of a potent HAT agent, which led to increases in yields and a lowering of the stoichiometries of the aryl bromide coupling partner. NMR titration experiments and Stern–Volmer quenching studies provide evidence for complexation to and oxidation of bromide by the photocatalyst, while elementary steps involving deprotonation of the N-alkylbenzamide or 1,5-HAT were ruled out through mechanistic probes and kinetic isotope effect analysis. This study serves as a valuable tool to better understand the α-arylation of N-alkylbenzamides, and has broader implications in halide-mediated C–H functionalization reactions.

Phosphorus‐Directed Rhodium‐Catalyzed C−H Arylation of 1‐Pyrenylphosphines Selective at the K‐Region

AbstractC−H arylation of 1‐pyrenylphosphine derivatives catalyzed by rhodium and directed by a diphenylphosphino group is selectively achieved at the K‐region, i. e. 4‐, 5‐, 9‐, or 10‐position of the pyrene moiety. This peri C−H activation/arylation of pyrenes using (hetero)aryl bromide coupling partners tolerates both electron‐donating and electron‐withdrawing groups on the arene, and provides isolated yields of products between 25% to 90%, including from bulky polyaromatic bromoarene substrates. We achieved investigations directed at the formation and reactivity of pertinent intermediate species in this C−H arylation reaction. The P‐ligand coordination at rhodium was established using 31P NMR and XRD analysis, and we isolated five‐membered rhodacycles as intermediates to the directed C−H functionalization. The data obtained overall supported the occurrence of a cationic rhodium catalytic process. We further described the access to a large class of pyrenylphosphine ligands and their selenated derivatives. Phosphine selenation allows to rapidly estimate from 1JP=Se values the basic character of the ligand in the perspective of their use for coordination. Accordingly, linear P‐coordinated Au(I) gold complexes were isolated, in addition to the variously coordinated Rh(III) complexes. The present methodology significantly extends the scope of polyaromatics that are functionalizable at the K‐Region by direct C−H activation, beyond smaller‐sized naphtalenes and aminopyrenes.magnified image

Buchwald-Hartwig Amination of Aryl Halides with Heterocyclic Amines in the Synthesis of Highly Fluorescent Benzodifuran-Based Star-Shaped Organic Semiconductors.

The study of palladium-catalyzed amination of bromobenzene with aromatic and heterocyclic amines, widely used in the synthesis of organic semiconductors, was performed. The best conditions for the coupling of aryl bromides with carbazole, diphenylamine, phenoxazine, phenothiazine, 9,9-dimethyl-9,10-dihydroacridine, and their derivatives have been developed. Based on the results, nine new star-shaped organic semiconductors, exhibiting up to 100% fluorescent quantum yield in the 400–550 nm range, have been synthesized in good yields. The TDDFT calculations of the absorption spectra revealed a good correlation with experimental results and slight solvatochromic effects with a change in the polarity of the solvent.

ChemBead Enabled High-Throughput Cross-Electrophile Coupling Reveals a New Complementary Ligand.

High-throughput experimentation (HTE) methods are central to modern medicinal chemistry. While many HTE approaches to C-N and Csp2 -Csp2 bonds are available, options for Csp2 -Csp3 bonds are limited. We report here how the adaptation of nickel-catalyzed cross-electrophile coupling of aryl bromides with alkyl halides to HTE is enabled by AbbVie ChemBeads technology. By using this approach, we were able to quickly map out the reactivity space at a global level with a challenging array of 3×222 micromolar reactions. The observed hit rate (56 %) is competitive with other often-used HTE reactions and the results are scalable. A key to this level of success was the finding that bipyridine 6-carboxamidine (BpyCam), a ligand that had not previously been shown to be optimal in any reaction, is as general as the best-known ligands with complementary reactivity. Such "cryptic" catalysts may be common and modern HTE methods should facilitate the process of finding these catalysts.

Easily Prepared Mono(N,N‐dialkylamino)phosphine Palladium(II) Complexes: Structural and Catalytic Evaluation

AbstractThe search for efficient, active and universal catalyst systems for transition‐metal catalyzed cross‐coupling reactions, continues to be of interest to researchers world‐wide. Herein, we report two new Pd(II) complexes, effortlessly prepared from N,N‐dialkylamino‐phosphines for Suzuki‐Miyaura cross‐coupling reactions. These sufficiently hindered (% VBur=30.0–31.5 %) and electron rich (vCO=1947.41–1946.29 cm−1) aminophosphines formed active catalysts for Suzuki‐Miyaura coupling of aryl bromides and chlorides.

Oxalohydrazide Ligands for Copper‐Catalyzed C−O Coupling Reactions with High Turnover Numbers

AbstractHere, we report a class of ligands based on oxalohydrazide cores and N‐amino pyrrole and N‐amino indole units that generates long‐lived copper catalysts for couplings that form the C−O bonds in biaryl ethers. These Cu‐catalyzed coupling of phenols with aryl bromides occurred with turnovers up to 8000, a value which is nearly two orders of magnitude higher than those of prior couplings to form biaryl ethers and nearly an order of magnitude higher than those of any prior copper‐catalyzed coupling of aryl bromides and chlorides. This ligand also led to copper systems that catalyze the coupling of aryl chlorides with phenols and the coupling of aryl bromides and iodides with primary benzylic and aliphatic alcohols. A wide variety of functional groups including nitriles, halides, ethers, ketones, amines, esters, amides, vinylarenes, alcohols and boronic acid esters were tolerated, and reactions occurred with aryl bromides in pharmaceutically related structures.

Oxalohydrazide Ligands for Copper-Catalyzed C-O Coupling Reactions with High Turnover Numbers.

Here, we report a class of ligands based on oxalohydrazide cores and N-amino pyrrole and N-amino indole units that generates long-lived copper catalysts for couplings that form the C-O bonds in biaryl ethers. These Cu-catalyzed coupling of phenols with aryl bromides occurred with turnovers up to 8000, a value which is nearly two orders of magnitude higher than those of prior couplings to form biaryl ethers and nearly an order of magnitude higher than those of any prior copper-catalyzed coupling of aryl bromides and chlorides. This ligand also led to copper systems that catalyze the coupling of aryl chlorides with phenols and the coupling of aryl bromides and iodides with primary benzylic and aliphatic alcohols. A wide variety of functional groups including nitriles, halides, ethers, ketones, amines, esters, amides, vinylarenes, alcohols and boronic acid esters were tolerated, and reactions occurred with aryl bromides in pharmaceutically related structures.

Aerobic Cu and amine free Sonogashira and Stille couplings of aryl bromides/chlorides with a magnetically recoverable Fe3O4@SiO2 immobilized Pd(II)-thioether containing NHC

Two value added CC cross coupling reactions; Sonogashira and Stille couplings were achieved at milder conditions in the catalytic presence of a magnetically recoverable heterogeneous catalyst Fe3O4@SiO2@NHC^SPh-Pd(II). The catalyst was earlier reported for Suzuki-Miyaura reaction, and as an extension of its catalytic efficiency, the Stille and Sonogashira cross coupling reactions under aerobic condition has been explored in present report. The Sonogashira coupling of aryl bromides and terminal alkynes produced an excellent yield (~96% at 0.25 mol% Pd) of the desired coupling product under copper and amines free conditions. Moreover, an excellent Stille coupling of readily available and more latent aryl chlorides and trialkylstannane was obtained (yields up to 95% at 0.25 mol% Pd) in absence of toxic fluorides additives. The broad substrate scope of the catalyst for both the coupling reactions and the magnetically recoverable feature of catalyst make this reaction highly desirable for industrial applications of present heterogeneous catalysis.

Nickel-catalyzed cross-electrophile coupling of aryl bromides and cyclic secondary alkyl bromides with spiro-bidentate-pyox ligands

The cross-electrophile coupling catalyzed by nickel/spiro-bidentate-pyox ligands with lithium chloride as the additive was reported, which has good functional group tolerance (19 examples).

A Widely Applicable Dual Catalytic System for Cross-Electrophile Coupling Enabled by Mechanistic Studies.

A dual catalytic system for cross-electrophile coupling reactions between aryl halides and alkyl halides that features a Ni catalyst, a Co cocatalyst, and a mild homogeneous reductant is described. Mechanistic studies indicate that the Ni catalyst activates the aryl halide, while the Co cocatalyst activates the alkyl halide. This allows the system to be rationally optimized for a variety of substrate classes by simply modifying the loadings of the Ni and Co catalysts based on the reaction product profile. For example, the coupling of aryl bromides and aryl iodides with alkyl bromides, alkyl iodides, and benzyl chlorides is demonstrated using the same Ni and Co catalysts under similar reaction conditions but with different optimal catalyst loadings in each case. Our system is tolerant of numerous functional groups and is capable of coupling heteroaryl halides, di-ortho-substituted aryl halides, pharmaceutically relevant druglike aryl halides, and a diverse range of alkyl halides. Additionally, the dual catalytic platform facilitates a series of selective one-pot three-component cross-electrophile coupling reactions of bromo(iodo)arenes with two distinct alkyl halides. This demonstrates the unique level of control that the platform provides and enables the rapid generation of molecular complexity. The system can be readily utilized for a wide range of applications as all reaction components are commercially available, the reaction is scalable, and toxic amide-based solvents are not required. It is anticipated that this strategy, as well as the underlying mechanistic framework, will be generalizable to other cross-electrophile coupling reactions.