Visible‐Light‐Induced Nickel‐Catalyzed Negishi Cross‐Couplings by Exogenous‐Photosensitizer‐Free Photocatalysis

The merging of photoredox and transition‐metal catalysis has become one of the most attractive approaches for carbon–carbon bond formation. Such reactions require the use of two organo‐transition‐metal species, one of which acts as a photosensitizer and the other one as a cross‐coupling catalyst. We report herein an exogenous‐photosensitizer‐free photocatalytic process for the formation of carbon–carbon bonds by direct acceleration of the well‐known nickel‐catalyzed Negishi cross‐coupling that is based on the use of two naturally abundant metals. This finding will open new avenues in cross‐coupling chemistry that involve the direct visible‐light absorption of organometallic catalytic complexes.     

Mild Cobalt‐Catalyzed Negishi Cross‐Couplings of (Hetero)arylzinc Reagents with (Hetero)aryl Halides

A catalytic system consisting of CoCl₂ ? 2 LiCl (5 mol %) and HCO₂Na (50 mol %) enables the cross‐coupling of various N‐heterocyclic chlorides and bromides as well as aromatic halogenated ketones with various electron‐rich and ‐poor arylzinc reagents. The reactions reached full conversion within a few hours at 25 °C.     

Palladium‐Catalyzed Heck‐Type Cross‐Couplings of Unactivated Alkyl Iodides

A palladium‐catalyzed, intermolecular Heck‐type coupling of alkyl iodides and alkenes is described. This process is successful with a variety of primary and secondary unactivated alkyl iodides as reaction partners, including those with hydrogen atoms in the β position. The mild catalytic conditions enable intermolecular C? C bond formations with a diverse set of alkyl iodides and alkenes, including substrates containing base‐ or nucleophile‐sensitive functionality.     

Palladium‐Catalyzed Cross‐Coupling of Alkenyl Carboxylates

Carboxylate esters have many desirable features as electrophiles for catalytic cross‐coupling: they are easy to access, robust during multistep synthesis, and mass‐efficient in coupling reactions. Alkenyl carboxylates, a class of readily prepared non‐aromatic electrophiles, remain difficult to functionalize through cross‐coupling. We demonstrate that Pd catalysis is effective for coupling electron‐deficient alkenyl carboxylates with arylboronic acids in the absence of base or oxidants. Furthermore, these reactions can proceed by two distinct mechanisms for C?O bond activation. A Pd^0/II catalytic cycle is viable when using a Pd⁰ precatalyst, with turnover‐limiting C?O oxidative addition; however, an alternative pathway that involves alkene carbopalladation and β‐carboxyl elimination is proposed for Pd^II precatalysts. This work provides a clear path toward engaging myriad oxygen‐based electrophiles in Pd‐catalyzed cross‐coupling.     

Fast,Efficient and Low E‐Factor One‐Pot Palladium‐Catalyzed Cross‐Coupling of (Hetero)Arenes

The homocoupling of aryl halides and the heterocoupling of aryl halides with either aryl bromides or arenes bearing an ortho‐lithiation directing group are presented. The use of a Pd catalyst, in combination with t‐BuLi, allows for the rapid and efficient formation of a wide range of polyaromatic compounds in a one pot procedure bypassing the need for the separate preformation of an organometallic coupling partner. These polyaromatic structures are obtained in high yields, in 10 min at room temperature, with minimal waste generation (E‐factors as low as 1.5) and without the need for strict inert conditions, making this process highly efficient and practical in comparison to classical methods. As illustration, several key intermediates of widely used BINOL‐derived structures are readily prepared.     

Continuous‐Flow Synthesis of Biaryls by Negishi Cross‐Coupling of Fluoro‐ and Trifluoromethyl‐Substituted (Hetero)arenes

A continuous‐flow method for the regioselective arylation of fluoroarenes and fluoropyridines has been developed. The telescoped procedure reported here consists of a three‐step metalation, zincation, and Negishi cross‐coupling sequence, providing efficient access to a variety of functionalized 2‐fluorobiaryl products. Precise temperature control of the metalation step, made possible by continuous‐flow technology, allowed for the efficient preparation of the arylated products in high yields and short residence times. Additionally, several examples of the regioselective arylation of benzotrifluoride derivatives are also provided.     

Addressing Challenges in Palladium‐Catalyzed Cross‐Coupling Reactions Through Ligand Design

The development of palladium‐catalyzed cross‐coupling reactions has revolutionized the synthesis of organic molecules on both bench‐top and industrial scales. While significant research effort has been directed toward evaluating how modifying various reaction parameters can influence the outcome of a given cross‐coupling reaction, the design and implementation of novel ancillary ligand frameworks has played a particularly important role in advancing the state‐of‐the‐art. This Review seeks to highlight notable examples from the recent chemical literature, in which newly developed ancillary ligands have enabled more challenging substrate transformations to be addressed with greater selectivity and/or under increasingly mild conditions. Throughout, the importance and subtlety of ligand effects in palladium‐catalyzed cross‐coupling reactions are described, in an effort to inspire further development and understanding within the field of ancillary ligand design.     

Palladium‐Catalyzed Oxygenative Cross‐Coupling of Ynamides and Benzyl Bromides by Carbene Migratory Insertion

A palladium‐catalyzed oxygenative cross‐coupling of ynamides and benzyl bromides has been developed. After subsequent hydrogenation, α,α‐disubstituted amide derivatives were obtained in good yields. Migratory insertion of α‐oxo palladium carbene species, generated by intermolecular oxidation, is proposed as the key step in this reaction. The study demonstrates the potential of ynamides to serve as carbene precursors in palladium‐catalyzed C?C bond‐forming cross‐coupling reactions.     

Catalyst Activation,Deactivation, and Degradation in Palladium‐Mediated Negishi Cross‐Coupling Reactions

Pd‐mediated Negishi cross‐coupling reactions were studied by a combination of kinetic measurements, electrospray‐ionization (ESI) mass spectrometry, ³¹P NMR and UV/Vis spectroscopy. The kinetic measurements point to a rate‐determining oxidative addition. Surprisingly, this step seems to involve not only the Pd catalyst and the aryl halide substrate, but also the organozinc reagent. In this context, the ESI‐mass spectrometric observation of heterobimetallic Pd–Zn complexes [L₂PdZnR]⁺ (L=S‐PHOS, R=Bu, Ph, Bn) is particularly revealing. The inferred presence of these and related neutral complexes with a direct Pd–Zn interaction in solution explains how the organozinc reagent can modulate the reactivity of the Pd catalyst. Previous theoretical calculations by González‐Pérez et al. (Organometallics­ 2012 , 31, 2053) suggest that the complexation by the organozinc reagent lowers the activity of the Pd catalyst. Presumably, a similar effect also causes the rate decrease observed upon addition of ZnBr₂. In contrast, added LiBr apparently counteracts the formation of Pd–Zn complexes and restores the high activity of the Pd catalyst. At longer reaction times, deactivation processes due to degradation of the S‐PHOS ligand and aggregation of the Pd catalyst come into play, thus further contributing to the appreciable complexity of the title reaction.     

Visible Light Activation of Boronic Esters Enables Efficient Photoredox C(sp2)–C(sp3) Cross‐Couplings in Flow

We report herein a new method for the photoredox activation of boronic esters. Using these reagents, an efficient and high‐throughput continuous flow process was developed to perform a dual iridium‐ and nickel‐catalyzed C(sp²)–C(sp³) coupling by circumventing solubility issues associated with potassium trifluoroborate salts. Formation of an adduct with a pyridine‐derived Lewis base was found to be essential for the photoredox activation of the boronic esters. Based on these results we were able to develop a further simplified visible light mediated C(sp²)–C(sp³) coupling method using boronic esters and cyano heteroarenes under flow conditions.     

Iron‐Catalyzed Cross‐Couplings in the Synthesis of Pharmaceuticals: In Pursuit of Sustainability

The scarcity of precious metals has led to the development of sustainable strategies for metal‐catalyzed cross‐coupling reactions. The establishment of new catalytic methods using iron is attractive owing to the low cost, abundance, ready availability, and very low toxicity of iron. In the last few years, sustainable methods for iron‐catalyzed cross‐couplings have entered the critical area of pharmaceutical research. Most notably, iron is one of the very few metals that have been successfully field‐tested as highly effective base‐metal catalysts in practical, kilogram‐scale industrial cross‐couplings. In this Minireview, we critically discuss the strategic benefits of using iron catalysts as green and sustainable alternatives to precious metals in cross‐coupling applications for the synthesis of pharmaceuticals. The Minireview provides an essential introduction to the fundamental aspects of practical iron catalysis, highlights areas for improvement, and identifies new fields to be explored.     

“(Diphosphine)Nickel”‐Catalyzed Negishi Cross‐Coupling: An Experimental and Theoretical Study

The use of a strongly donating “(bis‐dialkylphosphine)Ni” fragment promotes the catalytic coupling of a large range of ArCl and ArZnCl derivatives under mild conditions. Stoichiometric mechanistic investigations and DFT calculations prove that a Ni⁰/Ni^II cycle is operative in this system.     

HandaPhos: A General Ligand Enabling Sustainable ppm Levels of Palladium‐Catalyzed Cross‐Couplings in Water at Room Temperature

The new monophosphine ligand HandaPhos has been identified such that when complexed in a 1:1 ratio with Pd(OAc)₂, enables Pd‐catalyzed cross‐couplings to be run using ≤1000 ppm of this pre‐catalyst. Applications to Suzuki–Miyaura reactions involving highly funtionalized reaction partners are demonstrated, all run using environmentally benign nanoreactors in water at ambient temperatures. Comparisons with existing state‐of‐the‐art ligands and catalysts are discussed herein.