Nickel-Catalyzed Ipso/Ortho Difunctionalization of Aryl Bromides with Alkynes and Alkyl Bromides via a Vinyl-to-Aryl 1,4-Hydride Shift.

Polysubstituted arenes are ubiquitous structures in a myriad of medicinal agents and complex molecules. Herein, we report a new catalytic blueprint that merges the modularity of nickel catalysis for bond formation with the ability to enable a rather elusive 1,4-hydride shift at arene sp2 C-H sites, thus allowing access to ipso/ortho-difunctionalized arenes from readily available aryl halides under mild conditions and exquisite selectivity profile.

Nickel-Catalyzed Reductive Carboxylation and Amidation Reactions.

The ubiquity and importance of carboxylic acids and amides in peptides, pharmaceuticals, agrochemicals, and synthetic materials has challenged chemists to design de novo catalytic carboxylation and amidation protocols. They represent a powerful alternative to canonical oxidation of alcohols and aldehydes, hydrolysis of nitriles, transamidation reactions, or condensation techniques for the synthesis of these functional groups. Among various scenarios, the recent years have witnessed considerable advances in Ni-catalyzed reductive carboxylation and amidation reactions utilizing carbon dioxide and isocyanate counterparts. This Account aims to highlight the progress made in this arena with a historical perspective, with particular emphasis on the methodologies that have emanated from our laboratories without losing sight of the underlying principles by which these reactions operate, with the ultimate goal of allowing the transition from comprehension to prediction in this exciting field.Unlike the utilization of conventional polar yet highly reactive organometallic reagents in carboxylation or amidation reactions, the utilization of nickel catalysts has allowed the use of carbon dioxide and isocyanates with less reactive and less-polarized counterparts for the formations of carboxylic acids and amides. These less reactive groups include organic halides and pseudohalides (i.e., alkyl bromides and chlorides, esters, alcohols, and ammonium salts), unsaturated hydrocarbons (i.e., alkynes, styrenes, unactivated alkenes, and dienes) or even C-H bonds, where forging the targeted C-C bond at previously unfunctionalized C-H linkages was possible, thus giving access to densely functionalized compounds that would be difficult to access otherwise. The C-H functionalization includes chain-walking scenarios, where subtle changes in the ligand and reaction conditions marked the selectivity of the transformations, and reactions via a [1,4]-Ni shift, where selective carboxylation in aromatic rings could be achieved. Conceptuality and practicality aside, these transformations have even offered the possibility of modulating and dictating the site-selectivity pattern, thus providing not only new vistas when controlling the selectivity of bond-forming reactions at specific sites within the side chain but also new knowledge in retrosynthetic analysis when accessing carboxylic acids and amide backbones. Importantly, these techniques have shown to be particularly suited for the preparation of isotopically labeled molecules when using 13CO2 or even 14CO2, thus becoming a useful endeavor in the drug discovery pipeline. Although mechanistic understanding at the molecular level still constitutes the "Achilles heel" of these transformations, the recent empirical discoveries and the rapid adoption of these protocols by the community augurs well for the widespread utilization of reductive carboxylation and amidation reactions in both academic and industrial laboratories.

Remote sp2 C-H Carboxylation via Catalytic 1,4-Ni Migration with CO2.

A remote catalytic reductive sp2 C-H carboxylation of arenes with CO2 (1 bar) via 1,4-Ni migration is disclosed. This protocol constitutes the first catalytic 1,4-Ni migration reported to date, thus offering new vistas in the Ni-catalyzed reductive coupling arena while providing an unconventional new platform for incorporating electrophilic sites at remote sp2 C-H linkages.

Site-Selective Ni-Catalyzed Reductive Coupling of α-Haloboranes with Unactivated Olefins.

A mild, chemo- and site-selective catalytic protocol that allows for incorporating an alkylboron fragment into unactivated olefins is described. The use of internal olefins enables C-C bond-formation at remote sp3 C-H sites, constituting a complementary and conceptually different approach to existing borylation techniques that are currently available at sp3 centers.

Transition-Metal-Catalyzed Carboxylation Reactions with Carbon Dioxide.

Driven by the inherent synthetic potential of CO2 as an abundant, inexpensive and renewable C1 chemical feedstock, the recent years have witnessed renewed interest in devising catalytic CO2 fixations into organic matter. Although the formation of C-C bonds via catalytic CO2 fixation remained rather limited for a long period of time, a close look into the recent literature data indicates that catalytic carboxylation reactions have entered a new era of exponential growth, evolving into a mature discipline that allows for streamlining the synthesis of carboxylic acids, building blocks of utmost relevance in industrial endeavors. These strategies have generally proven broadly applicability and convenient to perform. However, substantial challenges still need to be addressed reinforcing the need to cover metal-catalyzed carboxylation area in a conceptual and concise manner, delineating the underlying new principles that are slowly emerging in this vibrant area of expertise.

Switchable Site-Selective Catalytic Carboxylation of Allylic Alcohols with CO2.

A switchable site-selective catalytic carboxylation of allylic alcohols has been developed in which CO2 is used with dual roles, both facilitating C-OH cleavage and as a C1 source. This protocol is characterized by its mild reaction conditions, absence of stoichiometric amounts of organometallic reagents, broad scope, and exquisite regiodivergency which can be modulated by the type of ligand employed.

Metal-Catalyzed Carboxylation of Organic (Pseudo)halides with CO2.

The recent years have witnessed the development of metal-catalyzed reductive carboxylation of organic (pseudo)halides with CO2 as C1 source, representing potential powerful alternatives to existing methodologies for preparing carboxylic acids, privileged motifs in a myriad of pharmaceuticals and molecules displaying significant biological properties. While originally visualized as exotic cross-coupling reactions, a close look into the literature data indicates that these processes have become a fertile ground, allowing for the utilization of a variety of coupling partners, even with particularly challenging substrate combinations. As for other related cross-electrophile scenarios, the vast majority of reductive carboxylation of organic (pseudo)halides are characterized by their simplicity, mild conditions, and a broad functional group compatibility, suggesting that these processes could be implemented in late-stage diversification. This perspective describes the evolution of metal-catalyzed reductive carboxylation of organic (pseudo)halides from its inception in the pioneering stoichiometric work of Osakada to the present. Specific emphasis is devoted to the reactivity of these coupling processes, with substrates ranging from aryl-, vinyl-, benzyl- to unactivated alkyl (pseudo)halides. Despite the impressive advances realized, a comprehensive study detailing the mechanistic intricacies of these processes is still lacking. Some recent empirical evidence reveal an intriguing dichotomy exerted by the substitution pattern on the ligands utilized; still, however, some elementary steps within the catalytic cycle of these reactions remain speculative, in many instances invoking a canonical cross-coupling process. Although tentative, we anticipate that these processes might fall into more than one distinct mechanistic category depending on the substrate utilized, suggesting that investigations aimed at unraveling the mechanistic underpinnings of these processes will likely bring new and innovative research grounds in this vibrant area of expertise.

Ni-Catalyzed Carboxylation of Unactivated Alkyl Chlorides with CO2.

A catalytic carboxylation of unactivated primary, secondary, and tertiary alkyl chlorides with CO2 at atmospheric pressure is described. This protocol represents the first intermolecular cross-electrophile coupling of unactivated alkyl chlorides, thus leading to new knowledge in the cross-coupling arena.