Stereodivergent, Kinetically Controlled Isomerization of Terminal Alkenes via Nickel Catalysis.

Because internal alkenes are more challenging synthetic targets than terminal alkenes, metal-catalyzed olefin mono-transposition (i.e., positional isomerization) approaches have emerged to afford valuable E- or Z- internal alkenes from their complementary terminal alkene feedstocks. However, the applicability of these methods has been hampered by lack of generality, commercial availability of precatalysts, and scalability. Here, we report a nickel-catalyzed platform for the stereodivergent E/Z-selective synthesis of internal alkenes at room temperature. Commercial reagents enable this one-carbon transposition of terminal alkenes to valuable E- or Z-internal alkenes via a Ni-H-mediated insertion/elimination mechanism. Though the mechanistic regime is the same in both systems, the underlying pathways that lead to each of the active catalysts are distinct, with the Z-selective catalyst forming from comproportionation of an oxidative addition complex followed by oxidative addition with substrate and the E-selective catalyst forming from protonation of the metal by the trialkylphosphonium salt additive. In each case, ligand sterics and denticity control stereochemistry and prevent over-isomerization.

Benchtop Nickel Catalysis Invigorated by Electron-Deficient Diene Ligands.

ConspectusDue to the rarity of precious metals like palladium, nickel catalysis is becoming an increasingly important player in organic synthesis, especially for the formation of bonds with sp3-hybridized carbon centers. Traditionally, catalytic processes involving active Ni(0) species have relied on Ni(COD)2 or in situ reduction of Ni(II) salts. However, Ni(COD)2 is an air- and temperature-sensitive material that requires use in an inert-atmosphere glovebox, and in situ reduction protocols of Ni(II) salts using metallic or organometallic reductants add additional complications to reaction development.This Account chronicles the development of air-stable Ni(0) precursors as replacements for Ni(COD)2 or in situ reduction. Based on Schrauzer's seminal discovery of Ni(COD)(DQ) as an air-stable zerovalent organonickel complex, our research laboratories at Scripps Research and Bristol Myers Squibb have developed a class of precatalysts based on the Ni(COD)(EDD) (EDD = electron-deficient diene) framework, relying on the steric and electronic properties of the supporting diene to render the metal center stable to air, moisture, and even silica gel but reactive to ligand substitution and redox changes.The stable Ni(0) complexes can be accessed through ligand exchange with Ni(COD)2, through reduction of Ni(acac)2 using DIBAL-H, or electrochemically via cathodic reduction of Ni(acac)2 to Ni(COD)2, followed by addition of an EDD ligand in one pot. As a toolkit, the complexes demonstrate reactivity that is equivalent or enhanced compared to Ni(COD)2, catalyzing C-C and C-N cross-couplings, Miyaura borylations, C-H activations, and other transformations. Since the initial report on Ni(COD)(DQ), its reactivity in C(sp2)-CN activation, metallophotoredox, and electric field-induced cross-coupling have also been demonstrated.By incorporating the precatalyst toolkit into reaction discovery campaigns, our laboratories have been able to perform C(sp3)-S(alkyl) couplings and metallonitrenoid carboamination, both of which represent challenging transformations that were inaccessible with traditional phosphine, nitrogen, or electron-deficient olefin ligands. Computational and experimental studies demonstrate how the quinone ligands are hemilabile, adopting η1(O)-bound geometries to relieve steric strain or stabilize transition states and intermediates; redox-active, able to transiently oxidize the metal center; and electron-withdrawing or -donating, depending on metal oxidation state and coordination geometry. These studies show how the ligands enable key steps in catalysis beyond imparting air-stability.Since our report documenting the catalytic activity of Ni(COD)(DQ), many other laboratories have also observed unique reactivity with this precatalyst. Ni(COD)(DQ) was found to offer superior reactivity to Ni(COD)2 in C-N cross coupling to form N,N-diaryl sulfonamides and in preparation of biaryls from aryl halides and benzene through a Ni-mediated, base-assisted homolytic aromatic substitution.

Nickel-Electrocatalytic Decarboxylative Arylation to Access Quaternary Centers.

There is a pressing need, particularly in the field of drug discovery, for general methods that will enable direct coupling of tertiary alkyl fragments to (hetero)aryl halides. Herein a uniquely powerful and simple set of conditions for achieving this transformation with unparalleled generality and chemoselectivity is disclosed. This new protocol is placed in context with other recently reported methods, applied to simplify the routes of known bioactive building blocks molecules, and scaled up in both batch and flow. The role of pyridine additive as well as the mechanism of this reaction are interrogated through Cyclic Voltammetry studies, titration experiments, control reactions with Ni(0) and Ni(II)-complexes, and ligand optimization data. Those studies indicate that the formation of a BINAPNi(0) is minimized and the formation of an active pyridine-stabilized Ni(I) species is sustained during the reaction. Our preliminary mechanistic studies ruled out the involvement of Ni(0) species in this electrochemical cross-coupling, which is mediated by Ni(I) species via a Ni(I)-Ni(II)-Ni(III)-Ni(I) catalytic cycle.

Electroreductive Synthesis of Nickel(0) Complexes.

Over the last fifty years, the use of nickel catalysts for facilitating organic transformations has skyrocketed. Nickel(0) sources act as useful precatalysts because they can enter a catalytic cycle through ligand exchange, without needing to undergo additional elementary steps. However, most Ni(0) precatalysts are synthesized with stoichiometric aluminum-hydride reductants, pyrophoric reagents that are not atom-economical and must be used at cryogenic temperatures. Here, we demonstrate that Ni(II) salts can be reduced on preparative scale using electrolysis to yield a variety of Ni(0) and Ni(II) complexes that are widely used as precatalysts in organic synthesis, including bis(1,5-cyclooctadiene)nickel(0) [Ni(COD)2 ]. This method overcomes the reproducibility issues of previously reported methods by standardizing the procedure, such that it can be performed anywhere in a robust manner. It can be transitioned to large scale through an electrochemical recirculating flow process and extended to an in situ reduction protocol to generate catalytic amounts of Ni(0) for organic transformations. We anticipate that this work will accelerate adoption of preparative electrochemistry for the synthesis of low-valent organometallic complexes in academia and industry.

Radical Hydrocarboxylation of Unactivated Alkenes via Photocatalytic Formate Activation.

Herein we disclose a strategy to promote the hydrocarboxylation of unactivated alkenes using photochemical activation of formate salts. We illustrate that an alternative initiation mechanism circumvents the limitations of prior approaches and enables hydrocarboxylation of this challenging substrate class. Specifically, we found that accessing the requisite thiyl radical initiator without an exogenous chromophore eliminates major byproducts that have plagued attempts to exploit similar reactivity for unactivated alkene substrates. This redox-neutral method is technically simple to execute and effective across a broad range of alkene substrates. Feedstock alkenes, such as ethylene, are hydrocarboxylated at ambient temperature and pressure. A series of radical cyclization experiments indicate how the reactivity described in this report can be diverted by more complex radical processes.

Structurally Diverse Bench-Stable Nickel(0) Pre-Catalysts: A Practical Toolkit for In Situ Ligation Protocols.

A flurry of recent research has centered on harnessing the power of nickel catalysis in organic synthesis. These efforts have been bolstered by contemporaneous development of well-defined nickel (pre)catalysts with diverse structure and reactivity. In this report, we present ten different bench-stable, 18-electron, formally zero-valent nickel-olefin complexes that are competent pre-catalysts in various reactions. Our investigation includes preparations of novel, bench-stable Ni(COD)(L) complexes (COD=1,5-cyclooctadiene), in which L=quinone, cyclopentadienone, thiophene-S-oxide, and fulvene. Characterization by NMR, IR, single-crystal X-ray diffraction, cyclic voltammetry, thermogravimetric analysis, and natural bond orbital analysis sheds light on the structure, bonding, and properties of these complexes. Applications in an assortment of nickel-catalyzed reactions underscore the complementary nature of the different pre-catalysts within this toolkit.

Three-Component Asymmetric Ni-Catalyzed 1,2-Dicarbofunctionalization of Unactivated Alkenes via Stereoselective Migratory Insertion.

An asymmetric 1,2-dicarbofunctionalization of unactivated alkenes with aryl iodides and aryl/alkenylboronic esters under nickel/bioxazoline catalysis is disclosed. A wide array of aryl and alkenyl nucleophiles are tolerated, furnishing the products in good yield and with high enantioselectivity. In addition to terminal alkenes, 1,2-disubstituted internal alkenes participate in the reaction, establishing two contiguous stereocenters with high diastereoselectivity and moderate enantioselectivity. A combination of experimental and computational techniques shed light on the mechanism of the catalytic transformation, pointing to a closed-shell pathway with an enantiodetermining migratory insertion step, where stereoinduction arises from synergistic interactions between the sterically bulky achiral sulfonamide directing group and the hemilabile bidentate ligand.

Transition-Metal-Catalyzed, Coordination-Assisted Functionalization of Nonactivated C(sp3)-H Bonds.

Transition-metal-catalyzed, coordination-assisted C(sp3)-H functionalization has revolutionized synthetic planning over the past few decades as the use of these directing groups has allowed for increased access to many strategic positions in organic molecules. Nonetheless, several challenges remain preeminent, such as the requirement for high temperatures, the difficulty in removing or converting directing groups, and, although many metals provide some reactivity, the difficulty in employing metals outside of palladium. This review aims to give a comprehensive overview of coordination-assisted, transition-metal-catalyzed, direct functionalization of nonactivated C(sp3)-H bonds by covering the literature since 2004 in order to demonstrate the current state-of-the-art methods as well as the current limitations. For clarity, this review has been divided into nine sections by the transition metal catalyst with subdivisions by the type of bond formation. Synthetic applications and reaction mechanism are discussed where appropriate.

Iridium-Catalyzed Silylation of Five-Membered Heteroarenes: High Sterically Derived Selectivity from a Pyridyl-Imidazoline Ligand.

The steric effects of substituents on five-membered rings are less pronounced than those on six-membered rings because of the difference in bond angles. Thus, the regioselectivities of reactions that occur with selectivities dictated by steric effects, such as the borylation of C-H bonds, have been poor in many cases. We report that the silylation of five-membered ring heteroarenes occurs with high sterically derived regioselectivity when catalyzed by the combination of [Ir(cod)(OMe)]2 and a phenanthroline ligand or a new pyridyl-imidazoline ligand that further increases the regioselectivity. The silylation reactions with these catalysts produce high yields of heteroarylsilanes from functionalization at the most sterically accessible C-H bonds of these rings under conditions that the borylation of C-H bonds with previously reported catalysts formed mixtures of products or products that are unstable. The heteroarylsilane products undergo cross-coupling reactions and substitution reactions with ipso selectivity to generate heteroarenes that bear halogen, aryl and perfluoroalkyl substituents.

Iridium-Catalyzed Silylation of Five-Membered Heteroarenes: High Sterically Derived Selectivity from a Pyridyl-Imidazoline Ligand.

The steric effects of substituents on five-membered rings are less pronounced than those on six-membered rings because of the difference in bond angles. Thus, the regioselectivities of reactions of five-membered heteroarenes that occur with selectivities dictated by steric effects, such as the borylation of C-H bonds, have been poor in many cases. We report that the silylation of five-membered-ring heteroarenes occurs with high sterically derived regioselectivity when catalyzed by the combination of [Ir(cod)(OMe)]2 (cod=1,5-cyclooctadiene) and a phenanthroline ligand or a new pyridyl-imidazoline ligand that further increases the regioselectivity. The silylation reactions with these catalysts produce high yields of heteroarylsilanes from functionalization at the most sterically accessible C-H bonds of these rings under conditions that the borylation of C-H bonds with previously reported catalysts formed mixtures of products or products that are unstable. The heteroarylsilane products undergo cross-coupling reactions and substitution reactions with ipso selectivity to generate heteroarenes that bear halogen, aryl, and perfluoroalkyl substituents.