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.

Ligand-Enabled Carboamidation of Unactivated Alkenes through Enhanced Organonickel Electrophilicity.

Catalytic carboamination of alkenes is a powerful synthetic tool to access valuable amine scaffolds from abundant and readily available alkenes. Although a number of synthetic approaches have been developed to achieve the rapid buildup of molecular complexity in this realm, the installation of diverse carbon and nitrogen functionalities onto unactivated alkenes remains underdeveloped. Here we present a ligand design approach to enable nickel-catalyzed three-component carboamidation that is applicable to a wide range of alkenyl amine derivatives via a tandem process involving alkyl migratory insertion and inner-sphere metal-nitrenoid transfer. With this method, various nitrogen functionalities can be installed into both internal and terminal unactivated alkenes, leading to differentially substituted diamines that would otherwise be difficult to access. Mechanistic investigations reveal that the tailored Ni(cod)(BQiPr) precatalyst modulates the electronic properties of the presumed π-alkene-nickel intermediate via the quinone ligand, leading to enhanced carbonickelation efficiency across the unactivated C═C bond. These findings establish nickel's ability to catalyze multicomponent carboamidation with a high efficiency and exquisite selectivity.

Catalytic σ-Bond Annulation with Ambiphilic Organohalides Enabled by ß-X Elimination.

We describe a catalytic cascade sequence involving directed C(sp3 )-H activation followed by ß-heteroatom elimination to generate a PdII (π-alkene) intermediate that then undergoes redox-neutral annulation with an ambiphilic aryl halide to access 5- and 6-membered (hetero)cycles. Various alkyl C(sp3 )-oxygen, nitrogen, and sulfur bonds can be selectively activated, and the annulation proceeds with high diastereoselectivity. The method enables modification of amino acids with good retention of enantiomeric excess, as well as σ-bond ring-opening/ring-closing transfiguration of low-strain heterocycles. Despite its mechanistic complexity, the method employs simple conditions and is operationally straightforward to perform.

Enantioselective Hydroalkenylation and Hydroalkynylation of Alkenes Enabled by a Transient Directing Group: Catalyst Generality through Rigidification.

The catalytic enantioselective synthesis of α-chiral alkenes and alkynes represents a powerful strategy for rapid generation of molecular complexity. Herein, we report a transient directing group (TDG) strategy to facilitate site-selective palladium-catalyzed reductive Heck-type hydroalkenylation and hydroalkynylation of alkenylaldehyes using alkenyl and alkynyl bromides, respectively, allowing for construction of a stereocenter at the δ-position with respect to the aldehyde. Computational studies reveal the dual beneficial roles of rigid TDGs, such as L-tert-leucine, in promoting TDG binding and inducing high levels of enantioselectivity in alkene insertion with a variety of migrating groups.

Redox-Paired Alkene Difunctionalization Enables Skeletally Divergent Synthesis.

Multistep organic synthesis enables conversion of simple chemical feedstocks into a more structurally complex product that serves a particular function. The target compound is forged over several steps, with concomitant generation of byproducts in each step to account for underlying mechanistic features of the reactions (e.g., redox processes). To map structure-function relationships, libraries of molecules are often needed, and these are typically prepared by iterating an established multistep synthetic sequence. An underdeveloped approach is designing organic reactions that generate multiple valuable products with different carbogenic skeletons in a single synthetic operation. Taking inspiration from paired electrosynthesis processes that are widely used in commodity chemical production (e.g., conversion of glucose to sorbitol and gluconic acid), we report a palladium-catalyzed reaction that converts a single alkene starting material into two skeletally distinct products in a single operation through a series of carbon-carbon and carbon-heteroatom bond-forming events enabled by mutual oxidation and reduction, a process that we term redox-paired alkene difunctionalization. We demonstrate the scope of the method in enabling simultaneous access to reductively 1,2-diarylated and oxidatively [3 + 2]-annulated products, and we explore the mechanistic details of this unique catalytic system using a combination of experimental techniques and density functional theory (DFT). The results described herein establish a distinct approach to small-molecule library synthesis that can increase the rate of compound production. Furthermore, these findings demonstrate how a single transition-metal catalyst can mediate a sophisticated redox-paired process through multiple pathway-selective events along the catalytic cycle.

Revised Mechanism of C(sp3)-C(sp3) Reductive Elimination from Ni(II) with the Assistance of a Z-Type Metalloligand.

Reductive elimination is a key step in Ni-catalyzed cross-couplings. Compared with processes that proceed from Ni(III) or Ni(IV) intermediates, C(sp3)-C(sp3) reductive eliminations from Ni(II) centers are challenging due to the weak oxidizing ability of Ni(II) species. In this report, we present computational evidence that supports a mechanism in which Zn coordination to the nickel center as a Z-type ligand accelerates reductive elimination. This Zn-assisted pathway is found to be lower in energy compared with direct reductive elimination from a σ-coordinated Ni(II) intermediate, providing new insights into the mechanism of Ni-catalyzed cross-coupling with organozinc nucleophiles. Mayer bond order, Hirshfield charge, Laplacian of the electron density, orbital, and interaction region indicator analyses were conducted to elucidate details of the reductive elimination process and characterize the key intermediates. Theoretical calculations indicate a significant Z-type Ni-Zn interaction that reduces the electron density around the Ni center and accelerates reductive elimination. This mechanistic study of reductive elimination in Ni(0)-catalyzed conjunctive cross-couplings of aryl iodides, organozinc reagents, and alkenes is an important case study of the involvement of Zn-assisted reductive elimination in Ni catalysis. We anticipate that the novel Zn-assisted reductive elimination mode may extend to other cross-coupling processes and explain the unique effectiveness of organozinc nucleophiles in many instances.

A Sterically Tuned Directing Auxiliary Promotes Catalytic 1,2-Carbofluorination of Alkenyl Carbonyl Compounds.

The site-selective palladium-catalyzed three-component coupling of unactivated alkenyl carbonyl compounds, aryl- or alkenylboronic acids, and N-fluorobenzenesulfonimide is described herein. Tuning of the steric environment on the bidentate directing auxiliary enhances regioselectivity and facilitates challenging C(sp3 )-F reductive elimination from a PdIV intermediate to afford 1,2-carbofluorination products in moderate to good yields.

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.

Regio- and Stereoselective 1,2-Oxyhalogenation of Non-Conjugated Alkynes via Directed Nucleopalladation: Catalytic Access to Tetrasubstituted Alkenes.

A catalytic 1,2-oxyhalogenation method that converts non-conjugated internal alkynes into tetrasubstituted alkenes with high regio- and stereoselectivity is described. Mechanistically, the reaction involves a PdII /PdIV catalytic cycle that begins with a directed oxypalladation step. The origin of regioselectivity is the preference for formation of a six-membered palladacycle intermediate, which is facilitated by an N,N-bidentate 2-(pyridin-2-yl)isopropyl (PIP) amide directing group. Selectivity for C(alkenyl)-X versus -N (X=halide) reductive elimination from the PdIV center depends on the identity of the halide anion; bromide and iodide engage in C(alkenyl)-X formation, while intramolecular C(alkenyl)-N reductive elimination occurs with chloride to furnish a lactam product. DFT calculations shed light on the origins of this phenomenon.

Directed, nickel-catalyzed 1,2-alkylsulfenylation of alkenyl carbonyl compounds.

We report a regioselective, nickel-catalyzed syn-1,2-carbosulfenylation of non-conjugated alkenyl carbonyl compounds with alkyl/arylzinc nucleophiles and tailored N-S electrophiles. This method allows the simultaneous installation of a variety of C(sp3) and S(Ar) (or Se(Ar)) groups onto unactivated alkenes, which complements previously developed 1,2-carbosulfenylation methodology in which only C(sp2) nucleophiles are compatible. A bidentate directing auxiliary controls regioselectivity, promotes high syn-stereoselectivity with a variety of E- and Z-internal alkenes, and enables the use of an array of electrophilic sulfenyl (and seleno) electrophiles. Among compatible electrophiles, those with N-alkyl-benzamide leaving groups were found to be especially effective, as determined through comprehensive structure-reactivity mapping.

Low-valent tungsten redox catalysis enables controlled isomerization and carbonylative functionalization of alkenes.

The controlled isomerization and functionalization of alkenes is a cornerstone achievement in organometallic catalysis that is now widely used throughout industry. In particular, the addition of CO and H2 to an alkene, also known as the oxo-process, is used in the production of linear aldehydes from crude alkene feedstocks. In these catalytic reactions, isomerization is governed by thermodynamics, giving rise to functionalization at the most stable alkylmetal species. Despite the ubiquitous industrial applications of tandem alkene isomerization/functionalization reactions, selective functionalization at internal positions has remained largely unexplored. Here we report that the simple W(0) precatalyst W(CO)6 catalyses the isomerization of alkenes to unactivated internal positions and subsequent hydrocarbonylation with CO. The six- to seven-coordinate geometry changes that are characteristic of the W(0)/W(II) redox cycle and the conformationally flexible directing group are key factors in allowing isomerization to take place over multiple positions and stop at a defined unactivated internal site that is primed for in situ functionalization.

PdII -Catalyzed C(alkenyl)-H Activation Facilitated by a Transient Directing Group.

Palladium(II)-catalyzed C(alkenyl)-H alkenylation enabled by a transient directing group (TDG) strategy is described. The dual catalytic process takes advantage of reversible condensation between an alkenyl aldehyde substrate and an amino acid TDG to facilitate coordination of the metal catalyst and subsequent C(alkenyl)-H activation by a tailored carboxylate base. The resulting palladacycle then engages an acceptor alkene, furnishing a 1,3-diene with high regio- and E/Z-selectivity. The reaction enables the synthesis of enantioenriched atropoisomeric 2-aryl-substituted 1,3-dienes, which have seldom been examined in previous literature. Catalytically relevant alkenyl palladacycles were synthesized and characterized by X-ray crystallography, and the energy profiles of the C(alkenyl)-H activation step and the stereoinduction model were elucidated by density functional theory (DFT) calculations.

Electrophilic Sulfur Reagent Design Enables Directed syn-Carbosulfenylation of Unactivated Alkenes.

A multi-component approach to structurally complex organosulfur products is described via the nickel-catalyzed 1,2-carbosulfenylation of unactivated alkenes with organoboron nucleophiles and tailored organosulfur electrophiles. The key to the development of this transformation is the identification of a modular N-alkyl-N-(arylsulfenyl)arenesulfonamide family of sulfur electrophiles. Tuning the electronic and steric properties of the leaving group in these reagents controls pathway selectivity, favoring three-component coupling and suppressing side reactions, as examined via computational studies. The unique syn-stereoselectivity differs from traditional electrophilic sulfenyl transfer processes involving a thiiranium ion intermediate and arises from the directed arylnickel(I) migratory insertion mechanism, as elucidated through reaction kinetics and control experiments. Reactivity and regioselectivity are facilitated by a collection of monodentate, weakly coordinating native directing groups, including sulfonamides, alcohols, amines, amides, and azaheterocycles.

Mapping Ambiphile Reactivity Trends in the Anti-(Hetero)annulation of Non-Conjugated Alkenes via PdII /PdIV Catalysis.

In this study, we systematically evaluate different ambiphilic organohalides for their ability to participate in anti-selective carbo- or heteroannulation with non-conjugated alkenyl amides under PdII /PdIV catalysis. Detailed optimization of the reaction conditions has led to protocols for synthesizing tetrahydropyridines, tetralins, pyrrolidines, and other carbo/heterocyclic cores via [n+2] (n=3-5) (hetero)annulation. Expansion of scope to otherwise unreactive ambiphilic haloketones through PdII /amine co-catalysis is also demonstrated. Compared to other annulation processes, this method proceeds via a distinct PdII /PdIV mechanism involving Wacker-type directed nucleopalladation. This difference results in unique reactivity and selectivity patterns, as revealed through assessment of reaction scope and competition experiments.

(CAAC)Copper Catalysis Enables Regioselective Three-Component Carboboration of Terminal Alkynes.

Cyclic(alkyl)(amino)carbene (CAAC) ligands are found to perturb regioselectivity of the copper-catalyzed carboboration of terminal alkynes, favoring the less commonly observed internal alkenylboron regiosomer through an α-selective borylcupration step. A variety of carbon electrophiles participate in the reaction, including allyl alcohols derivatives and alkyl halides. The method provides a straightforward and selective route to versatile tri-substituted alkenylboron compounds that are otherwise challenging to access.

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.