Nickamine and Analogous Nickel Pincer Catalysts for Cross-Coupling of Alkyl Halides and Hydrosilylation of Alkenes

CONSPECTUS: Ligand development plays an essential role in the advance of homogeneous catalysis. Tridentate, meridionally coordinating ligands, commonly termed pincer ligands, have been established as a privileged class of ligands in catalysis because they confer high stability while maintaining electronic tenability to the resulting metal complexes. Pincer ligands containing "soft" donors such as phosphines are typically used for late transition-metal ions, which are considered "soft" acids. Driven by our interest to develop base-metal catalysis and in view of the "hard" character of base-metal ions, our group explored a pincer ligand containing only "hard" nitrogen donors. A prototypical nickel complex of this ligand, "Nickamine", turned out to be an efficient catalyst in a wide range of organic reactions. Because of its propensity to mediate single-electron redox chemistry, Nickamine is particularly suited to catalyze cross-coupling of nonactivated alkyl halides through radical pathways. These coupling partners have been challenging substrates for traditional, palladium-based catalysts because of difficult oxidative addition and nonproductive beta-H elimination. The high activity of Nickamine for cross-coupling leads to high chemoselectivity and functional group tolerance, even when reactive Grignard reagents are employed as nucleophiles. The scope of the catalysis is broad and encompasses spa(3)-spa(3), sp(3)-sp(2), and sp(3)-sp cross-coupling. The defined nature of Nickamine facilitated the mechanistic study of cross-coupling reactions. Experiments involving radical-probe substrates, presumed intermediates and dormant species, kinetics, and density functional theory computations revealed a bimetallic oxidative addition pathway. In this pathway, two Ni centers each provide one electron to support the two-electron activation of an alkyl halide substrate. The success of Nickamine motivated our systematic structure-activity studies aiming at improved activity in certain reactions through ligand modification. Indeed, better catalysts have been developed for cross-coupling of secondary alkyl halides as well as direct alkynylation of alkyl halides. The improvement is attributed to a more accessible Ni center in the new catalysts than in Nickamine. Surprisingly, the improvement could be obtained simply by replacing a dimethyl amino group in Nickamine with a pyrrolidino group. During the study of the catalytic cycle of Nickamine in cross-coupling reactions, we synthesized the corresponding Ni-H species. Consequently, we explored the catalytic application of Nickamine in Ni-H mediated reactions, such as hydrosilylation. To our delight, Nickamine is a chemoselective catalyst for hydrosilylation of alkenes while tolerating a reactive C=O group. An analogous Ni pincer complex was found to catalyze unusual hydrosilylation reactions using alkoxy hydrosilanes as surrogates of gaseous silanes.

Mechanistic Studies Related to Nickel-Catalyzed Alkyl-Alkyl Cross Coupling Reactions

Jan Breitenfeld

Cross-coupling reactions of non-activated alkyl halides are potentially useful chemical transformations. At the same time, however, they are challenging due to a series of unproductive side reactions. Recently, significant progress has been made to overcome these difficulties. With judicious choice of metal, ligands, and reaction conditions, the normally problematic β- H elimination can be suppressed. As a consequence, a number of examples of the successful coupling of non-activated alkyl halides have been demonstrated. The mechanistic understanding of such reactions is, in most cases, still primitive. In the majority of cases, the active catalysts are generated in situ and remain unidentified and unknown. This dissertation is devoted to mechanistic studies of alkyl-alkyl cross-coupling catalyzed by a well-defined nickel pincer complex [(MeNN2)Ni-Cl] (1; Nickamine). This complex showed excellent activity for the cross-coupling of unactivated alkyl halides. Moreover, several nickel alkyl complexes bearing β-hydrogen atoms have been isolated. These features offered a unique platform to carry out mechanistic studies to gain a better understanding of nickel-catalyzed crosscoupling reactions. Chapter one provides examples of palladium-, iron-, cobalt-, and nickel-catalyzed alkyl-alkyl cross-coupling reactions. In each case mechanistic details are discussed. At the end of the chapter cross-coupling reactions using Nickamine are presented. In chapter two the propensity of isolated nickel alkyl complexes to undergo -hydride elimination is explored. Isomerization and olefin exchange experiments show that -hydride elimination is kinetically viable but thermodynamically unfavorable in [(MeNN2)Ni-alkyl] complexes. The intermediacy of an [(MeNN2)Ni-H] (6) species was corroborated by trapping experiments. The alkyl complex [(MeNN2)Ni-propyl] catalyzes olefin isomerization reactions. In chapter three the aforementioned nickel(II) hydride complex 2 was synthesized by reaction of [(MeNN2)Ni-OMe] (10) with Ph2SiH2, and was characterized by NMR and IR spectroscopy, as well as X-ray crystallography. Complex 6 was unstable in solution, and decomposed via two reaction pathways. The first pathway was through intramolecular N-H reductive elimination to III give MeNN2H and Ni particles. The second pathway was intermolecular, giving H2, Ni particles, and a five-coordinate Ni(II) complex [(MeNN2)2Ni] (12) as the products. Compound 6 reacted with ethylene and acetone, forming [(MeNN2)Ni-Et] (2) and [(MeNN2)Ni-OiPr] (13), respectively. Complex 6 also reacted with alkyl halides, yielding nickel(II) halide complexes and alkanes. The reduction of alkyl halides was rendered catalytic, using 1 as catalyst, NaOiPr or NaOMe as base, and Ph2SiH2 or Me(EtO)2SiH as the hydride source. The catalysis appeared to operate via a radical mechanism. In chapter four a detailed mechanistic study of alkyl-alkyl Kumada coupling catalyzed by the preformed nickel(II) pincer complex 1 is reported. The coupling proceeds through a radical process, involving two nickel centers for the oxidative addition of alkyl halide. The catalysis is 2nd order in Grignard reagent, 1st order in catalyst, and 0th order in alkyl halide. A transient species, (MeNN2)Ni-Alkyl2, is identified as the key intermediate responsible for the activation of alkyl halide, the formation of which is the turnover-determining step of the catalysis. Finally, a catalytic cycle for Nickamine-catalyzed cross-coupling reactions was established. This dissertation elaborates the properties of nickel-alkyl and nickel-hydride complexes of the Nickamine system. It elucidates many mechanistic features of the alkyl-alkyl Kumada coupling reactions catalyzed by Nickamine, and establishes, for the first time, a bimetallic oxidative addition mechanism for nickel-catalyzed coupling reactions. The work significantly enhances the current understanding of cross-coupling reactions of alkyl halides.

EPFL2013

Mechanistic Studies of Two Ni-Catalyzed Reactions: Reductive Amidation of Esters with Nitroarenes and Hydrosilylation of Alkenes

Marten Leendert Ploeger

Mechanistic investigations into homogeneously catalyzed reactions are essential for the fur-ther development of synthetic methodologies. Insights in the overall reaction pathway and vital steps such as the rate-determining and selectivity-determining steps allow for rational design of improved catalysts. Moreover, mechanistic investigations may reveal the existence of unexpected intermediates in the catalytic cycle. The discovery of such intermediates may inspire new methodologies that would not have been considered if their formation was un-known. Because of economic advantages over heavier congeners, there has been a recent surge in the use of nickel -based homogeneous catalysts. Although much progress has been made into methodology development, the mechanistic understanding of the new reactivities is relatively primitive. In-depth mechanistic investigations into nickel catalyzed reactions are therefore of considerable interest. Chapters 2-4 deal with the mechanism of reductive coupling of nitroarenes and esters to form amides. In chapter 2, the initial reduction pathway that occurs before the reaction with ester is investigated, revealing the crucial intermediate to be azobenzene and the source of the proton in the final amide product. In chapter 3, kinetics, Hammett plots, competition experi-ments and stoichiometric reactions with a potential intermediate are described. These studies reveal azobenzene is reductively cleaved by low-valent nickel before the ester gets involved in the reaction. Moreover, ZnCl2, a byproduct of the reduction of the nickel precursor by zinc, is revealed to play an important role in several steps of the reaction. In chapter 4, the computa-tional investigation based on the experimental data is discussed. By combining the computa-tional exploration of the potential energy surface with qualitative kinetic analysis, a catalytic cycle for the reaction between azobenzene and ester could be proposed. The finding that the reaction between azobenzene and ester goes through nickel imide inter-mediates is intriguing as nickel imides are known to react with a variety of substrates and azo-benzene would be a relatively benign precursor to them. Chapter 5 reports a preliminary explo-ration of several types of reactivities can be expected to work on the basis that the reactivity with imides is already known. Several types of these reactivities seem to be inaccessible as they are incompatible with the highly reductive nature of the nickel catalyst that is required for the azobenzene activation. However, some other reactivities show promise. Chapter 6 reports an investigation in the alkene hydrosilylation catalyzed by a nickel pincer complex developed in our group. Previous investigations had indicated a nickel alkyl complex was the resting state. However, a combination of reaction progress analysis, transmission elec-tron microscopy and competition reactions reveal that this is merely a precatalyst. Under cata-lytic conditions, it slightly decomposes under to form the true catalyst, which is tentatively identified as nickel nanoparticles.

EPFL2020

A Well-Defined Ni Pincer Catalyst for Cross Coupling of Non-Activated Alkyl Halides and Direct C-H Alkylation

Oleg Vechorkin

Carbon-carbon bond forming reactions are among the most important and useful methods for organic synthesis. During the last years, significant progress has been made in this field. Whereas many catalysts were developed for the coupling of aryl, alkenyl, and alkynyl halides, non-activated alkyl halides remain challenging substrates, mainly due to unproductive β-hydride elimination and difficulty in oxidative addition of alkyl halides. This dissertation is devoted to the development of a well-defined nickel catalyst for cross coupling of non-activated alkyl halides and direct alkylation of C–H bonds. Chapter 2 describes the synthesis of a new pincer MeN2N ligand and its Ni complexes. This ligand can be obtained by Pd-catalyzed C–N coupling of 2-amino-N,N-dimethylaniline and 2-bromo-N,N-dimethylaniline. Reaction of its Li salt with Ni(dme)Cl2 gives [(MeN2N)Ni-Cl] (1). Complex 1 can be akylated with Grignard reagents to give [(MeN2N)Ni-Alkyl] species. Stability of the alkyl complexes against β-hydride elimination inspired us to use the [(MeN2N)Ni-Cl] complex as a catalyst for cross coupling of carbon nucleophiles with alkyl halides. After investigating different experimental conditions, we found that complex 1 is an active catalyst for cross coupling of non-activated alkyl polyhalides (Chapter 3) and alkyl monohalides (Chapter 4) with alkyl Grignard reagents. The reaction with alkyl monohalides can be done at -35 °C in DMA and only 30min is required to accomplish the formation of the desired products. The high activity of the catalyst resulted in a high group tolerance. Ester, ketone, amide, nitrile, heterocyclic, and acetal groups didn't pose problems. In Chapter 5, the catalysis was extended to include aryl and heteroaryl Grignard reagents as nucleophiles. The best results were obtained with primary alkyl bromides and iodides and cyclic secondary alkyl iodides in THF and at room temperature. Addition of an additive such as TMEDA or bis[2-(N,N-dimethylaminoethyl)]ether (O-TMEDA) was necessary to prevent the formation of undesired homocoupling products. Functionalized Grignard reagents could be readily coupled. The [(MeN2N)Ni-Cl] catalyst was then used for the Sonogashira coupling of alkyl halides with alkynes (Chapter 6). A wide range of functionalized alkyl halides could be used for this reaction. Not only alkyl iodides and bromides but also alkyl chlorides can be used. Moreover, by changing reaction conditions (additive and temperature), selective coupling of C–Br bond in the presence of C–Cl bond, and of C–I bond in the presence of both C–Br and C–Cl bonds can be achieved. This feature allowed us to carry out multiple and selective Sonogashira coupling of the substrates containing different alkyl halide bonds. We could combine Sonogashira coupling with Kumada-Corriu-Tamao coupling. Utilization of these two methods leads to a simple and rapid synthesis of organic molecules. Similar conditions were then applied for the direct alkylation of aromatic heterocycles in Chapter 7. Aromatic heterocyclic compounds are widely used as bio-active molecules, pharmaceuticals, and organic materials. Direct C–H functionalization represents the most straightforward way for the derivatization of these compounds. Despite of the developments during the last years, direct alkylation of C–H bond with alkyl halides is still challenging. Utilization of our [(MeN2N)Ni-Cl] catalyst gives the desired products in high yields and a wide range of aromatic heterocyclic compounds can be used for the reaction. The well-defined nature and a high stability of [(MeN2N)Ni-Cl] complex and its derivatives enabled us to perform detailed mechanistic investigations of the catalytic transformations. Presumed intermediates of catalytic cycles were determined and some of them were synthesized or separated from the reaction mixture. The resting states of the catalysts were also defined in most of the cases, giving important information for the mechanistic elucidation. In the last part (Chapter 8) we developed a direct C–H carboxylation chemistry for aromatic heterocycles. The carboxylation can be done under catalyst-free conditions and with a mild base Cs2CO3. The unstable carboxylic acids were converted to the more stable esters by a one-pot reaction with MeI. A wide substrate scope was achieved.

EPFL2011