Catalytic Applications and Mechanistic Investigations of Iron Bis(oxazolinylphenyl)amino Pincer Complexes in Kumada Cross Coupling and Hydrosilylation Reactions

The aim of the project was to investigate iron bis(oxazolinylphenyl)amino (bopa) pincer complexes as pre-catalysts in the enantioselective Kumada cross-coupling of non-activated alkyl halides with aryl Grignard reagents. From this preliminary cross-coupling studies we were able to isolate potential intermediate iron species that were then investigated for their catalytic activity. Further reactivity studies, kinetic studies, and DFT computations revealed the feasible catalytic cycles. Some intermediate species also proved to be relevant in the enantioselective hydrosilylation reaction of ketones. In the first chapter, a short overview is given of state-of-the-art iron pincer complexes and their catalytic application. The focus was put on symmetric pincer systems which are rigidified with aromatic rings in the ligand backbone. They proved themselves as highly active catalysts for the hydrogenation and hydrosilylation reaction of olefins, acetylenes, and carbonyls. There are also some examples given for trapping and releasing of hydrogen as potential applications for the storage of hydrogen on a molecular level. Examples for C-C bond formations are given to a lesser extent. In chapter two, the enantioselective Kumada cross-coupling of alkyl halides with aryl Grignard reagents was investigated. Iron(III) bopa pincer complexes are efficient pre-catalysts for the cross-coupling of non-activated primary and secondary alkyl halides with aryl Grignard reagents. The reactions proceed at room temperature in moderate to excellent yields. A variety of functional groups can be tolerated. The enantioselectivity of the coupling of secondary alkyl halides is low. The cross-coupling with secondary benzylic bromides solely yielded the homo-coupling products, 2,3-diphenylbutane and biphenyl. Modifications on the oxazoline, and diphenylamino moiety showed similar reactivity but did not improve the enantiomeric excess (ee). In chapter three, we isolated and characterised well-defined iron complexes and probed and supported their catalytic roles. Reactivity studies identified an Fe(II) "ate" complex, [Fe(Bopa-Ph)(Ph)2]-, as the active species for the oxidative addition of alkyl halide. Experiments using radical-probe substrates and DFT computations reveal a bimetallic and radical mechanism for the oxidative addition. The kinetics of the coupling of an alkyl iodide with PhMgCl indicates that formation of the "ate" complex, rather than oxidative addition, is the turnover determining step. In chapter four, the preliminary results on a possible mechanism in the enantioselective hydrosilylation of 4-acetylbiphenyl is presented. We could show that [(Fe(bopa)OAc)2], a 5-coordinated dimeric iron complex, is formed as the catalytic active species from the reaction of bopa ligands with Fe(OAc)2. The gathered results are consistent with an inner sphere reaction pathway, including the formulation of an iron-hydride species. For the reactions with zinc, no mechanism could yet be proposed.

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

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

Synthesis and structure-activity studies of well-defined nickel complexes as catalysts for cross coupling of alkyl electrophiles

Pablo Marcelo Perez Garcia

This dissertation is devoted to the development of well-defined nickel complexes as catalysts for cross coupling processes of alkyl electrophiles. In chapter one, we summarize recent cross coupling methodologies of alkyl electrophiles using nickel based catalysts. The description of each study includes the coupling conditions, the substrate scope and the mechanistic considerations. In chapter two, we report the development of high diastereoselective alkyl-alkyl Kumada coupling method for 1,3- and 1,4-substituted cyclohexyl halides and tetrahydropyrans using an amido bis(amine) nickel complex "Nickamine" as catalyst. The stereochemical properties of the starting materials and of the coupling products were determined by NMR techniques. The mechanistic investigations of the coupling provided evidence of a reversible activation of the alkyl halide. In chapter three, we present the synthesis of new bidentate amido â amine ligands derived from 2,5-dimethylpyrrolidine or Î±-methylbenzylamine. The ligands were used to synthesize well-defined bidentate nickel complexes by transmetallation from the corresponding lithium complexes. A complex having an Î±-methylbenzylamine derived ligand and 2,4-lutidine as co-ligand was an effective catalyst for the coupling of non-activated secondary iodides with alkyl Grignard reagents. An enantiomerically pure version of this complex was synthesized and no racemization was observed during the synthesis. The chiral complex showed no asymmetric induction capacity as a cross coupling catalyst. In chapter four, the synthesis of new amido bis(amine) pincer ligands derived from Î±-methylbenzylamine or pyrrolidine are described. The metallation of a NNN ligand derived from Î±-methylbenzylamine was not possible by transmetallation from the corresponding lithium complex or by oxidative addition from the corresponding chloroamine. A well-defined pincer nickel complex was synthesized by Li â Ni transmetallation using a NNN ligand having dimethyl amino and pyrolidine donors. Crystal structure analysis shows that the pyrrolidine donor is slightly less hindered. This complex is an effective catalyst for alkyl-alkyl and alkyl-aryl Kumada coupling of non-activated primary and secondary alkyl halides. The coupling process shows good functional group tolerance. This is the first time that a well-defined nickel pincer complex shows high catalytic activity for Kumada coupling reactions of sterically hindered alkyl substrates. In chapter 5, a well-defined nickel pincer complex bearing an alkyl amine donor is synthesized. The complex is able to catalyzed direct coupling of non-activated primary halides with terminal alkynes at room temperature. The catalysis has a good substrate scope and high functional group tolerance. Kinetic data suggest that the new pincer ligand is hemilabile, and the dissociation of the alkyl amine donor is the turnover-determining step of the catalysis. An intermediate Ni-alkynyl species has been isolated and structurally characterized. The reactivity of this species gives insight into the nature of the active species for the activation of alkyl halide.

EPFL2015