A Structure-Activity Study of Ni-Catalyzed Alkyl-Alkyl Kumada Coupling. Improved Catalysts for Coupling of Secondary Alkyl Halides

A structure–activity study was carried out for Ni catalyzed alkyl–alkyl Kumada-type cross coupling reactions. A series of new nickel(II) complexes including those with tridentate pincer bis(amino)amide ligands (RN2N) and those with bidentate mixed amino-amide ligands (RNN) were synthesized and structurally characterized. The coordination geometries of these complexes range from square planar, tetrahedral, to square pyramidal. The complexes had been examined as precatalysts for cross coupling of nonactivated alkyl halides, particularly secondary alkyl iodides, with alkyl Grignard reagents. Comparison was made to the results obtained with the previously reported Ni pincer complex [(MeN2N)NiCl]. A transmetalation site in the precatalysts is necessary for the catalysis. The coordination geometries and spin-states of the precatalysts have a small or no influence. The work led to the discovery of several well-defined Ni catalysts that are significantly more active and efficient than the pincer complex [(MeN2N)NiCl] for the coupling of secondary alkyl halides. The best two catalysts are [(HNN)Ni(PPh3)Cl] and [(HNN)Ni(2,4-lutidine)Cl]. The improved activity and efficiency was attributed to the fact that phosphine and lutidine ligands in these complexes can dissociate from the Ni center during catalysis. The activation of alkyl halides was shown to proceed via a radical mechanism.

Creating Tertiary and Quaternary Carbon Centers by Nickel and Copper-Catalyzed Cross-Coupling Reactions of Alkyl Electrophiles

Peng Ren

Transition-metal-catalyzed C-C coupling reactions have been extensively studied in the past three decades. These reactions have become invaluable to fundamental research and industrial applications, because they can be used construct complicated molecules from simple precursors. Among them, the coupling systems of aryl, alkenyl, and alkynyl halides have been well-optimized, while the coupling of non-activated alkyl halides, especially secondary alkyl halides, is still difficult. In the first chapter, the development of the transition-metal-catalyzed alkyl-alkyl cross-coupling reactions is introduced and summarized, and the difficulties and potential improvements are discussed. In chapter 2, a structure-activity study is described for Ni-catalyzed alkyl-alkyl Kumada- type cross coupling reactions. A series of new nickel(II) complexes bearing bidentate and tridentate amino-amide ligands were synthesized and structurally characterized. The coordination geometries of these complexes include square planar, tetrahedral, and square pyramidal. The complexes had been examined as pre-catalysts for the cross coupling of non- activated alkyl halides, particularly secondary alkyl iodides, with alkyl Grignard reagents. Comparison was made to the results obtained with the previously reported Ni pincer complex [(MeN2N)NiCl] (1). A transmetalation site in the pre-catalysts is necessary for the catalysis. The coordination geometries and spin-states of the pre-catalysts have little or no influence. The work led to the discovery of several well-defined Ni catalysts that are significantly more active and efficient than the pincer complex (1) for the coupling of secondary alkyl halides. The best catalysts are [(HNN)Ni(PPh3)Cl] (24) and [(HNN)Ni(2,4-lutidine)Cl] (27). The improved activity and efficiency were attributed to the fact that the phosphine and lutidine ligands in these complexes could dissociate from the Ni center during catalysis. The activation of alkyl halides was shown to proceed via a radical mechanism. After investigating how secondary alkyl halides could couple with primary Grignard reagents in high yields using nickel catalysts, the complementary methodology, the coupling of non-activated alkyl electrophiles with secondary and tertiary alkyl nucleophiles, is described in chapter 3. It was found that simple copper(I) chloride could catalyze the cross- coupling of non-activated primary alkyl halides and tosylates with secondary and tertiary alkyl Grignard reagents. The method is highly efficient, practical, and general. A wide range of functional groups can be tolerated, such as ester, ketone, amide, nitrile, and heterocylic groups. In chapter 4, a series of new copper complexes bearing hemilabile ligands were synthesized and structurally characterized. Among them, the copper complex [(MeN2N)Cu(PPh3)] (36) was shown to have the highest catalytic activity towards alkylation of benzoxazoles with secondary alkyl halides. The higher efficiency of 36 relative to other copper catalysts might result from a hemilabile property of the pincer ligand. An important additive, bis[2-(N,N-dimethylamino)ethyl] ether (BDMAEE) is also identified. This is the first time that non-activated secondary alkyl halides have been used as electrophiles in the alkylation of benzoxazoles.

EPFL2012

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

Structure, dynamics and catalytic activity of ruthenium(II)-arene phosphine complexes

This thesis encompasses work on the coordination chemistry and catalytic activity of half sandwich ruthenium(II)-arene phosphine complexes. The investigation of phosphine dissociation and association reactions of these complexes represents the unifying theme of this study and, in addition to providing fundamental insights into the coordination chemistry of these compounds, allowed structure-activity relationships to be made and assisted in the development of new synthetic procedures. The thesis is organised into three parts according to the type of phosphine ligand investigated. The dissociation characteristics and catalytic activity of bis-phosphine complexes are presented in Chapter 2. The former properties were established by kinetic studies of ligand exchange and gasphase fragmentation analysis by tandem mass spectrometry, and helped to rationalise trends in the observed catalytic activity for the hydrogenation of styrene to ethylbenzene. The more active complexes were also shown to be chemoselective catalysts for the hydrogenation of aldehydes in the presence of olefinic bonds. Mechanistic studies were carried out in order to rationalise the preferential hydrogenation of aldehydes, which is consequently suggested to proceed via an ionic outer-sphere mechanism. Chapter 3 describes investigations on the coordination chemistry of ruthenium(II)-arene complexes containing diphosphine ligands. Complexes containing κ1-coordinated diphosphine ligands, with or without triphenylphosphine as a co-ligand, were prepared or characterised as the corresponding borane adducts. Mechanistic studies, including determination of enthalpies, entropies and, in two cases, volumes of activation, for the chelation reactions of the isolated κ1-diphosphine complexes were undertaken. The coordination chemistry of a chiral diphosphine, (R)-BINAPO, was also investigated; the synthesis of complexes containing this ligand in a range of coordination modes was achieved. The final chapter concerns the reactivity and catalytic activity of ruthenium(II) complexes containing (PPh2CH2)3CMe (triphos). Investigations of the catalytic activity of ruthenium(II)-arene complexes containing the κ2-coordinated triphos ligand were carried out together with pertinent reactivity studies and comparisons to structural analogues, which helped rationalise the observed activities. The reactivity and catalytic chemistry of one of the structural analogues, a ruthenium(II)-acetate κ3-triphos complex, was also investigated in detail as it proved to be a highly active catalyst for the hydrogenation of 1-alkenes.

EPFL2007