Nickel Complexes of a Pincer Amidobis(amine) Ligand: Synthesis, Structure, and Activity in Stoichiometric and Catalytic C—C Bond Forming Reactions of Alkyl Halides

NiII complexes of the new pincer amidobis(amine) ligand are described. The Ni chloride complex catalyzes Kumada-Corriu-Tamao coupling of unactivated alkyl halides with alkyl Grignard reagents, as well as double C-C coupling of CH2Cl2 with alkyl Grignard reagents (see schemes). The synthesis, properties, and reactivity of nickel(II) complexes of a newly developed pincer amidobis(amine) ligand (MeNN2) are described. Neutral or cationic complexes [(MeNN2)NiX] (X=OTf (6), OC(O)CH3 (7), CH3CN (8), OMe (9)) were prepared by salt metathesis or chloride abstraction from the previously reported [(MeNN2)NiCl] (1). The Lewis acidity of the {(MeNN2)Ni} fragment was measured by the 1H NMR chemical shift of the coordinated CH3CN molecule in 8. Electrochemical measurements on 1 and 8 indicate that the electron-donating properties of NN2 are similar to those of the analogous amidobis(phosphine) (pnp) ligands. The solid-state structures of 6-8 were determined and compared to those of 1 and [(MeNN2)NiEt] (3). In all complexes, the MeNN2 ligand coordinates to the NiII ion in a mer fashion, and the square-planar coordination sphere of the metal is completed by an additional donor. The coordination chemistry of MeNN2 thus resembles that of other three-dentate pincer ligands, for example, pnp and arylbis(amine) (ncn). Reactions of 2 with alkyl monohalides, dichlorides, and trichlorides were investigated. Selective CC bond formation was observed in many cases. Based on these reactions, efficient Kumada-Corriu-Tamao coupling of unactivated alkyl halides and alkyl Grignard reagents with 1 as the precatalyst was developed. Good yields were obtained for the coupling of primary and secondary iodides and bromides. Double C-C coupling of CH2Cl2 with alkyl Grignard reagents by 1 was also realized. The scope and limitations of these transformations were studied. Evidence was found for a radical pathway in Ni-catalyzed C-C cross-coupling reactions, which involves NiII alkyl intermediates.

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

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

Suzuki-Miyaura cross-coupling of non-activated alkyl halides catalyzed by well-defined nickel pincer complexes

Thomas Clément Di Franco

Metal-catalyzed cross-coupling reactions are powerful and widespread methods for the carbon-carbon bond formation. Among the electrophile partners, non-activated alkyl halides remain challenging substrates because of their reluctance towards oxidative addition and their tendency to undergo the competitive ß-hydride elimination reaction. Due to the stability, availability and low toxicity of boron reagents, the Suzuki-Miyaura reaction is one of the most advantageous cross-coupling reaction. This dissertation is devoted to the development of Ni-catalyzed Suzuki-Miyaura reactions of non-activated alkyl halides. Chapter 2 describes the alkyl¿alkyl and alkyl¿aryl Suzuki¿Miyaura reactions of unactivated alkyl halides catalyzed by a well-defined pincer complex, Nickamine (1). The coupling of 9-alkyl-9-borabicyclo[3.3.1]nonane and 9-phenyl-9-borabicyclo[3.3.1]nonane (9-BBN) reagents with primary alkyl halides was achieved in modest to good yields. The reactions tolerated a variety of useful functional groups including ester, ether, furan, thioether and acetal. Reaction attempts with other boron reagents are also presented. In chapter 3, the first Ni-catalyzed Suzuki¿Miyaura coupling of alkyl halides with alkenyl-(9-BBN) reagents is reported. Both primary and secondary alkyl halides including alkyl chlorides can be coupled. The coupling method can be combined with hydroboration of terminal alkynes, allowing the expedited synthesis of functionalized alkyl alkenes from readily available alkynes with complete (E)-selectivity in one-pot. The method was successfully applied to the total synthesis of (±)-Recifeiolide, a natural macrolide. Replacement of a dimethyl amino group of the amidobis(amine) nickel(II) pincer complex (1), [(MeN2N)Ni¿Cl], by a pyrrolidino group resulted in a new nickel(II) pincer complex (2), [(PyrNMeNN)Ni¿Cl]. As shown in chapter 4, complex 2 is an efficient catalyst for Suzuki-Miyaura cross-coupling of non-activated secondary alkyl halides, while complex 1 is largely inactive. In contrast to the dimethylamino group in 1, the pyrrolidino group in 2 appears to be ¿hemilabile¿, which explains the significant activity difference towards the coupling of secondary alkyl halides. Synthesis and characterization of a new series of Ni-NNN pincer complexes are presented in chapter 5. No major structural difference was found between the new complexes except for the C-N-C angle of the various substituents of the side arm amino groups. The influence of these substituents on the catalytic performance of the Ni-complexes in alkyl-alkyl Kumada and Suzuki-Miyaura cross-coupling reactions was systematically investigated. No correlation was found between the catalytic activity and the key structural parameter (C-N-C angle), redox properties or Lewis acidity of the complexes. The cross-coupling of secondary alkyl halides is highly desirable since a stereogenic carbon center can be created during the process. Chapter 6 resumes the synthesis of new chiral pincer ligands in order to develop an enantioselective cross-coupling. Chiral centers were first introduced in the pyrrolidino group of the pincer ligand but the resulting Ni-complexes did not succeed in achieving a stereoconvergent reaction. The introduction of an oxazolino group in the pincer ligand structure resulted in more promising Ni-catalysts, efficient for both primary and secondary alkyl halides.

EPFL2016