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

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.

Hu, Xile
Lausanne, EPFL
Other identifiers:
urn: urn:nbn:ch:bel-epfl-thesis7142-5

Note: The status of this file is: EPFL only

 Record created 2016-08-25, last modified 2018-03-17

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