Nickel-catalyzed cross-couplings via activation of alkyl carbon-nitrogen bonds
Date
2018
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Publisher
University of Delaware
Abstract
This dissertation focuses on investigations of nickel-catalyzed cross-couplings of alkyl amine electrophiles via carbon-nitrogen bond activation. ☐ Chapter 1 describes a stereospecific nickel-catalyzed Miyaura borylation of enantioenriched benzylic ammonium salts with bis(pinacolato)diboron. Under the mild conditions identified, a variety of electronically and sterically diverse secondary benzylic boronates are obtained in good yields and high enantioenrichment. Ni(cod)2 in conjunction with a phosphine or N-heterocyclic carbene ligand provides borylated products from both naphthyl- and phenyl-substituted ammonium salts. Additionally, the practicality of this transformation was demonstrated by performing the reaction on the bench using air- and moisture-stable Ni(OAc)2•4H2O. Mechanistic investigations suggest that the oxidative addition step proceeds through an SN2’ pathway. Importantly, this was the first example of a stereospecific Miyaura borylation of a benzylic electrophile to deliver benzylic boronates in high enantioenrichment. ☐ Chapter 2 describes a nickel-catalyzed Suzuki-Miyaura cross-coupling of alkyl pyridinium salts with aryl boronic acids. This reaction utilizes alkyl amines as sources of unactivated alkyl groups via the intermediacy of redox-active Katritzky pyridinium salts which can be easily obtained in a single step from the primary amine. The optimized conditions, which employ a combination of Ni(OAc)2•4H2O and bathophenanthroline, deliver both primary and secondary alkyl arenes in good yield and excellent functional group tolerance. Importantly, this transformation is amenable to cross-couplings of pyridyl or quinolinyl boronic acids and pyridinium salts derived from drug-intermediates or amino acids. Mechanistic studies, including radical clock and radical trap experiments, suggest that a NiI/III catalytic cycle is operative. ☐ Chapter 3 describes a nickel-catalyzed Negishi alkylation of alkyl pyridinium salts with primary alkyl zinc halides. Ni(acac)2•xH2O, in conjunction with a redox non-innocent terpyrine or bis(N-pyrazolyl)pyridine ligand, has been identified as an optimal catalyst system that furnishes a variety of functionally diverse products with new alkyl-alkyl bonds. Both primary and secondary alkyl pyridinium salts can be efficiently cross-coupled. Additionally, a number of pyridinium salts derived from drugs or drug-intermediates are competent electrophiles in this transformation. ☐ Chapter 4 describes my efforts toward the development of a nickel-catalyzed reductive coupling of alkyl pyridinium salts with heteroaromatic halides. A variety of reaction parameters have been screened including nickel precursors, ligands, and stoichiometric reductants. However, the identity of the reductant and the inclusion of a salt additive have proven most crucial in this transformation, with Mn0 and LiCl delivering the highest yield to date (64%). Optimization of this reaction is ongoing. ☐ Chapter 5 describes a nickel-catalyzed Suzuki-Miyaura arylation of α-pyridinium salts with aryl and heteroaryl boroxines. The pyridinium salts are synthesized in a single step from commercially available α-amino esters and serve as a readily available electrophile for the metal-catalyzed formation of α-aryl propionic acid derivatives.
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Keywords
Pure sciences, Coupling, Nickel, Organic