Cross Coupling with Iminium Ions

Abstract

Transition metal-catalyzed cross coupling is among the most powerful strategies for carbon–carbon bond formation, but its scope has traditionally been limited to organohalide electrophiles. In recent years, contributions from our group and others have allowed for similar reactivity with non-halide electrophiles, greatly enhancing the capabilities of cross coupling. This thesis describes two distinct strategies for the use of iminium ions in Ni-catalyzed cross coupling to provide α-substituted amine products.

The first strategy leverages a unique redox mechanism involving Ni(0) oxidative addition to iminium π-systems in the context of a Negishi coupling of pyridinium ions. Initial studies with 4-methoxypyridine allowed for the highly enantioselective synthesis of 2-aryl-2,3-dihydro-4-pyridones, and further optimization enabled the use of pyridine to access stereodefined 2-aryl-1,2-dihydropyridines. Both classes of product are valuable intermediates for further organic synthesis, as demonstrated by a number of derivatization reactions for the formation of a diverse array of chiral piperidine derivatives. Preliminary studies provide strong support for the proposed mechanism in the form of a crystallographically characterized Ni(II)–(π allyl) complex formed by oxidative addition of Ni(0) to a 4 methoxypyridinium salt.

The second strategy makes use of a Ni-catalyzed reductive coupling manifold to achieve a carbon–carbon bond-forming analogue of reductive amination. This modular, three-component coupling is effective with a range of organic electrophiles, which undergo bond formation with iminium ions generated in situ from benzaldehydes and N-trimethylsilyl amines. The reductive coupling is also successful in intramolecular contexts, providing ready access to fused ring and N-heterocyclic products. The mechanism of this reaction is still under active investigation, but comparisons to a previously developed reductive cross coupling of oxocarbenium ions suggest that a pathway involving α-amino radical formation and addition to Ni is unlikely.