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Mechanistic Investigations and Development of Ni-Catalyzed Cross- Electrophile Coupling Reactions


Turro, Raymond Farnon (2023) Mechanistic Investigations and Development of Ni-Catalyzed Cross- Electrophile Coupling Reactions. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/na61-ed84.


Transition metal-catalyzed cross-coupling reactions have proven to be a powerful technology for the modular construction of carbon-carbon and carbon-heteroatom bonds over the last half century. More recently, reductive cross-coupling catalyzed by nickel has emerged as a complementary synthetic approach that couples electrophilic fragments and is rendered catalytic by the inclusion of a terminal reductant. These reactions are advantageous because the use electrophiles as coupling partners which display greater stability, functional group tolerance, and commercial availability over the corresponding nucleophilic coupling partners. Additionally, Ni catalysts are less prone to β-hydride elimination compared to later transition metals which enables C(sp³)–C(spⁿ) couplings. The challenge with using coupling partners of the same polarity is developing a catalyst that can activate each electrophile in a mechanistically distinct way in order to get high levels off cross-selectivity, over statistical mixtures of cross- and homocoupled products.

Herein, we describe a mechanistic investigation on Ni-catalyzed cross-electrophile couplings developed in our lab; specifically, the asymmetric reductive alkenylation of N-hydroxyphthalimide (NHP) esters and benzylic chlorides. Investigations of the redox properties of the Ni-bis(oxazoline) catalyst, the reaction kinetics, and mode of electrophile activation show divergent mechanisms for these two related transformations. Notably, the mechanism of C(sp³) activation changes from a Ni-mediated process when benzyl chlorides and Mn⁰ are used to a reductant-mediated process that is gated by a Lewis acid when NHP esters and tetrakis(dimethylamino)ethylene is used. Kinetic experiments show that changing the identity of the Lewis acid can be used to tune the rate of NHP ester reduction. Spectroscopic studies support a Ni^(ɪɪ)–alkenyl oxidative addition complex as the catalyst resting state. DFT calculations suggest an enantiodetermining radical capture step and elucidate the origin of enantioinduction for this Ni-BOX catalyst.

Efforts to expand the scope of coupling partners in XEC reactions to include novel classes of electrophiles, such as N-alkyl imines, are also described. The preparation of heterobenzylic amines by a Ni-catalyzed reductive cross-coupling between heteroaryl imines and C(sp³) electrophiles is reported. This umpolung-type alkylation proceeds under mild conditions, avoids the pre-generation of organometallic reagents, and exhibits good functional group tolerance. Mechanistic studies are consistent with the imine substrate acting as a redox-active ligand upon coordination to a low-valent Ni center. The resulting bis(2-imino)heterocycle·Ni complexes can engage in alkylation reactions with a variety of C(sp³) electrophiles, giving heterobenzylic amine products in good yields.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Organic Chemistry, Synthesis, Kinetics, Nickel, Catalysis, Mechanism, Electrochemistry, Reaction Development, Cross-Electrophile Coupling
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Reisman, Sarah E.
Thesis Committee:
  • Robb, Maxwell J. (chair)
  • Stoltz, Brian M.
  • Agapie, Theodor
  • Reisman, Sarah E.
Defense Date:22 May 2023
Funding AgencyGrant Number
Record Number:CaltechTHESIS:05312023-172947562
Persistent URL:
Related URLs:
URLURL TypeDescription adapted for Chapter 3
Turro, Raymond Farnon0000-0001-9774-4556
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:15243
Deposited By: Raymond Turro
Deposited On:01 Jun 2023 16:40
Last Modified:20 Jun 2023 22:38

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