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The Synthesis of Diverse Families of Organic Compounds via Nickel-Catalyzed Nucleophilic Substitution Reactions


Freas, Dylan Joshua (2022) The Synthesis of Diverse Families of Organic Compounds via Nickel-Catalyzed Nucleophilic Substitution Reactions. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/e76h-vh27.


Transition metal-catalyzed cross-coupling has provided an exceptionally powerful approach to carbon–carbon bond formation, allowing chemists to solve a number of important problems in organic synthesis. However, by the early 2000s, its application to the formation of alkyl–alkyl bonds had been limited by the slow oxidative addition of palladium catalysts toward alkyl halides and the tendency of transition-metal-alkyls to undergo β-hydride elimination. Since then, complexes based on nickel, an earth-abundant metal, have emerged as efficient catalysts for the nucleophilic substitution of alkyl electrophiles. The propensity for nickel to access a range of oxidation states allows it to react via one-electron pathways to generate radical intermediates, opening the door to couplings of sterically-hindered electrophiles and offering a ready mechanism for enantioconvergence.

Our group has applied nickel catalysts to substitution reactions of activated and unactivated 2o and 3o alkyl electrophiles by carbon– as well as by heteroatom-based nucleophiles, including a number of enantioconvergent processes. However, given the enormous range of conceivable coupling partners, many interesting challenges have yet to be addressed. The application of nickel-catalyzed substitution reactions to the synthesis of diverse families of compounds, particularly those with frequent uses in organic synthesis and pharmaceutical science, is described in this thesis. While reaction development is the primary focus of this work, a variety of synthetic applications and mechanistic investigations are also detailed within.

Chapter 2 describes two methods for the catalytic enantioconvergent synthesis of amines, which involve the coupling of an alkylzinc reagent with a racemic electrophile (specifically, an α-phthalimido alkyl chloride and an N-hydroxyphthalimide ester of a protected α-amino acid). A one-pot variant of this transformation is possible, enabling the efficient enantioselective synthesis of a range of interesting target molecules. Several mechanistic insights are also detailed.

Chapter 3 outlines the nickel-catalyzed alkylation of racemic α-haloglycine derivatives, a class of electrophile previously unemployed in metal-catalyzed asymmetric cross-coupling reactions, with alkylzinc reagents to generate protected unnatural α-amino acids. This method is applied to the generation of several enantioenriched unnatural α-amino acids that have previously been shown to serve as useful intermediates in the synthesis of bioactive compounds.

Chapter 4 details the development of a nickel-catalyzed cross-coupling for the asymmetric synthesis of protected thiols. The synthesis of an N-hydroxyphthalimide ester containing a geminal thioester (a previously unreported class of molecule with no applications to cross-coupling) is described, along with its reactivity toward alkylzinc reagents and other classes of organometallic nucleophiles.

Chapter 5 examines the ability of nickel to catalyze the nucleophilic fluorination of unactivated alkyl halides, a transformation whose application to the synthesis of alkyl fluorides has been impeded by the low nucleophilicity and high basicity of fluoride. The reactivities of unactivated 1o, 2o, and 3o alkyl bromides, as well as several preliminary mechanistic investigations, are presented.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:nickel, catalysis, cross-coupling, nucleophilic substitution, enantioconvergent, amine, amino acid, nucleophilic fluorination
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Fu, Gregory C.
Thesis Committee:
  • Reisman, Sarah E. (chair)
  • Stoltz, Brian M.
  • Agapie, Theodor
  • Fu, Gregory C.
Defense Date:15 November 2021
Funding AgencyGrant Number
National Science Foundation Graduate Research FellowshipDGE-1745301
National Institutes of HealthR01-GM062871
Dow Next-Generation Educator FundUNSPECIFIED
Record Number:CaltechTHESIS:11182021-220809412
Persistent URL:
Related URLs:
URLURL TypeDescription adapted for Chapter 2 adapted for Chapter 3
Freas, Dylan Joshua0000-0003-0611-7907
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:14428
Deposited By: Dylan Freas
Deposited On:01 Dec 2021 23:44
Last Modified:08 May 2024 17:20

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