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Scholarly Works (4 results)

  • Thesis
  • Peer Reviewed
UC Berkeley Electronic Theses and Dissertations (2019)

The following dissertation discusses the development of transition-metal catalysts for selective hydroboration and hydroamination of unconjugated and unstrained alkenes, termed “unactivated alkenes.” These reactions proceed with high levels of enantioselectivity and, for reactions of unsymmetrical internal alkenes, with high regioselectivity.

Chapter 1 is an overview of transition-metal-catalyzed hydrofunctionalization of unactivated alkenes. This review focuses on the challenges and strategies for achieving asymmetric hydroamination and hydroboration of unactivated alkenes, particularly unactivated internal alkenes. Mechanistic aspects of these reactions are also discussed. The summary of previous literature precedents highlights how the work described in this dissertation fills knowledge gaps in this field.

Chapter 2 describes the development of copper-catalyzed regioselective and enantioselective hydroboration of unsymmetrical internal alkenes. This process, coupled with a series of subsequent stereospecific transformations of the enantioenriched hydroboration products, constitutes a formal hydrofunctionalization that efficiently converts internal alkenes to a diverse set of enantioenriched compounds with distinct functional groups.

Chapter 3 describes the mechanistic study of the copper-catalyzed asymmetric hydroboration of alkenes. A comprehensive study by both experiment and computation reveals the fundamental principles that govern the efficiency of the copper catalysts for reactions with alkenes and selectivity observed for the alkene hydroboration.

Chapter 4 describes the development of new bisphosphine ligands for asymmetric hydroboration of 1,1-disubstituted alkenes. Trimethylgermanyl groups on the bisphosphine ligand significantly increase enantioselectivity of the hydroboration of 1,1-disubstituted alkenes. In addition, this new set of ligands forms a catalyst that is highly active toward the hydroboration of unactivated 1,2-disubstituted alkenes.

Chapter 5 describes the development of copper-catalyzed formal hydroamination of unsymmetrical internal alkenes. Similar to the hydroboration discussed in Chapter 2, the hydroamination occurs with high enantioselectivity and regioselectivity. This work revealed that the polar functional groups proximal to the alkene controlled the regioselectivity through inductive effects.

Chapter 6 describes the development of iridium-catalyzed asymmetric hydroamination of unactivated internal alkenes. A combination of a cationic iridium complex and 2-amino-6-methylpyridine, was essential to the development of the hydroamination. This is the first example of a direct, highly enantioselective addition of an N-H bond to an unactivated internal alkene.

    Cover page: Development of Transition-Metal Catalysts for Selective Hydrofunctionalization of Unactivated Alkenes
    • Article
    • Peer Reviewed
    UC Berkeley Previously Published Works (2020)
    Hydroamination of alkenes, the addition of the N-H bond of an amine across an alkene, is a fundamental, yet challenging, organic transformation that creates an alkylamine from two abundant chemical feedstocks, alkenes and amines, with full atom economy1-3. The reaction is particularly important because amines, especially chiral amines, are prevalent substructures in a wide range of natural products and drugs. Although extensive efforts have been dedicated to developing catalysts for hydroamination, the vast majority of alkenes that undergo intermolecular hydroamination have been limited to conjugated, strained, or terminal alkenes2-4; only a few examples occur by the direct addition of the N-H bond of amines across unactivated internal alkenes5-7, including photocatalytic hydroamination8,9, and no asymmetric intermolecular additions to such alkenes are known. In fact, current examples of direct, enantioselective intermolecular hydroamination of any type of unactivated alkene lacking a directing group occur with only moderate enantioselectivity10-13. Here we report a cationic iridium system that catalyses intermolecular hydroamination of a range of unactivated, internal alkenes, including those in both acyclic and cyclic alkenes, to afford chiral amines with high enantioselectivity. The catalyst contains a phosphine ligand bearing trimethylsilyl-substituted aryl groups and a triflimide counteranion, and the reaction design includes 2-amino-6-methylpyridine as the amine to enhance the rates of multiple steps within the catalytic cycle while serving as an ammonia surrogate. These design principles point the way to the addition of N-H bonds of other reagents, as well as O-H and C-H bonds, across unactivated internal alkenes to streamline the synthesis of functional molecules from basic feedstocks.
      Cover page: Catalytic asymmetric addition of an amine N–H bond across internal alkenes
      • Article
      • Peer Reviewed
      UC Berkeley Previously Published Works (2023)
      Remote hydrofunctionalizations of alkenes incorporate functional groups distal to existing carbon-carbon double bonds. While remote carbonylations are well-known, remote hydrofunctionalizations are most common for addition of relatively nonpolar B-H, Si-H, and C-H bonds with alkenes. We report a system for the remote hydroamination of disubstituted alkenes to functionalize an alkyl chain selectively at the subterminal, unactivated, methylene position. Critical to the high regioselectivity and reaction rates are the electronic properties of the substituent on the amine and the development of the ligand DIP-Ad-SEGPHOS by evaluating the steric and electronic effects of ligand modules on reactivity and selectivity. The remote hydroamination is compatible with a broad scope of alkenes and aminopyridines and enables the regioconvergent synthesis of amines from an isomeric mixture of alkenes. The products can be derivatized by nucleophilic aromatic substitution on the amino substituent with a variety of nucleophiles.
        Cover page: Remote Hydroamination of Disubstituted Alkenes by a Combination of Isomerization and Regioselective N-H Addition.
        • Article
        • Peer Reviewed
        UC Berkeley Previously Published Works (2022)
        Asymmetric alkene hydroamination could be a direct route to valuable chiral amines from abundant feedstocks. However, most asymmetric hydroaminations have limited synthetic value because they require a large excess of alkene, occur with modest enantioselectivity, and proceed with limited tolerance of functional groups. We report an enantioselective, intermolecular hydroamination of unactivated terminal alkenes that occurs with equimolar amounts of alkene and amine, tolerates many functional groups, and occurs in high yield, with high enantioselectivity and turnover numbers. Mechanistic studies revealed factors, including reversibility of the addition, reversible oxidation of the product amine, competing isomerization of the alkene reactant, and unfavorable replacement of sacrificial ligands in standard catalyst precursors by the chiral bisphosphine, that needed to be addressed to achieve enantioselective N-H additions to alkenes.
          Cover page: Enantioselective hydroamination of unactivated terminal alkenes
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