Development of Transition Metal Catalyzed Metallonitrene and Metallocarbene Group Transfer Reactions Open Access

Weldy, Nina (2015)

Permanent URL:


Group transfer reactions provide a powerful approach for formation of complex molecules for pharmaceutical and natural product synthesis. Our study of group 9 transition metal complexes has provided a range of group transfer reactions for formation of C-C, C-N, and C-O bonds from simple starting materials. In Chapter 1, we discuss the intermolecular metallonitrene/alkyne cascade. Previous studies in our laboratory established the direct unveiling of an intermediate with an α-iminometallocarbene reactivity profile by an intramolecular metallonitrene-initiated oxidative cascade process. We extended the utility of this cascade process to intermolecular trapping of the reactive intermediate by a variety of allyl ethers to provide α-oxyimine products in which new C=N, C-O and C-C bonds have all been generated. A variety of substrates were explored, enantioenriched products were able to be generated by efficient transfer of stereochemical information from simple enantioenriched allyl ethers, and the usefulness of the process was demonstrated by an efficient synthesis of the core ring system of the Securinega alkaloids. Our study of racemic and enantioselective C-H amination strategies is described in Chapter 2. A quinoline-oxazoline amide ligand framework was designed for C-H amination with aryl azides. Ir(I) complexes of this ligand were synthesized. Iridium(III) bis(oxazolinyl)phenyl and bis(imidazolinyl)phenyl complexes were capable of benzylic C-H amination in moderate enantioselectivity. In collaboration with the MacBeth laboratory, a dinuclear Co(II) complex with a redox-active ligand system was found to efficiently catalyze C-H amination to form indolines from aryl azides. The catalyst system was capable of forming 5-, 6-, and 7-membered rings and tolerated medicinally relevant heterocycles, such as pyridine and indole. The ease of synthesis and tunability of the redox-active ligand system make this method advantageous for selective C-H amination. Finally, Chapter 3 details our enantioselective C-H functionalization with acceptor-only metallocarbenes catalyzed by an iridium(III) bis(imidazolinyl)phenyl catalyst family to give phthalan- and 2,5-dihydrofuran derivatives in excellent yield and enantioselectivity. The reaction was found tolerant of a variety of substitution patterns of the diazoacetate, while the steric and electronic properties of the substrate greatly influenced the reaction yield and selectivity. These results showcased the potential for reaction design based on an interaction of experimental and computational results in developing a foundation for further expansion into highly selective reactions with novel classes of acceptor-only metallocarbenes.

Table of Contents

Chapter 1. Intermolecular Cascade Reactions Through Alkyne Oxidative Amination with Metallonitrenes

1.1 Introduction to Metallonitrene Cascade Reactions. 2

1.1.1 Background of Cascade Reactions. 2

1.1.2 Generation of Metallonitrenes. 3

1.1.3 Metallonitrene Cascade Reactions. 6 Metallonitrene/Alkene Cascade Reactions. 6 Azide-Initiated Metallonitrene/Alkene Cascade Reactions. 6 Intermolecular Alkene Oxyamination. 14 Metallonitrene/Allene Cascade Reactions. 15 Aminocyclopropane-Forming Metallonitrene/Allene Cascade Reactions. 15 2-Amidoallylcation [3+2] Annulation. 19 Cascades with 1,4-Diazaspiro[2.2]pentane (DASP) Scaffolds. 22 Metallonitrene/Alkyne Cascade Reactions. 27 Intramolecular Metallonitrene/Alkyne Cascade Reactions. 27 Intermolecular Metallonitrene/Alkyne Cascade Reactions. 36

1.2 Intermolecular Metallonitrene/Alkyne Cascade Optimization. 42

1.3 Intermolecular Metallonitrene/Alkyne Cascade Substrate Scope. 44

1.4 Viroallosecurinine Core Synthesis. 59

1.4.1. Previous Syntheses of Securinega Alkaloids. 59

1.4.2 Retrosynthetic Analysis of Viroallosecurinine and Preliminary Results. 63

1.4.3 Streamlined Route to Viroallosecurinine Core. 68

1.5 Conclusions. 71

1.6. Experimental Procedures and Compound Characterization. 73

References. 96

Chapter 2. Group 9 Transition Metal Catalyzed C-H Amination with Aryl Azides

2.1 Introduction to Metallonitrene C-H Amination. 104

2.1.1 Qualities of an Ideal C-H Amination. 104

2.1.2 Azides as Metallonitrene Precursors. 105 Metallonitrene C-H Amination Utilizing Azides with Electron-Withdrawing Groups. 106 Metallonitrene C-H Amination Utilizing Aryl and Vinyl Azides. 111 Metallonitrene C-H Amination Utilizing Alkyl Azides. 113

2.1.3 Challenges in C-H Amination Utilizing Azide Metallonitrene Precursors. 114 Use of First Row Transition Metals in Metallonitrene C-H Amination Utilizing Aryl Azides. 115 Enantioselectivity in Metallonitrene C-H Amination Utilizing Aryl Azides. 116

2.2 Modular Ligand Design for Enantioselective Catalysis. 119

2.2.1 Oxazoline-Based Modular Ligands. 119

2.2.2 Linear Regression Mathematical Modeling for Catalyst Optimization. 120

2.2.3 Planned Synthetic Routes to Quinoline/Oxazoline Amide Ligands. 123

2.3 Enantioselective C-H Amination with Iridium(I) and Iridium(III) Catalysts. 126

2.3.1 Quinoline/Oxazoline Amide Ligand Synthesis. 126

2.3.2 Quinoline/Oxazoline Amide Ligand Metalation and Resultant Complex Characterization. 135

2.3.3 Iridium(I) quinoline-oxazoline amide Catalyzed C-H Amination with Aryl Azides. 145

2.3.4 Iridium(III) Phebox and Phebim Catalyzed Enantioselective C-H Amination with Aryl Azides. 148

2.4 Cobalt(II) Catalyzed C-H Amination with Aryl Azides. 160

2.4.1 Catalysis with a Cobalt(II) Dimer with Redox-Active Ligand Scaffold NH(o-PhNHC(O)iPr)2. 160

2.4.2 Aryl Azide Substrate Syntheses. 161

2.4.3 Cobalt(II) Catalyzed C-H Amination Results. 174

2.5 Conclusions. 180

2.6 Experimental Procedures and Compound Characterization. 182

References. 237

Chapter 3. Enantioselective Acceptor-Only Metallocarbene C-H Functionalization

3.1 Introduction to Enantioselective C-H Functionalization Utilizing Metallocarbenes. 244

3.1.1 Intermolecular Enantioselective C-H Insertion with Acceptor-Only Diazoacetate Metallocarbene Precursors. 245 Intermolecular Enantioselective C-H Insertion with Alkyl Diazoacetates. 246 Racemic C-H Insertion and Enantioselective Cyclopropanation with Ethyl Diazoacetate. 251

3.1.2 Iridium(III) Phebox and Phebim Catalysts for C-H Functionalization. 253 Development and Previous Uses of the Phebox and Phebim Ligand Scaffolds. 253 Enantioselective Iridium(III) Phebox Catalyzed Donor/Acceptor Metallocarbene C-H Functionalization. 258 Enantioselective Iridium(III) Phebox Catalyzed Ethyl Diazoacetate C-H Functionalization. 260

3.2 Enantioselective Iridium(III) Phebim Catalyzed Acceptor-Only Diazoacetate C-H Functionalization. 263

3.2.1 Iridium(III) Phebim Catalyst Synthesis. 264

3.2.2 Iridium(III) Phebim Catalyst Optimization with Ethyl Diazoacetate. 266

3.2.3 Acceptor-Only Diazoacetate Scope. 267

3.2.4 Phthalan-Derived Substrate Synthesis. 271

3.2.5 Ethyl Diazoacetate C-H Insertion Substrate Scope. 276

3.2.6 Kinetic Resolution. 279

3.2.7 Determination of Absolute Stereochemistry of C-H Insertion Products. 281

3.2.8 Kinetic Isotope Effect of Ethyl Diazoacetate C-H Insertion into Tetrahydrofuran. 282

3.3 Conclusions. 285

3.4 Experimental Procedures and Compound Characterization. 287

References. 326

About this Dissertation

Rights statement
  • Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.
  • English
Research field
Committee Chair / Thesis Advisor
Committee Members
Last modified

Primary PDF

Supplemental Files