The Development of Complementary Allylic C-H Amination and Amidation Conditions for the Regioselective Functionalization of Group IX MCp*-π-Allyl Intermediates Restricted; Files Only

Burman, Jacob (Fall 2019)

Permanent URL: https://etd.library.emory.edu/concern/etds/np193b238?locale=en
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Abstract

The following work will describe the research efforts aimed to uncover novel reactivity in the field of allylic C‑H amination of mono‑, di‑, and trisubstituted olefins via π‑allyl intermediates.  The discovery, development, and related studies with Group IX MCp* catalysts for complementary reaction conditions to selectively target either amine regioisomer will also be discussed. Chapter 1 will cover the rising need for alternative contemporary methods to prepare target allylic amine products, focusing on the current approaches and mechanistic distinctions for allylic C‑H amination techniques that proceed through metallonitene and/or π‑allyl intermediates.

Chapter 2 will outline the research efforts for the discovery of reaction conditions for unprecedented intermolecular reactivity to target conjugated regioisomers from unsymmetrically disubstituted styrene derivatives. A significant expansion of nucleophile scope is shown for preferentially substituted amines bearing a single electron‑withdrawing group. Additional preliminary work shows efficacy for the selective allylic C‑H amination of terminal and trisubstituted olefins. Mechanistic details support the intermediacy of π‑allyl intermediates and related studies determine the origin of high regioselectivity stems from a discrete thermodynamic equilibration process for C‑N bond formation.

Chapter 3 will highlight the identification and use of dioxazolone amidating reagents to alter the mechanistic pathway for C‑N bond formation toward an inner‑sphere reductive elimination event from an acyl‑nitrene a hypothesized M(V)Cp* intermediate. The reaction is highly tolerant for a variety of functional groups and provides complementary regioselectivity for the benzylic/branched amidation product from terminal, di‑, or trisubstituted olefins. Studies reveal a necessity for effective pairing of catalyst and olefin substrate high yield and regioselectivity. Whereby RhCp* catalysts result in high yield and selectivity for disubstituted olefins, IrCp* catalysts show similar results when paired with terminal or trisubstituted olefins. Applications for the branched selective methodology have shown promise for the diastereoselective synthesis of anti‑1,2‑amino alcohol motifs.

Table of Contents

Chapter 1:  Introduction and Background: Hypothesis Driven Approach to the Development of Regiodivergent Conditions for the Allylic C‑H Amination and Amidation of Disubstituted Olefins

1.1 Relevance of Nitrogen Containing Molecules for Drug Discovery ................2

1.2. Allylic Amines as Highly Desirable Intermediates for Targeted Synthesis .......3

1.3. Allylic C-H Amination Methods: Key Developments for Contemporary Knowledge .........4

1.3.1. A Metallonitrene Approach for Allylic C-H Amination ....................5

1.3.2. Allylic C-H Amination Proceeding Through π-Allyl Intermediates .......12

1.3.3. Redefining Strategy with Allylic C-H Amination via π-Allyl Intermediates ........17

1.3.3.1. Intramolecular Allylic C-H Amination as Key Step .............17

1.3.3.2. Intermolecular Allylic C-H Amination as Key Step .............18

1.4. RhCp-Derivatives as Catalysts for Allylic C-H Functionalization via π-Allyl Intermediates .....19

1.5. Addressing the Challenges of Intermolecular Reactivity for the Allylic C-H Amination of Olefins via π-Allyl Intermediates ...22

References ........................................................................................24

Chapter 2: Reaction Discovery and Development for Conjugated Selective Oxidative Allylic C-H Amination of Disubstituted Olefins via RhCp*-π-Allyl Intermediates

2.1. Reaction Design for Probing Allylic C-H Amination ..................................30

2.1.1. Substrate Design Choice ..................................................................30

2.1.2. Reaction Design and Development with Initial Experiments ...........31

2.2. Optimization of Allylic C-H Amination on trans-1,3-Diphenylpropene ................35

2.3. Amine Nucleophile Studies for Allylic C-H Functionalization of DPP ................... 39

2.3.1. Successful Amination Nucleophiles for DPP ...................................39

2.3.2. Unsuccessful Amination Nucleophiles for DPP ...............................41

2.3.3. Conclusion of Key Advances for Allylic C-H Amination Nucleophiles ............. 42

2.4. Efforts Towards Regioselective Allylic C-H Amination of Unfunctionalized Olefins .............. 43

2.4.1. Studies for Allylic C-H Amination of Unsymmetrical Disubstituted Olefins ....................... 43

2.4.1.1. Design Choice and Access to Unsymmetrical trans-ß-Alkylstyrene Derivatives ................ 43

2.4.1.2 Amination of Disubstituted Olefins ......................................45

2.4.1.3. Steric Effects at the Homo-Allylic Center for Allylic C-H Amination ................................. 48

2.4.1.4. Allylic C-H Amination of cis-Disubstituted Olefins ...........49

2.4.2. Preliminary Investigation for Amination of Terminal Olefins ...............................................51

2.4.3. Preliminary Investigation for Allylic Amination of a Trisubstituted Olefin ........................... .52

2.5. Initial Mechanistic Experiments for Allylic C-H Amination .......................53

2.5.1 Revelation of Thermodynamic Equilibration ...................................53

2.5.2. Initial Insight into Reversibility of C-H Cleavage ............................54

2.5.3. RhCpE-π-Allyl Complex as Mechanistic Intermediate .....................55

2.6. Attempts for Enantioselective Allylic C-H Functionalization via π-Allyl Intermediates ............ 56

2.6.1. Efforts with Cramer Group’s Chiral RhCpX Catalysts .....................56

2.6.1.1. Background and Analysis for Investigation ..........................56

2.6.1.2. Amine Nucleophiles for Enantioselectivity ..........................61

2.6.1.3. Indoles as Nucleophiles for Enantioselectivity .....................65

2.6.2. Dual Allylic C-H Activation / Allylic Substitution for Enantioselectivity via Allylic Acetate Intermediate. ...... 66

2.6.3. Interpretation of Enantioselectivity through Mechanistic Findings ...................................... .67

2.7. Conclusion and Future Directions ................................................................69

Experimental Procedures and Characterization Data ...........................................................71

References ...........................................................................................................................131

Chapter 3: Group IX MCp* Benzylic/Branched Selective Amidation: Revelation of Catalyst-Substrate Matching for Efficient Catalysis

3.1. Introduction and Hypothesis for Benzylic Selective Allylic C-H Amidation ................. 136

3.2. Reaction Discovery of Benzylic Selective Allylic C-H Amidation ............139

3.3. Optimization and Control Experiments for Benzylic Selective Allylic ......................... 142

3.4. Synthesis and Access to Novel 3-Substiuted Dioxazolone Amidating Reagents .............144

3.5. Dioxazolone Substituent Effects for the Allylic C-H Amidation of Allylbenzene ............ 146

3.6. Studies for Efficient MCp*-Catalyzed Allylic C-H Amidation of Terminal Olefins ............ 149

3.6.1. RhCp*-Catalyzed Allylic Amidation of Allylbenzene Derivatives ..................................... 149

3.6.2. Studies to Determine IrCp* is Optimal for Terminal Olefins .........150

3.7. Catalyst Studies for Benzylic Selective Amidation of Disubstituted Olefins .........................152

3.8. Studies for the Allylic Amidation of a Model Trisubstituted Olefin ..........155

3.9. Stoichiometric Studies and Preparation of M(III)Cp*-π-Allyl Complexes ............................156

3.9.1. Synthesis and Characterization for the RhCp*- and IrCp*-π-Allyl Complexes ....................156

3.9.2. Stoichiometric Amidation Reactions of MCp*-π-Allyl Complexes ....... .................158

3.10. Diastereoselective Allylic C-H Amidation for the Synthesis of 1,2-Amino Alcohols ........... .159

3.10.1. 1,2-Amino Alcohols in Synthesis and Methods Development .......159

3.10.2. Plans for Synthesis and Determination Stereochemistry for 1,2-Amino Alcohols ..............160

3.10.3. Derivatization Studies of Amidation Product to Access syn-Benzyl Amine ........................161

3.10.4. Amidation of Protected Homo-Allylic Alcohols ............................165

3.10.5. Determination of anti-Selective Allylic C-H Amidation of Homo-Allylic Ethers .................168

3.10.6. Mechanistic Evaluation of Anti-Diastereoselectivity for Allylic C-H Amidation .................171

3.11. Conclusion and Future Directions ..............................................................173

Experimental Procedures and Characterization Data .........................................................175

X-Ray Crystallography Data ...............................................................................................254

References ...........................................................................................................................289

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