Arene Dearomatization via Radical Hydrofunctionalization Open Access

McDaniel, Kelly (Fall 2021)

Permanent URL:


Dearomative functionalization methods are highly sought-after for their ability to efficiently transform simple, planar aromatics to more complex, three-dimensional structures. We envisioned the extension of previously developed olefin hydroarylation systems to the hydroarylation of arenes. We initially found success in the photoredox-catalyzed hydroarylation of indoles, where an organic cyanoarene catalyst and trialkylamine reductant proved key to selective product formation. Mechanistically, radical termination occurred primarily via stepwise reduction/protonation, with a small contribution from concerted hydrogen atom transfer. This mechanistic understanding prompted the extension of this reactivity to benzenoid dearomatization, where aryl radical cyclization onto unactivated arenes yielded spirocyclic 1,4-diene products. In this case, selectivity is dictated by regioselective protonation of the Birch-like dienyl anion. This broadly applicable method allowed for the rapid synthesis of an NPY Y5 receptor antagonist. Finally, the dearomative cyclization of α-acyl radicals to form spirocyclic lactam products was demonstrated. In exploring this reactivity, we discovered that the rate of reductive radical formation must be slower than the rate of reductive radical-polar crossover. Otherwise, a buildup of the cyclized radical intermediate occurs, leading to dimerization via radical-radical coupling. This method was effective across a broad range of (hetero)arenes. Derivatization of the resulting spirocyclic lactam/cyclohexadiene products was shown, including the synthesis of the anticonvulsant Gabapentin. The transformations described herein demonstrate the rapid formation of drug-like, three-dimensional products from simple aromatic precursors.

Table of Contents

Chapter 1 Introduction to Radical Dearomatization. 1

1.1 Dearomatization. 2

1.1.1 Established dearomatization methods. 3

1.1.2 Hypothesis: Dearomatization with high-energy aryl radicals. 5

1.2 Aryl radicals. 5

1.2.1 Traditional methods for aryl radical generation. 5

1.2.2 Aryl radical generation via photoredox catalysis. 6

1.3 Dearomatization via photocatalytically-generated radicals. 12

Chapter 2 Dearomatization Through Photoredox Hydroarylation: Discovery of a Radical-Polar Crossover Strategy. 14

2.1 Introduction. 15

2.2 Results and Discussion. 16

2.2.1 Optimization of reaction conditions for indole hydroarylation. 18

2.2.2 Scope of dearomative hydroarylation. 20

2.2.3 Mechanism of indole hydroarylation reaction and analysis of termination event. 21

2.2.4 Extension of reactivity to the hydroarylation of unactivated arenes. 22

2.3 Conclusions. 23

2.4 Supporting Information. 24

2.4.1 General. 24

2.4.2 Optimization Details. 26

2.4.3 General Procedures. 28

2.4.4 Computational Details. 30

2.4.5 Preparation of Starting Materials. 34

2.4.6 Characterization Data. 45

2.4.7 Deuterium Labeling Study. 54

Chapter 3 : Hydroarylation of Arenes via Reductive Radical-Polar Crossover. 56

3.1 Introduction. 57

3.2 Results and Discussion. 58

3.2.1 Optimization of system for the dearomative hydroarylation of unactivated arenes. 58

3.2.2 Mechanism of benzene hydroarylation reaction. 59

3.2.3 Scope of the dearomative hydroarylation of benzene derivatives. 61

3.2.4 Efficient synthesis of NPY Y5 receptor antagonist. 63

3.3 Conclusions. 64

3.4 Supporting Information. 65

3.4.1 General Information. 65

3.4.2 General Procedures. 67

3.4.3 Example of Selectivity. 70

3.4.4 Fluorescence Quenching and Stern-Volmer Plots. 71

3.4.5 Electrochemical Reaction Optimization Procedure. 72

3.4.6 Unsuccessful Substrates. 73

3.4.7 Preparation of Starting Materials. 74

3.4.8 Preparation of Dearomatized Spirocycles. 98

3.4.9 Computational Details. 118

Chapter 4 : Dearomatization of Unactivated Arenes via Catalytic Hydroalkylation. 123

4.1 Introduction. 124

4.2 Results and Discussion. 126

4.2.1 Mechanistic design of dearomative hydroalkylation system. 126

4.2.2 Scope of dearomative hydroalkylation. 130

4.2.3 Factors influencing cyclization efficiency. 131

4.2.4 Derivatization of spirolactam products. 134

4.3 Conclusions. 136

4.4 Supporting Information. 137

4.4.1 General Information. 137

4.4.2 General Procedures. 139

4.4.3 Optimization Details. 141

4.4.4 Deuterium Labeling Study. 143

4.4.5 Electrochemical Measurements. 144

4.4.6 Computational Details. 147

4.4.7 Preparation of Starting Materials. 169

4.4.8 Preparation of Spirolactam Products. 198

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