Development of Intermolecular Couplings of Aryl Radical Species with Olefins Público

Abstract

The intermolecular hydroarylation of simple alkenes with pyridyl radicals has been achieved using a photoredox radical mechanism. The regiospecific single-electron reduction of halogenated pyridines with a commercially available iridium catalyst, followed by radical addition to unactivated alkene substrates, which occurs with exclusive anti-Markovnikov selectivity. This system was then expanded to include pyridyl radical addition to vinyl heteroatoms, as well as alkynes (giving the linear anti-Markovnikov product). Through mechanistic investigations, we hypothesize that this protocol is operating through a proton coupled electron transfer mechanism, uniquely enabled by slightly acidic 2,2,2-trifluoroethanol as the reaction solvent to give an electrophilic, protonated pyridyl radical intermediate which then engages electron-rich olefins. Additionally, an organocatalyzed photoredox protocol for the regioselective synthesis of arylethylamines via aryl radicals has been developed. While arylethylamine synthesis strategies have been previously reported utilizing styrene hydroamination, we offered a complementary approach, where photoinduced reduction of aryl halides and intermolecular coupling to vinylamine derivatives afforded a wide range of arylethylamine structures. Both hydroarylation systems are mild, scalable, tolerant of many functional groups, and effective for the preparation of a wide range of medicinally relevant scaffolds with complete regiocontrol.

Table of Contents

Table of Contents

CHAPTER 1: (HETERO)ARYL RADICALS – FORMATION AND REACTIVITY

1.1      Aryl radicals from diazoniums and aryl halides

1.2      Aryl radicals from photoredox catalysis

CHAPTER 2: ANTI-MARKOVNIKOV HYDROARYLATION OF NEUTRAL OLEFINS VIA PYRIDYL RADICAL INTERMEDIATES

2.1 Pyridine functionalization via radical intermediates

2.2 Pyridyl radical conjugate addition, chain cyclization

2.3 Hydroarylation of neutral olefins with pyridine units

2.4 Optimization of the coupling of pyridyl radicals with 1-octene

2.6 Application of the hydroarylation conditions to biaryl coupling

2.7 Competition experiment

2.8 Conclusion

2.9 Supporting information

2.9-I. General Information

2.9-II. General Procedures for Hydropyridylation of Simple Olefins

2.9-III. Optimization Details

2.9-IV. Preparation of Starting Materials

2.9-V. Procedure and Characterization Data

2.9-VI. Equation 1

CHAPTER 3: HYDROARYLATION OF FUNCTIONALIZED OLEFINS AND MECHANISTIC INVESTIGATIONS OF PYRIDYL RADICAL INTERMEDIATES

3.1 Pyridyl radical reactivity

3.2 Pyridyl radical addition to vinyl heteroatoms-development of polarity-matched HAT conditions

3.3 Expanded pyridyl radical hydroarylation scope

3.4 Hydroarylation mechanistic analysis

3.5 Conclusion

3.6 Supporting information

3.6-I. General Information

3.6-II. General Procedures

3.6-III. Optimization Table:

3.6-IV. Preparation of starting materials:

3.6-V. Preparation of Substrates

3.6-VII. Scale up

3.6-VIII. Flow synthesis

3.6-IX. Mechanistic Investigation

3.6-X. Reaction Limitations

CHAPTER 4: PHOTOCATALYTIC STRATEGY FOR COMPLEX ARYLETHYLAMINE SYNTHESIS VIA ARYL RADICAL INTERMEDIATES

4.1 Arylethylamines: a highly privileged pharmacophore

4.2 Aryl radicals as synthetic intermediates

4.3 Reaction development for arylethylamine synthesis via aryl radicals

4.4 Reaction scope

4.5 Aryl chlorides as radical precursors

4.6 Catalytic thiol enables intermolecular reactivity

4.7 Native neurotransmitter synthesis via hydroarylation

4.8 Application to the synthesis of an agrochemical and derivatives

4.9 Perovskites

4.10 Conclusion

4.11 Supporting Information

4.11-I. General Information

4.11-II. General Procedures

4.11-III. Optimization Procedure

4.11-IV. Stern Volmer Fluorescence Quenching

4.11-V Quantum Yield Calculations

4.11-VI. Light/Dark Experiment

4.11-VII. Thiol Loading Experiment

4.11-VIII. Thiol Loading Experiment for Iodo/Bromo/Chloro-methylbenzoate

4.11-IX. Preparation of Starting Materials

4.11-X. Characterization Data for Substrates

About this Dissertation

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School	Laney Graduate School
Department	Chemistry
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Chemistry, Organic
Palabra Clave	radical chemistry heterocycles photochemistry Catalysis aryl radicals
Committee Chair / Thesis Advisor	Dennis Liotta, Emory University Simon Blakey, Emory University Nathan Jui, Emory University

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