University of Groningen
Harnessing the reactivity of alkenyl heteroarenes through copper catalysis and Lewis acids
Lanza, Francesco
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Publication date: 2018
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Lanza, F. (2018). Harnessing the reactivity of alkenyl heteroarenes through copper catalysis and Lewis acids. University of Groningen.
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Harnessing the Reactivity of Alkenyl Heteroarenes Through
Copper Catalysis and Lewis Acids
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The work described in this thesis was carried out at the Stratingh Institute for Chemistry,
University of Groningen (The Netherlands).
This work was financially supported by NWO.
Printed by Ridderprint BV, Ridderkerk, The Netherlands.
Cover picture by Emanuela Lanza.
ISBN: 978-94-034-0761-6 (Printed Book)
ISBN: 978-94-034-0762-3 (Ebook)
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Harnessing the reactivity of alkenyl
heteroarenes through copper
catalysis and Lewis acids
PhD thesis
to obtain the degree of PhD at the
University of Groningen
on the authority of the
Rector Magnificus Prof. E. Sterken
and in accordance with
the decision by the College of Deans.
This thesis will be defended in public on
Friday 15 June 2018 at 14.30 hours
by
Francesco Lanza
born on 19 August 1987
in Messina, Italië
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Supervisors
Prof. S. Harutyunyan
Prof. J.G. Roelfes
Assessment Committee
Prof. E. Otten
Prof. F.J. Dekker
Prof. A. Alonso
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Table of Contents
List of abbreviations ... 9
Chapter 1 Synthesis and Functionalization of Aliphatic and Aromatic Heterocycles ... 11
1.1 Introduction ... 12
1.2 Pyridines ... 12
1.3 Benzoxazoles and Its Analogues ... 16
1.4 Conclusions ... 20
1.5 Outline of the Thesis ... 20
1.6 Bibliography ... 21
Chapter 2 Copper Catalysed Conjugate Addition of Grignard Reagent to Alkenyl Aromatic Heterocycles .. 25
2.1 Introduction ... 26
2.2 Results and Discussion ... 27
2.3 Conclusion ... 35
2.4 Experimental Section ... 37
2.4.1 General Information ... 37
2.4.2 Synthesis and Characterizations of Substrates ... 37
2.4.3 General Procedure A: Cu-Catalyzed Asymmetric Grignard Addition to N-Containing Aromatic Heterocycles ... 42
2.4.4 General Procedure B: Synthesis of Racemic Products ... 43
2.4.5 Catalytic Asymmetric Addition of EtMgBr to (E)-1i and (Z)-1i ... 58
2.4.6 Controlled Experiments ... 58
2.4.7 (E)/(Z) Photoisomerization Experiments ... 59
2.4.8 (E)/(Z) Isomerization Experiments of (Z)-10i ... 59
2.4.9 Determination of Absolute Configuration ... 59
2.5 Bibliography ... 61
Chapter 3 Hetero Aromatic Enolate Trapping Promoted by BF3⋅OEt2 ... 63
3.1 Introduction ... 64
3.2 Rseults and Discussion ... 65
3.3 Conclusion ... 74
3.4 Experimental Section ... 75
3.4.1 General Information ... 75
3.4.2 Synthesis and characterizations of substrates ... 75
3.4.3 General Procedure A: Enantioselective Conjugate Addition/Trapping Process ... 79
3.4.4 General Procedure B: Racemic Conjugate Addition/Trapping Process ... 80
3.4.5 Crystallographic Data ... 83
3.5 Bibliography ... 85
Chapter 4 Copper Catalysed Alkylation of β-Substituted 2- and 4-Alkenyl Pyridines ... 87
4.1 Introduction ... 88
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4.3Conclusion ... 96
4.4 Experimental Section ... 97
4.4.1General information ... 97
4.4.2 Synthesis and Characterizations of Substrates ... 97
4.4.3General Procedure A: Cu-Catalyzed Asymmetric Grignard Addition to 4-Alkenyl Pyridines. ... 101
4.4.4General Procedure B: Cu-Catalyzed Asymmetric Grignard Addition to 2-Alkenyl Pyridines. ... 101
4.4.5 General Procedure C: synthesis of Racemic Products ... 102
4.4.6Synthesis and Characterizations of Products (13a-d, 15a-f, and 16a-j) ... 102
4.4.7Controlled Experiments ... 111
4.4.8Synthesis and Characterization of Functionalized Pyridines (17-21) ... 112
4.4.9Synthesis and Characterization of Cu-Complexes Derived From Ligand L7 and L8 ... 117
4.4.10Determination of Absolute Configuration by X-Ray Analysis of 2a’ ... 118
4.5 Bibliography ... 121
Chapter 5 On the Cu Catalysed Conjugated Addition of Grignard Reagent to Alkenyl Pyridine Derivatives: a Mechanistic Study ... 123
5.1 Introduction ... 124
5.2 Result and Discussion ... 126
5.3Conclusion ... 135
5.4 Experimental Section ... 136
5.4.1 General Information ... 136
5.4.2 Synthesis and Characterizations of Substrates 17 and 18 ... 136
5.4.3 Synthesis and Characterizations of Products 19 ... 137
5.4.4 Synthesis and characterizations of product 20 ... 138
5.4.5 (E)/(Z) Isomerization Studies ... 138
5.4.6NMR Studies ... 142
5.4.7 General Procedure for Preparation of Pyridine-LA and Pyridine-EtMgBr Complexes ... 142
5.5 Bibliography ... 143
Summary ... 145
Nederlandse Samenwatting ... 147
