University of Groningen
Carbon-carbon bond formations using organolithium reagents
Heijnen, Dorus
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Publication date: 2018
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Heijnen, D. (2018). Carbon-carbon bond formations using organolithium reagents. University of Groningen.
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Cover : Tip of a needle of tert-Butyllithium, a highly pyrophoric organolithium reagent. Credits : Dusan Kolarski
The work described in this thesis was carried out at the Stratingh Institute for Chemistry (University of Groningen, The Netherlands) and was financially supported by a NWO-TOP grant
Printed by : Ipskamp Printing, Enschede, The Netherlands ISBN (printed) 978-94-028-1146-9
Carbon-Carbon Bond Formations Using
Organolithium Reagents
Proefschrift
Ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen op
gezag van de rector magnificus prof. dr. E. Sterken en volgens besluit van het
College voor Promoties
De openbare verdediging zal plaatsvinden op
Vrijdag 7 september 2018 om 16:15
door
Dorus Heijnen
Geboren op 16 juli 1988
te Nijmegen
Promotor
Prof. dr. B.L. Feringa
Copromotor
Prof. dr. S. R. Harutyunyan
Beoordelingscommissie
Prof. dr. J.H. van Maarseveen
Prof. dr. K. Barta
Table of Contents
Chapter 1: Introduction Organolithium Reagents : Discovery, Preparation, Properties and
Applications ... 9
1.1 Discovery and preparation ... 10
1.2 Properties ... 11
1.3 Transmetallations and catalysis ... 14
Direct cross coupling with organolithium compounds ... 16
Faster ... 18
Cheaper ... 20
Functional group compatibility ... 21
Applications ... 22
1.4 References. ... 25
Chapter 2: Palladium-Catalyzed Cross-Coupling of (Trimethylsilyl)methyllithium with (Hetero)-Aryl Halides ... 28
2.1 Introduction ... 29
2.2 Catalyst optimization ... 30
2.3 Substrate scope with aryl chlorides ... 31
2.4 Substrate scope with aryl bromides ... 32
2.5 Selectivity ... 33
2.6 The sequential coupling of TMS-substituted toluene derivatives... 34
2.7 Conclusions ... 35
2.8 References ... 36
2.9 Experimental section ... 39
Chapter 3: Pd-Catalyzed, tBuLi-Mediated Dimerization of Aryl Halides and its Application in the Atropselective Total Synthesis of Mastigophorene ... 47
3.1 Introduction ... 48
3.2 Optimization and Scope ... 50
3.3 Synthesis of Mastigophorene ... 53
3.4 Conclusions ... 57
3.5 References ... 57
3.6 Experimental section ... 60
Chapter 4 : One-Pot Strategies for Developing Synthetic Methods with Organolithium Reagents ... 78
4.1 Introduction ... 79
4.2 One-Pot, Modular Approach to Functionalized Ketones via Nucleophilic Addition of Alkyllithium Reagents to Benzamides and Pd-Catalyzed α-Arylation ... 79
4.2.1 Introduction ... 79
4.2.2 Optimization ... 80
4.2.3 Scope of the reaction ... 83
4.2.4 Competition studies ... 84
4.2.5 Other use of the tetrahedral intermediate ... 85
4.2.6 Conclusions ... 86
4.2.7 References ... 86
4.2.8 Experimental section ... 88
4.3 The Synthesis of Substituted Benzaldehydes via a Two-Step, One-Pot Reduction/Cross-Coupling Procedure ... 99
4.4.1 Introduction ... 100
4.4.2 Optimization ... 101
4.4.3 Substrate scope ... 102
4.4.4 In situ reduction of ketones... 105
4.4.5 Conclusions ... 105
4.4.6 References ... 105
4.4.7 Experimental section ... 107
4.4 Conclusions and outlook ... 114
Chapter 5 : Synthesis of chiral catalysts for palladium catalyzed organolithium cross coupling reactions. ... 115
5..1 Introduction ... 116
5.2 Initial testing ... 117
5.3 Design of potential chiral ligands for atroposelective coupling. ... 118
5.3.1 Chiral backbone ... 118
5.3.2 Chiral flanking groups ... 121
5.4 Conclusions and outlook ... 123
5.5 References ... 123
5.6 Experimental section ... 125
Chapter 6 : Nickel-Catalyzed Cross-Coupling of Organolithium Reagents with (Hetero)Aryl Electrophiles ... 129
6.1 Introduction ... 130
6.2 Optimization and scope ... 131
6.3 Conclusions ... 138
6.4 References ... 139
6.5 Experimental section ... 141
Chapter 7 : Oxygen Activated, Palladium Nanoparticle Catalyzed, Ultrafast Cross-Coupling of Organolithium Reagents and its Application in Nuclear Medicine ... 155
7.1 Introduction ... 156
7.2 Oxygen activation ... 157
7.3 Scope ... 158
7.4 Active catalyst investigation ... 160
7.5 Application in the coupling of 11C and the synthesis of Celecoxib ... 164
7.6 Conclusions and outlook ... 165
7.7 Experimental section ... 165
Chapter 8 : The Cross-Coupling of Carbolithiated Acetylenes and the Synthesis of Z-Tamoxifen ... 188
8.1 Introduction ... 189
8.2 Atom economy, reaction mass efficiency and E-factor ... 189
8.3 Goal ... 190
Current syntheses ... 190
8.4 Optimization synthesis of Tamoxifen ... 191
Purification ... 195
One pot procedure and alternative electrophile coupling. ... 196
8.5 Conclusions and outlook ... 197
8.6 References ... 197
8.7 Experimental section ... 200
Chapter 9 : The Cross- Coupling of Organo-lithium Reagents at Cryogenic Temperatures ... 202
9.1 Introduction ... 203
9.2 Catalyst design and SAR ... 204
9.3 Scope ... 205
9.3.1 Sequential coupling ... 207
9.3.2 Attempts at improving the scope ... 209
9.4 Conclusion ... 211
9.5 References ... 212
9.6 Experimental section ... 214
Summary ... 231
Samenvatting ... 234
Summary for non chemists ... 237
