Exploration of the Nazarov Cyclization Reaction by Mariam Zaky Submitted in partial fulfillment of the requirements for the degree of Master of Science Dalhousie University Halifax, NS March 2016 ! Copyright by Mariam Zaky, 2016 ! ! ! ! Table of Contents List of Tables ................................................................................................................ iv List of Figures ................................................................................................................ v List of Schemes ............................................................................................................. vi Abstract ......................................................................................................................... ix List of Abbreviations and Symbols Used ...................................................................... x Acknowledgements .................................................................................................... xiii Chapter 1 - Introduction ................................................................................................. 1 1.1 The Classical Nazarov Reaction .................................................................... 1 1.1.2 Conformational Preference Influenced by "-Substituents ..................... 2 1.1.3 Polarized Nazarov reaction .................................................................... 2 1.2 The Interrupted Nazarov Reaction ................................................................. 3 1.2.1 Nazarov Reactions of Allenyl Vinyl Ketones ............................................... 5 1.2.2 Interrupted Nazarov Reactions of Allenyl Vinyl Ketones ............................. 7 1.3 Nazarov Reaction of Aromatic Substrates ................................................... 12 1.4 Thesis Chapters ............................................................................................ 14 Chapter 2 - Synthesis and Nazarov Cyclization of Allenyl Aryl Ketones ................... 16 2.1 Introduction .................................................................................................. 16 2.2 Results and Discussion ................................................................................ 17 2.2.1 Synthesis .............................................................................................. 17 2.2.2 Nazarov Reactions ...................................................................................... 18 2.2.3 Interrupted Nazarov reaction ...................................................................... 25 2.2.4 Computational Work ................................................................................ 27 2.3 Conclusions and Future Work ..................................................................... 29 ! ""! 2.4 Experimental Section ................................................................................... 30 2.4.1 General Information ................................................................................. 30 2.4.2 Synthesis and Characterization ................................................................ 31 Chapter 3 - Attempted Synthesis of a Tethered Allenyl Vinyl Ketone ....................... 59 3.1 Introduction .................................................................................................. 59 3.2 Results and Discussion ................................................................................ 60 3.2.1 Synthesis .................................................................................................. 60 3.3 Conclusions .................................................................................................. 65 3.4 Experimental Section ................................................................................... 66 3.4.1 Synthesis and Characterization ................................................................ 66 Chapter 4 - Trapping of Allenyl Vinyl Ketone by Allyltrimethylsilane ...................... 76 4.1 Introduction .................................................................................................. 76 4.2 Results and Discussion ................................................................................ 77 4.2.1 Synthesis .................................................................................................. 77 4.3 Conclusions ........................................................................................................ 79 4.4.1 Synthesis and Characterization ................................................................ 80 Chapter 5 – Conclusion ................................................................................................ 83 References .................................................................................................................... 85 Appendix A – NMR spectra for Chapter 2 .................................................................. 88 Appendix B – NMR spectra for Chapter 3 ................................................................ 135 Appendix C – NMR spectra for Chapter 4 ................................................................ 149 ! ! ! """! List of Tables ! Table 1. Nazarov reactions of allenyl aryl ketones ...................................................... 20! Table 2. Nazarov reaction of AAKs catalyzed by In(OTf)3 ........................................ 24! ! "#! List of Figures ! Figure 1.1 Three conformers of "-substituted divinyl ketone ....................................... 2! Figure 1.2 The s-trans/s-trans conformation of an AVK and a divinyl ketone ............. 7! Figure 2.1 Five substrates from the computational study ............................................ 27! Figure 2.2 Computed (#B97X-D/6-31G) transition state geometries for the BF3- mediated cyclizations of A, B, C, D, and E ......................................................... 29! Figure 4.1 Steric interactions in the s-trans/s-trans conformation of divinyl ketone with $-substituents ............................................................................................... 76! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! #! List of Schemes ! Scheme 1.1 Acid-catalyzed Nazarov reaction of a divinyl ketone ................................ 1! Scheme 1.2 Conrotatory and disrotatory ring closure ................................................... 2! Scheme 1.3 Polarized Nazarov cyclization .................................................................... 3! Scheme 1.4 The interrupted Nazarov reaction ............................................................... 3! Scheme 1.5 Intramolecular trapping of the oxyallyl cation generated from a trienone substrate ................................................................................................................. 4! Scheme 1.6 Oxyallyl cation interception using allyltrimethylsilane ............................. 5! Scheme 1.7 Electrocyclization and tandem (4 + 3) cycloaddition of divinyl ketone .... 5! Scheme 1.8 Synthesis of a cross-conjugated cyclopentenone from the Nazarov reaction of allene ether ........................................................................................... 6! Scheme 1.9 Nazarov cyclization of an AVK on silica gel ............................................. 7! Scheme 1.10 Resonance contributors of the oxyallyl cation formed from an allenyl vinyl ketone ............................................................................................................ 8! Scheme 1.11 Synthesis of a 5-hydroxycyclopent-2-enone by an interrupted Nazarov reaction ................................................................................................................... 9! Scheme 1.12 Halogenated cyclopentenones synthesized by interrupted Nazarov reactions ................................................................................................................. 9! Scheme 1.13 Nazarov cyclization and tandem (4 + 3) cycloaddition .......................... 10! Scheme 1.14 Nazarov cyclization and tandem (3 + 2) cycloaddition .......................... 10! Scheme 1.15 Nazarov cyclization and tandem (4 + 3) cycloaddition using an oxygen- substituted diene ................................................................................................... 11! Scheme 1.16 Trapping at positions a and c using a bulky carbon nucleophile ........... 11! Scheme 1.17 Trapping of an oxyallyl cation using tosyl-substituted pyrrole .............. 12! Scheme 1.18 Nazarov reaction of aryl vinyl ketone .................................................... 13! ! #"! Scheme 1.19 Nazarov reaction of aryl vinyl ketone to give an indanone .................... 13! Scheme 1.20 Nazarov reaction of oxazolidinone-substituted aryl vinyl ketone .......... 14! Scheme 1.21 Polarized Nazarov reaction of aromatic vinyl ketone ............................ 14! Scheme 2.1 5-endo-dig Cyclizations of allenyl aryl ketone reported by Nagao ......... 17! Scheme 2.2 Preparation of allenyl aryl ketones ........................................................... 18! Scheme 2.3 Grignard reaction with 4-methoxybenzaldehyde ..................................... 18! Scheme 2.4 Isomerization of Nazarov products .......................................................... 19! Scheme 2.5 Stabilizing effect of electron-donating group on oxyallyl cation of AAK .............................................................................................................................. 21! Scheme 2.6 Two regioisomers obtained from the Nazarov