SYNTHESIS OF NITROGENOUS HETEROCYCLES VIA GROUP 3 METAL- CATALYZED HYDROAMINATION AND ZINC (II) MEDIATED METALLOAMINATION by Adrian Robert Smith A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry MONTANA STATE UNIVERSITY Bozeman, Montana April 2015 ©COPYRIGHT by Adrian Robert Smith 2015 All Rights Reserved ii To my wife, Lauren. iii ACKNOWLEDGEMENTS The completion of this thesis could not have been possible without the support and guidance of many people in my life. Professor Tom Livinghouse has been a fantastic research advisor, giving his time, expertise, and even personal money towards furthering my research studies. Professors Paul Grieco, Mary Cloninger, Trevor Rainey, and Valerie Copie have been invaluable in helping me to grow intellectually through their teaching and guidance. Fellow group members and coauthors Dr. Bryce Sunsdahl and Dr. Helena Lovick have been wonderful to work with in producing results for shared papers. I also need to thank all group members, especially Bryon Anderson, for esoteric discussions and arguments of advanced organic chemistry. Most importantly, I need to thank my family and friends who have been supportive and understanding of the time and effort required for my studies. Their unwavering support has been a source of strength throughout my graduate career. I especially need to thank my wife Lauren, for her encouragement and endless love. This thesis is dedicated to her. iv TABLE OF CONTENTS 1. INTRODUCTION ...........................................................................................................1 Hydroamination ...............................................................................................................1 Metalloamination .............................................................................................................9 Organozinc Chemistry ...................................................................................................13 2. RESULTS AND DISCUSSION ....................................................................................16 Chapter 1: Donor Ligand Effects in Group 3 Metal-catalyzed Hydroaminations .......16 Chapter 2: Rapid and Efficient Procedure for the Synthesis of Group 3 Metal-Tris[bis(dimethylsilyl)amide] THF Complexes .............................26 Chapter 3: Intramolecular Hydroaminations of Secondary Aminoalkenes Catalyzed by New Group 3 Metal Trisamides ............................................................31 Chapter 4: Intramolecular Metalloaminations of N,N-Dimethylhydrazinoalkenes .....39 Chapter 5: Bidentate Anionic Ligands in the Zinc Metalloamination Reaction ..........49 3. CONCLUSION ..............................................................................................................58 4. EXPERIMENTAL INFORMATION ............................................................................59 Chapter 1 .......................................................................................................................60 Chapter 2 .......................................................................................................................62 Chapter 3 .......................................................................................................................65 Chapter 4 .......................................................................................................................72 General Procedure for CuCN Mediated Allylation of Metalloamination Intermediates ...................................................................................74 Synthesis of Cycles: General Procedure for Fukuyama Coupling of Metalloamination Cycles ........................................................77 Chapter 5 .......................................................................................................................81 REFERENCES CITED ......................................................................................................89 APPENDIX A: 1H NMR / 13C NMR Data ........................................................................94 v LIST OF TABLES Table Page 1. Hydroamination of Aminoalkenes with Silylamide Precursors ...........................5 2. Additive Effects of Ethereal Ligands .................................................................18 3. Effect of a Series of Donor Ligands on Y(III)-catalyzed Hydroaminations ......20 4. Additive-free Hydroamination Reactions ..........................................................22 5. Influence of Donor Ligands on Group 3 Metal Precatalysts .............................23 6. Diastereoselectivity Effects of Ethereal Ligands and Alternative Solvents on the Hydroamination of 1b ..............................................................24 7. Trials of Forming Group 3 Metal Complex 5b ..................................................28 8. Synthesis of Group 3 Metal Complexes 5a-5e ..................................................29 9. Hydroamination of Substrate 9a ........................................................................35 10. Hydroamination of Substrate 9b ......................................................................36 11. Hydroamination of Substrate 9c ......................................................................37 12. Hydroamination of Substrate 9d ......................................................................38 13. Metalloamination/allylation of Hydrazinoalkenes to Pyrrolidines ..................43 14. Metalloamination/allylation of Hydrazinoalkenes ...........................................44 15. Optimization of the Fukuyama Reaction from 13a .........................................47 16. Metalloamination/acylation of Hydrazinoalkenes ...........................................48 17. Screening of Miscellaneous Anionic Bidentate Ligands .................................51 18. Results of 1,1,1-trifluoro-4-(amino)pent-3-en-2-one Ligands in Metalloamination ...........................................................................53 19. Evaluation of 1,3-dicarbonyl Ligands 19a-19h ...............................................55 vi LIST OF TABLES – CONTINUED Table Page 20. Metalloamination/allylation Utilizing Ligated Organozincs ...........................57 vii LIST OF SCHEMES Scheme Page 1. Group 3 Metal Hydroamination Mechanism .......................................................3 2. Group 3 Metal Precatalysts With Diastereoselectivity and Enantioselectivity .................................................................................................6 3. Ligand Coordination via the “Silylamide Route” and “Extended Silylamide Route” ...............................................................................7 4. Ligation of a Chiral Binaphthyl Ligand from Trisamide 7f ................................9 5. Mechanism of Metalloamination / Electrophile Trapping .................................10 6. Heteroannulation of Titanium Imido Complex..................................................11 7. Application of Metalloamination Towards (±)-Ferruginine ..............................12 8. Previous Examples of Zinc Metalloamination ...................................................13 9. Products Made by sp3 C-Zn Precursors .............................................................14 10. The Negishi Reaction in the Industrial-scale Synthesis of PDE472 ................15 11. Fukuyama Coupling Towards (+)-Biotin ........................................................15 12. Simplified Mechanism of Yttrium-Catalyzed Intramolecular Hydroamination of 1b .............................................................25 13. Previous Synthesis of Group 3 Metal Complex 5b .........................................26 14. Substitution of tritox-H from Group 3 Metal Trisamides ................................30 15. Synthesis of New Group 3 Metal Trisamides 7b, 7f .......................................32 16. Synthesis of Secondary Aminoalkenes 9a-9d .................................................33 17. Hydroamination Utilizing Diethylzinc and Activator ......................................39 18. Early Metalloamination Trials .........................................................................40 19. Copper (I) Allylation of Intermediate 13a .......................................................41 viii LIST OF SCHEMES – CONTINUED Scheme Page 20. N,N-Dimethylhydrazineamine Substrate Synthesis .........................................42 21. Reversibility of Organozinc Intermediate 14d ................................................45 22. General Zinc Ligand Screening Scheme..........................................................49 23. Synthesis of Aryl 1,1,1-Trifluoroacetylenamines ............................................52 24. Synthesis of N,N-disubstituted Acetoacetamide Ligands ................................54 ix LIST OF FIGURES Figure Page 1. Hydrocodone ........................................................................................................1 2. Double Bond Isomerization Product ..................................................................21 3. Simple Group 3 Metal Precatalysts....................................................................33 x NOMENCLATURE C6D6 Benzene-d6 DCM Dichloromethane DMA Dimethylacetamide DME 1,2-Dimethoxyethane HMPA Hexamethylphosphoramide MTBE Methyl t-butyl ether r.t. Room Temperature (22-25 °C) THF Tetrahydrofuran TMEDA Tetramethylethylenediamine tritox-H tri-t-butyl-carbinol xi ABSTRACT Pyrrolidines