METAL AND NON-METAL CATALYZED -ALKYLATION OF SECONDARY ALCOHOLS: SCOPE AND MECHANISM. A Dissertation submitted to the Faculty of the Graduate School of Arts and Sciences of Georgetown University in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry By Monique Koppel, B.S. Washington, DC April 11, 2014 Copyright 2014 by Monique Koppel All Rights Reserved ii METAL AND NON-METAL CATALYZED -ALKYLATION OF SECONDARY ALCOHOLS: SCOPE AND MECHANISM. Monique Koppel, B.S. Thesis Advisor: Bahram Moasser, Ph.D. ABSTRACT Hydrogen Borrowing has emerged as an advantageous synthetic methodology due to its green chemistry nature.1,2 The concept of in-situ temporary alcohol oxidation followed by functionalization and reduction has been utilized to yield various functional groups with great success. In this work a commercially available catalyst, RuCl2(PPh3)3, was used as catalyst and a protocol was developed for β-alkylation of secondary alcohols with primary alcohols via hydrogen borrowing. The system was optimized for aromatic substrates with electron donating and withdrawing groups on both the primary and secondary alcohol under aerobic conditions garnering yields ranging from 66-100%. The same catalyst was used for aliphatic primary alcohols and secondary aromatic alcohols giving yields from 75-100%. The catalyst gave low yields when heterocyclic aromatic substrates or aliphatic secondary alcohols were used. A second system was developed for the same transformation catalyzed by potassium tert-butoxide under aerobic conditions and without use of a transition metal. This protocol was limited to aromatic primary and secondary alcohols but gave high yields for substrates bearing electron donating or withdrawing groups on either alcohol. The yields were comparable to the ruthenium catalyzed system with RuCl2(PPh3)3, ranging from 66-100%. A mechanistic investigation revealed that the catalysis is initiated by oxygen and the enone intermediate produces catalytic turnover by acting as the hydrogen carrier. Transfer hydrogenation between iii the enone and the deprotonated alcohols is mediated by the potassium in a direct hydrogen transfer. The third system utilized for this transformation introduced a newly designed ruthenium catalyst, [Ru(terpy)(en)Cl][BPh4]. Two synthetic routes for making this catalyst were developed starting from Ru(terpy)Cl3 with a reducing agent, either triethylamine or zinc, in the presence of the ethylenediamine ligand to give relatively good yields ~50%. The catalyst was tested for hydrogen borrowing with both aromatic and aliphatic alcohols. The new catalyst emerged as an exceptional catalyst for aliphatic substrates for either primary or secondary aliphatic alcohols providing higher than previously reported yields of 62-100%. The combination of these three protocols widens the scope of this reaction enhancing the synthetic value of this methodology and approach to synthesis of secondary alcohols. iv ACKNOWLEDGMENTS My graduate school experience was an exciting journey of scientific and personal growth. Besides developing knowledge and skills in chemistry I was reminded how important family and friends can be. Pursuing graduate studies as a wife and mother of three was a considerable challenge. At times it felt like my family’s journey was just as intense as my own. First of all, I want to thank my husband, Steven, and my children, Erin, Amit and Mia, for their love, encouragement and constant support. I would never have embarked on this endeavor if not for Steven’s belief in me. Next, I would like to thank my mother-in-law, Edith, for making this journey of seven years possible with her unremitting support. My gratitude also goes to my father-in-law, Elio Schaechter, for his steadfast interest in my research and the invaluable scholarly advice. For their love and understanding I thank my mother Georgette, my father Jojo, my sisters Sharon, Netta and Yaarit, my brother Shlomi, and my sister-in-law Jeanny. Although a continent away, my parents kept me in their prayers with an abundance of candles. They sacrificed on my behalf, guiding me to the best education possible and keeping faith in me throughout the years. I would also like to thank the people who assisted directly with my research. First of all, I appreciate my mentor Bahram Moasser for his guidance, advice and support throughout my time at Georgetown University. He taught me to see the potential and the beauty of the simple things in chemistry that we often take for granted. In addition, I am grateful for my committee members, Drs. Tim Warren, Christian Wolf and Travis Holman, who were instrumental to my success in the chemistry program. Special thanks go to Dr. Holman for his help with X-ray and v for his constant advice on professional and personal matters. Finally, I extend my gratitude to Dr. Fay Rubinson for her help with CV and Dr. Milena Shahu for her encouragement. With a strong sense of camaraderie my lab mates, Dr. Mengping Zhu, Dr. Sudeep Das, Arrey Enyong and Stephanee Synnott offered much helpful feedback and made my experience at Georgetown a pleasant one. In particular, I want to thank Mengping for his many constructive suggestions regarding my research but mostly for his friendship. Thank you to my best friend Zara for always being a phone call away from early in the morning until late at night through the good times and the difficult ones. I appreciate Dr. Brad Slepetz for his help with my 2B and for being a good friend. I also want to thank Dr. Allan Cardenas for his help with X-ray and synthesis and Nick Rosa for our insightful discussions and use of his group’s glove box. Thanks to Carina Minardi and Trevor Safko for reviewing my thesis and to Ves Dobrev for his help with NMR. I am grateful for the financial support of the Department of Chemistry, the Graduate School at Georgetown and the ARCS foundation. Last but not least, I would like to thank the department staff members, Mrs. Kay Bayne, Mrs. Inez Traylor, Dr. Mohammad Itani, Mrs. Tabi Lemlem, Mrs. Yen Miller and Mr. Travis Hall for their assistance. Monique Koppel vi TABLE OF CONTENTS Chapter 1 Introduction .....................................................................................................................1 1.1 Transfer hydrogenation ..............................................................................................................1 1.2 Hydrogen borrowing ..................................................................................................................7 1.3 Hydrogen borrowing as a green chemistry methodology ........................................................11 1.4 C-C Bond forming methodologies for secondary alcohol synthesis .......................................14 1.5 Dissertation overview ..............................................................................................................17 Chapter 2 β-Alkylation of secondary alcohols catalyzed by commercially available ruthenium catalyst .........................................................................................................21 2.1 Introduction ..............................................................................................................................21 2.2 Designing the catalytic system and optimization for aromatic substrates ...............................24 2.3 Scope of catalysis with aromatic substrates .............................................................................30 2.4 Catalysis optimization for aliphatic substrates ........................................................................38 2.5 Scope of catalysis with aliphatic alcohol substrates ................................................................41 2.6 Mechanistic aspects of the catalysis ........................................................................................51 2.7 Conclusion ...............................................................................................................................59 2.8 Experimental ............................................................................................................................59 Chapter 3 Non-metal catalyzed β-alkylation of secondary alcohols .............................................73 3.1 Introduction ..............................................................................................................................73 3.2 Optimization of base catalyzed reaction ..................................................................................78 3.3 Scope of base catalyzed β-alkylation of secondary alcohols ...................................................79 vii 3.4 Probing the base catalyzed mechanism....................................................................................80 3.5 Comparison of metal and non-metal catalysis .........................................................................86 3.6 Mechanistic aspects of the base catalyzed reaction .................................................................89 3.7 Conclusion .............................................................................................................................115 3.8 Experimental ..........................................................................................................................115 Chapter 4 New ruthenium catalyst for metal ligand bifunctional transfer hydrogenation and hydrogen borrowing .....................................................................123 4.1 Introduction ............................................................................................................................123