Activation of diboron reagents: The development of mild conditions for the synthesis of unique organoboron compounds Steven Brandon Thorpe Dissertation submitted to the faculty of the Virginia Polytechnic Institute and State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy In Chemistry Webster L. Santos, Chairman Paul R. Carlier David G. I. Kingston James M. Tanko March 23, 2012 Blacksburg, Virginia Keywords: borylation, diboron reagent, boronic ester, conjugate addition, copper catalysis © 2012 by Steven B. Thorpe Activation of diboron reagents: The development of mild conditions for the synthesis of unique organoboron compounds Steven Brandon Thorpe ABSTRACT The first successful synthesis and isolation of a boronic acid was reported in 1860 by Frankland in the pursuit of novel organometallic compounds. For more than a century, further studies of boronic acids were sparsely published. Suzuki and Miyaura jumpstarted the field in 1979 with an innovative carbon-carbon bond forming reaction employing an organoboronic acid and a carbon halide under palladium catalysis. Indeed, the Nobel Prize in Chemistry was awarded to Professor Akira Suzuki, along with Professors Richard Heck and Ei-ichi Negishi, in 2010 for their important contributions in palladium-catalyzed cross-coupling chemistry. Over the last 30 years, reports on organoboron compounds have increased exponentially. This dissertation describes the author’s contributions to the development of preparative methods for organoboronic acid derivatives using transition metal-catalyzed reactions of diboron reagents. A unique “mixed” diboron reagent was developed (PDIPA diboron) that contains sp2- and sp3-hybridized boron atoms, unambiguously confirmed by X-ray crystallography. PDIPA diboron is sufficiently activated internally through a dative-bonding amine to selectively transfer the sp2-hybridized boron regioselectively, in the presence of copper, to electron deficient alkenes including α,β-unsaturated ketones, esters, amides, aldehydes, and nitriles to provide the corresponding boratohomoenolates. A unique β,β-diboration of an α,β-acetylenic ketone was also discovered. The scope of PDIPA diboron reactions was then expanded to a set of substrates with a more complex structural backbone. Allenoates are α,β,γ-unsaturated esters with orthogonal pi systems, which pose several possible difficulties with the regioselectivity of addition, not to mention known isomerizations catalyzed by copper. However, we successfully installed the boron moiety regioselectively on the β-carbon of a variety of allenoates, providing a vinyl boronic ester, and also observed exclusive formation of the (Z)-isomer from racemic starting materials. The resulting vinyl boronic ester was then shown to be an excellent Suzuki-Miyaura cross-coupling partner, affording a diastereopure, trisubstituted alkene in quantitative yield. Commercially available bis(pinacolato)diboron has shown remarkable stability towards hydrolysis and autoxidation. Using this reagent, we developed a copper- and amine-catalyzed boration protocol performed entirely in water and open to air. Using only 1 mol% copper, extraordinary activity was observed. UV-Vis, 11B NMR, and solvent kinetic isotope experiments were employed to gain insight into the mechanism, which showed the possibility of autocatalysis. Attempts to control stereoselectivity were not successful, although these results were rationalized by a dynamic catalyst structure. iii Acknowledgements First and foremost, I would like to express my sincere gratitude to my advisor, Professor Webster L. Santos. He has taken a true personal interest in my development into a successful Ph.D. Chemist. Behind the relentless phrase, “so where’s my compound?” is a man who has always provided an inspiring environment for me to cultivate a stand-alone method of solving tough chemical problems, while also challenging me to develop and mature into a better person overall. He taught me how to set seemingly unachievable goals for myself and then how to manage my time, resources, and priorities to accomplish them. It is almost impossible to put into words what I have gained the past 5 years, but I know that I could not have achieved any of this without Dr. Santos by my side as both my leader, and my friend. I would also like to thank my advisory committee; Dr. Paul Carlier, Dr. David Kingston, and Dr. Jim Tanko. You have all made exceptional efforts to ensure that my fundamental techniques are flawless and that my learning is unhindered; teaching me how to understand, embrace and even implement alternative approaches to answering chemical problems. I am very grateful for your patience while I struggled through learning concepts that I am sure seemed elementary to you. Additionally, I would like to thank Dr. Paul Deck for always being eager to advise me on anything I needed. Somehow, he has the answer to every question. To my friends and colleagues, I would like to say thank you for the vital role you have played in my graduate career. From my first days here, when I was subjected to the rigorous training program of my mentor, Ken Knott, not a day has passed that I have not learned something new. I owe this primarily to the senior members of the Santos group; Ken Knott, Mithun Raje, David Bryson, Jason Crumpton, Mike Perfetti, Dr. Phileppe Bissel and Dr. Ming Gao, who have somehow simultaneously served as my role models, scientific advisors and iv friends. I would also like to recognize two individuals whom I had the pleasure of mentoring and befriending; Xi Guo and Joe Calderone. Finally, I would like to thank all of my friends and family outside of the lab. You have all been vital in maintaining my sanity throughout grad school by supporting me and encouraging my success. To my parents, Steve and Debbie Thorpe, and grandparents, Chuck and Georgianne Kennedy, I would never have made it this far without you. To my brother, Justin Thorpe and uncle, David Kennedy, you have both been dynamic in my development and some of my fondest memories are with you. To my roommates over the years, thank you for distracting me from work at every opportunity and being the best friends I could ask for. Lastly, I would like to thank Cathy Minichino, who has been my unwavering support through the toughest of times. I look forward to many happy years with you. I love you all. v Dedication To my parents and grandparents. You have been the most influential people in my life, and I love you. vi Table of contents List of schemes ......................................................................................................................x List of figures ..................................................................................................................... xii List of tables ...................................................................................................................... xiii Chapter 1 Boronic acids and their derivatives ...............................................1 1.1 Structure and properties of boronic acids and their derivatives ..................................1 1.2 Pharmaceutical applications of organoboron compounds ...........................................3 1.3 Synthetic intermediates – transforming the C-B bond ................................................6 1.4 Preparation of organoboron compounds ...................................................................16 1.5 Dissertation overview ................................................................................................21 1.6 References for Chapter 1 ...........................................................................................22 Chapter 2 Structure and reactivity of a preactivated sp2-sp3 diboron reagent: catalytic regioselective boration of α,β-unsaturated conjugated compounds ................................................................ 32 2.1 Contributions .............................................................................................................32 2.2 Abstract ......................................................................................................................33 2.3 Introduction ...............................................................................................................34 2.4 Design and synthesis of a novel “mixed” diboron reagent ........................................38 2.5 Reactivity of PDIPA diboron towards copper-catalyzed β-boration .........................39 2.6 Further development – introduction ..........................................................................43 2.7 Synthesis and characterization of (R,R)-PDIPA diboron ..........................................43 2.8 Re-optimization: additives .........................................................................................47 2.9 Re-optimization: stoichiometry and other reaction conditions .................................51 2.10 Full scope of ketones and aldehydes .........................................................................52 vii 2.11 Proposed catalytic cycle ............................................................................................55 2.12 Conclusions ...............................................................................................................56 2.13 References for Chapter 2 ...........................................................................................57 Chapter 3 Regio- and stereoselective copper-catalyzed β-borylation of allenoates by a