University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2012 Palladium-Catalyzed Borylation And Cross-Coupling Of Aryl And Heteroaryl Halides Utilizing Dibora Derivatives Sarah Little Jane Trice University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Organic Chemistry Commons Recommended Citation Trice, Sarah Little Jane, "Palladium-Catalyzed Borylation And Cross-Coupling Of Aryl And Heteroaryl Halides Utilizing Dibora Derivatives" (2012). Publicly Accessible Penn Dissertations. 712. https://repository.upenn.edu/edissertations/712 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/712 For more information, please contact [email protected]. Palladium-Catalyzed Borylation And Cross-Coupling Of Aryl And Heteroaryl Halides Utilizing Dibora Derivatives Abstract ABSTRACT PALLADIUM-CATALYZED BORYLATION AND CROSS-COUPLING OF ARYL AND HETEROARYL HALIDES UTILIZING DIBORA DERIVATIVES Sarah Little Jane Trice Professor Gary A. Molander Although much current research focuses on developing new boron reagents and identifying robust catalytic systems for the cross-coupling of these reagents, the fundamental preparations of the nucleophilic partners (i.e., boronic acids and derivatives) has been studied to a lesser extent. Most current methods to access boronic acids are indirect and require harsh conditions or expensive reagents. Therefore, we sought to provide a simple, efficient, and direct synthesis of arylboronic acids. Utilizing aryl halides and an underutilized reagent, tetrahydroxydiboron B2(OH)4, we developed a palladium-catalyzed method that now provides access to boronic acids in high yield. The method eliminates the necessity to employ the extremely wasteful and most commonly used source of boron, bis(pinacolato)diboron. The first method developed focused on the borylation of the less expensive and more commercially available aryl chlorides. We demonstrated that most functional groups are well tolerated under the mild reaction conditions, providing the corresponding trifluoroborate in good to excellent yield for most subtrates. We also demonstrated that the crude boronic acid could be easily and efficiently converted to a myriad of boronate esters. The method was later extended to include aryl and heteroaryls bromides, chlorides, and triflates. We went on to demonstrate that we could achieve similar results with the synthetic precursor to B2(OH)4, tetrakis(dimethylamino)diboron. We also demonstrated that we could perform a one-pot, two-step borylation/Suzuki cross-coupling reaction. And Finally, through the use of ethylene glycol as an additive to the borylation reaction with B2(OH)4, we were able to access heteroaryl substrates that were difficulto t obtain in good yield with our optimized methods. Using this strategy, we were able to access one-pot borylation/Suzuki cross-coupled products between two heteroaryls in high yield. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Chemistry First Advisor Gary A. Molander Keywords Bis-boronic acid (BBA), Boronic Acid, Palladium Catalysis, Suzuki-Miyaura Cross-Coupling, tetrahydroxydiboron, tetrakis(dimethylamino)diboron Subject Categories Organic Chemistry This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/712 PALLADIUM-CATALYZED BORYLATION AND CROSS-COUPLING OF ARYL AND HETEROARYL HALIDES UTILIZING DIBORA DERIVATIVES Sarah Little Jane Trice A DISSERTATION In Chemistry Presented to the Faculties of the University of Pennsylvania in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2012 Supervisor of Dissertation Gary A. Molander Professor of Chemistry Department Chair Graduate Group Chairperson Tobias Baumgart, Associate Professor of Chemistry Dissertation Committee Patrick Walsh, Professor of Chemistry Marisa Kozlowski, Professor of Chemistry Donna Huryn, Adjunct Professor of Chemistry PALLADIUM-CATALYZED BORYLATION AND CROSS-COUPLING OF ARYL AND HETEROARYL HALIDES UTILIZING DIBORA DERIVATIVES COPYRIGHT Sarah Little Jane Trice 2012 ii To my Grandmother Margaret, who always told me to “look it up!” iii ACKNOWLEDGEMENTS I would first like to thank my advisor, Dr. Molander, who took a chance on taking me into his lab. His guidance and freedom allowed me to grow into the scientist I have become today and for that I am very grateful. I would also like to thank my committee members, Patrick Walsh, Marisa Kozlowski, and Donna Huryn for their encouragement during my three short years under their care. Each one of them offered invaluable advice that helped guide me through my journey. I would like to thank all of the past and present Molander group members. I learned a lot from each and every one of them. Interestingly, the most important things I took away from my experiences with them had little to do with chemistry and more about people and growing up. I would like to extend a special thank you to Dr. Steven Kennedy for his enthusiasm for SCIENCE! Throughout our time together we accomplished a lot and produced truly beautiful work and for that I am eternally grateful. I would also like to thank Livia Cavalcanti for reminding me to sing and to follow my heart. Dee and Andreea, I thank them for being themselves and never wavering. A special thanks goes to Rosaura Padilla for being a true friend from the beginning to the end. Ro will always be in my fondest memories of graduate school. I had the great pleasure of mentoring an undergraduate student, Melvin Lim in my last year as a graduate student. Melvin taught me how to guide a student through the process of discovery and showed me that the most talented people merely need a gentle iv hand along the way. I would also like to thank Madeleine Jouillé for her kindness and support. I look forward to many more dinners and glasses of wine on her balcony. I am very grateful for the Wharton School and my professors there that offered me a new perspective on the world and my place in it. My time spent in the classes at Wharton will become an essential piece to my success as I re-enter the business world at Merck. I would also like to thank the members of my Wharton Crew. The many miles on the river taught me about teamwork, dedication, and how to have fun and work hard at the same time. I would not have been able to accomplish my doctoral degree without the support of Dr. Joseph Vacca. His belief in my talent and drive are what allowed me to pursue my dream of graduate school. I will never forget his kindness and guidance. I would also like to thank all of the past and present members of Merck Medicinal Chemistry, especially Pablo DeLeon for his constant cheering from the sidelines and for showcasing my methods to the department. He is truly an innovator. Finally, I would like to thank my family, whose unwavering support helped me to stay on the path to follow my dreams. I would like to especially thank my grandparents for their love of learning. They instilled in me the desire to always find the answer and to never stop learning. I thank my mother for taking my education seriously and for teaching me take care of myself. Her sacrifices and constant support helped make me into the strong and confident woman I am today. Lastly, I would like to thank Jourdan. Without his love and support I may not have made it through this. v ABSTRACT PALLADIUM-CATALYZED BORYLATION AND CROSS-COUPLING OF ARYL AND HETEROARYL HALIDES UTILIZING DIBORA DERIVATIVES Sarah Little Jane Trice Professor Gary A. Molander Although much current research focuses on developing new boron reagents and identifying robust catalytic systems for the cross-coupling of these reagents, the fundamental preparations of the nucleophilic partners (i.e., boronic acids and derivatives) has been studied to a lesser extent. Most current methods to access boronic acids are indirect and require harsh conditions or expensive reagents. Therefore, we sought to provide a simple, efficient, and direct synthesis of arylboronic acids. Utilizing aryl halides and an underutilized reagent, tetrahydroxydiboron B2(OH)4, we developed a palladium-catalyzed method that now provides access to boronic acids in high yield. The method eliminates the necessity to employ the extremely wasteful and most commonly used source of boron, bis(pinacolato)diboron. The first method developed focused on the borylation of the less expensive and more commercially available aryl chlorides. We demonstrated that most functional vi groups are well tolerated under the mild reaction conditions, providing the corresponding trifluoroborate in good to excellent yield for most subtrates. We also demonstrated that the crude boronic acid could be easily and efficiently converted to a myriad of boronate esters. The method was later extended to include aryl and heteroaryls bromides, chlorides, and triflates. BF3K KHF2 HO OH B B OH X HO OH B OH Pd(0) H O OH X = Cl, Br, I, OTf O B O We went on to demonstrate that we could achieve similar results with the synthetic precursor to B2(OH)4, tetrakis(dimethylamino)diboron. N X N N BF K Pd(0) B KHF2 3 + B B N N N We also demonstrated that we could perform a one-pot, two-step borylation/Suzuki cross-coupling reaction. HO OH B B OH aryl or X HO OH B heteroaryl halide OH Pd(0) X = Cl, Br vii And Finally, through the use of ethylene glycol as an additive to the borylation reaction with B2(OH)4, we were able to access heteroaryl substrates that were