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C-Metalated Nitriles: Diastereoselective Alkylations and Arylations

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C-Metalated Nitriles: Diastereoselective Alkylations and Arylations Duquesne University Duquesne Scholarship Collection Electronic Theses and Dissertations Fall 12-20-2019 C-Metalated Nitriles: Diastereoselective Alkylations and Arylations Robert John Mycka Duquesne University Follow this and additional works at: https://dsc.duq.edu/etd Part of the Organic Chemistry Commons Recommended Citation Mycka, R. J. (2019). C-Metalated Nitriles: Diastereoselective Alkylations and Arylations (Doctoral dissertation, Duquesne University). Retrieved from https://dsc.duq.edu/etd/1851 This Immediate Access is brought to you for free and open access by Duquesne Scholarship Collection. It has been accepted for inclusion in Electronic Theses and Dissertations by an authorized administrator of Duquesne Scholarship Collection. C-METALATED NITRILES: DIASTEREOSELECTIVE ALKYLATIONS AND ARYLATIONS A Dissertation Submitted to the Bayer School of Natural and Environmental Sciences Duquesne University In partial fulfillment of the requirements for the degree of Doctor of Philosophy By Robert J. Mycka December 2019 Copyright by Robert J. Mycka 2019 C-METALATED NITRILES: DIASTEREOSELECTIVE ALKYLATIONS AND ARYLATIONS By Robert J. Mycka Approved November 13, 2019 ________________________________ ________________________________ Dr. Bruce D. Beaver Dr. Jeffrey D. Evanseck Professor of Chemistry and Biochemistry Professor of Chemistry and Biochemistry (Committee Chair) (Committee Member) ________________________________ ________________________________ Dr. Shahed U. M. Khan Dr. Patrick T. Flaherty Associate Professor of Chemistry and Associate Professor of Pharmacy Biochemistry (Committee Member) (Committee Member) ________________________________ ________________________________ Dr. Fraser F. Fleming Dr. Ellen S. Gawalt Chair, Department of Chemistry, Drexel Chair, Department of Chemistry and University Biochemistry Professor of Chemistry Professor of Chemistry and Biochemistry (Committee Member) ________________________________ Dr. Philip Reeder Dean, Bayer School of Natural and Environmental Sciences iii ABSTRACT C-METALATED NITRILES: DIASTEREOSELECTIVE ALKYLATIONS AND ARYLATIONS By Robert J. Mycka December 2019 Dissertation supervised by Professor Fraser F. Fleming Development of an sp3 hybridized halogen-magnesium exchange route to Grignard reagents, chelation-controlled asymmetric induction of γ- and δ-hydroxynitriles as well as a diastereoselective arylation procedure for C-zincated nitriles have been explored. Sequential addition of i-PrMgCl and n-BuLi to 3- and 4-carbon iodoalcohols triggers a facile halogen-metal exchange to generate cyclic magnesium alkoxides capable of intercepting electrophiles to produce a diverse range of substituted alcohols. This work advances progress toward the synthesis of highly desirable chiral Grignard reagents. Double deprotonation of γ- and δ-acyclic hydroxynitriles with i-PrMgCl effects highly diastereoselective alkylations via a singly-chelated magnesiated nitriles. These alkylations are electrophile-dependent with either syn- or anti-addition occurring depending upon the electronic properties of the electrophile. These alkylations are the first electrophile-dependent alkylations of acyclic nitriles and exhibit a unique reactivity iv depending upon the nature of the Grignard reagent used for deprotonation. The work presented here addresses the long-standing challenge of stereoselective installation of quaternary carbons in conformationally mobile, acyclic nitriles. Lastly, deprotonating substituted cyclohexanecarbonitriles with the TMPZnCl·LiCl complex affords C-zincated nitriles that can couple in a diastereoselective manner with aryl bromides in the presence of catalytic Pd(OAc)2 and S-Phos. Ring substituents displaying a wide range of steric and stereoelectronic effects have been examined. Selectivity ranges from null to high depending upon the size and location of the substituent. The diastereoselectivity trends discovered here present an immense potential for the synthesis of substituted cyclohexanecarbonitriles, key intermediates and targets in active pharmaceutical agent synthesis. v DEDICATION For my parents, who taught me from a young age that I could achieve anything! vi ACKNOWLEDGEMENT First and foremost, I wish to thank my advisor and mentor Professor Fraser Fleming. I also wish to thank Dr. Fleming, not just for the chemistry knowledge, but also all of the life lessons, both philosophical and religious that you have taught me over the years. Our excursion to Munich really helped me to learn about myself. I appreciate all of your help and patience throughout our chemistry endeavors, as not all compounds were revealed as easily as we would have hoped. Nonetheless, we were able to overcome a lot of challenges and achieve a lot of good work that we hope people can use in the future. Next I would like to thank Dr. Bruce Beaver for all of your mentorship throughout this Ph.D. endeavor. I could never have become the chemist I am today if you hadn’t made me push arrows and learn mechanisms the way that you did. All of your lunches and talks where you provided me with both chemical and life guidance will be cherished forever. I couldn’t have achieved this without you. Thank you again! I especially need to thank Professor Patrick Flaherty. You are a wealth of knowledge about chemistry, reactions and life. I appreciate all of your help throughout this endeavor. I undoubtedly could not have achieved this degree without you. I absolutely appreciate everything that you have done for me throughout the past several years! I would like to thank the other people that have served on my dissertation committee at various times. These people include Dr. Tomislav Pintauer and Dr. Jeffrey D. Evanseck and Dr. Shahed U. M. Khan. I am ever grateful to the three of you for your help and support you gave me to help achieve this degree. vii Other professors I wish to thank include Professor Paul Knochel (“Uncle Paul”) for all of your help and mentorship in Munich. It was an absolute honor to work for you. I also would like to thank Professor Paul Floreancig for mentorship during this process. After all, “it was just chromatography.” Lastly, I would like to thank the late Dr. Mitchell E. Johnson. We had a lot of fun, and I learned a lot about academics from you. You may have passed away too soon; however, the memories we had talking football and otherwise will be cherished forever! I would also like to thank the various lab mates over the years that always made me feel like we were an unstoppable team for Dr. Fleming. These lab mates include Dr. Viet Anh Vu, Dr. Wang Liu, Dr. Guoqing Wei, Yunjing Wei, Subbu Gudipati, Som Ghosh, Dr. Pitta Bhaskar Reddy, Dr. Ponneri Chandrababu Ravikumar, Lihua Yao, Jenna Daggett, Brian Zlobecki, Kristen Carlisle and Kenny Drombosky. My lab mates in Munich were also gratefully acknowledged for all of the fun that we had. These people include: Dr. Andreas Wagner, Dr. Ben Haag, Dr. Tobias Thaler, Dr. Milica Jaric, Dr. Matthias Schade, Dr. Stéphanie Duez, Dr. Tobias Blümke, Dr. Sebastian Bernhardt, Simon Matthe, and last but not least, Vladimir Malakhov. Support from Dr. William Eckenhoff for X-Ray studies as well as HRMS measurements Dr. Timothy Fahrenholz are also gratefully acknowledged. In tandem with the measurements, I would like to thank Dave Hardesty, Danny Bodnar and Lance Crosby for keeping the instruments running, especially the NMRs. Lastly, I would like to thank Dean Philip Reeder. I appreciate all of your help in making the final step of this process come to fruition. viii TABLE OF CONTENTS ABSTRACT............................................................................................................................ iv DEDICATION ........................................................................................................................ vi ACKNOWLEDGEMENT .................................................................................................... vii LIST OF TABLES ................................................................................................................ xii LIST OF FIGURES .............................................................................................................. xiii LIST OF ABBREVIATIONS.............................................................................................. xiv Chapter 1 ...................................................................................................................................1 Prologue ....................................................................................................................................1 1.1 Introduction ...................................................................................................................1 1.2 Objectives ......................................................................................................................6 1.3 Organization ...................................................................................................................7 Chapter 2 ...................................................................................................................................9 NMR Studies of Nitrile Ions and Metalated Nitriles..............................................................9 2.1 Introduction to Metalated Nitriles ................................................................................9 2.2 13C NMR of Nitrile Stabilized Anions.......................................................................12 2.3 13C NMR of N-metalated Nitriles ..............................................................................18
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