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Strategies for the Synthesis of Ynamides

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Strategies for the Synthesis of Ynamides I. SYNTHESIS OF INDOLINES AND INDOLES VIA INTRAMOLECULAR [4 + 2] CYCLOADDITION OF YNAMIDES AND CONJUGATED ENYNES II. SYNTHESIS OF NITROGEN HETEROCYCLES IN SUPERCRITICAL CARBON DIOXIDE by Joshua Ross Dunetz B. A., Chemistry Haverford College, 2000 SUBMITTED TO THE DEPARTMENT OF CHEMISTRY IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY at the MASSACHUSETTS INSTITUTE OF TECHNOLOGY September 2005 © Massachusetts Institute of Technology, 2005 All rights reserved Signature of Author .................... ·Department of Chemistry September 1, 2005 a( / Certified by ................................... ................................ Rick L. Danheiser Arthur C. Cope Professor of Chemistry, Thesis Supervisor Acceptedby......................... ............................................ I.... 7 Robert W. Field MASSACHUSETSINSTn '.vE I F TrwfhNl erv-v I Chairman, Department Committee on Graduate Students OCT 1 2005 d }cl/CF , LIBRARIES ~ This doctoral thesis has been examined by a committee in the Department of Chemistry as follows: Professor Timothy F. Jamison . ... Chairman Professor Rick L. Danheiser ........... ... ............................ Thesis Supervisor Professor Barbara Imperiali. ...... ................................................ 2 ACKNOWLEDGMENTS All acknowledgments must begin with my thesis advisor, Rick Danheiser. I first remember meeting him at the Cambridge Brewing Company during recruiting weekend five years ago, and we sat for hours in the restaurant discussing the merits of the 2000 New York Mets and whether one of our favorite baseball teams had a chance to make the playoffs that year. Ultimately, I decided to attend MIT with the hope of joining his group, and during my time in his laboratory Rick has been an excellent mentor and chemistry role model. I continue to be amazed not only by the extent of his knowledge, but also by his ability to articulate chemical principles in an easy and straightforward manner. Rick is a teacher at heart, and I appreciate that he makes a special effort to foster the education of his students beyond first-year graduate classes. I will miss his 5.513 group meetings and take with me his mantra to think like a chemist. Finally, I appreciate that Rick allows his students the independence to pursue their own ideas. I hope to live up to his high standards as I continue my professional career. I would also like to thank thesis committee members Tim Jamison and Barbara Imperiali their helpful suggestions and comments pertaining to this thesis. Special thanks go to Tim Jamison for his helpful advice and support during my time at MIT. I would also like to acknowledge my undergraduate research advisor, Karin Akerfeldt. It was in her laboratory that I first began to appreciate and enjoy the daily challenges and rewards of scientific research. Her encouragement helped guide me to pursue a doctoral degree in organic chemistry, and I am very glad that we have kept in touch throughout the years. I would like to acknowledge the many people with whom I worked during my time at MIT. The research described in Part II of this thesis concerning the synthesis of nitrogen heterocycles in supercritical carbon dioxide was conducted in collaboration with the laboratories of Jefferson Tester (MIT, Department of Chemical Engineering) and Andrew Holmes (Cambridge University). Several graduate students and postdoctoral research assistants from the Tester group provided technical support for this project through the operation and maintenance of the higher pressure carbon dioxide reaction vessel. In chronological order, I would like to acknowledge: Michael Timko, AJ Allen, Dr. Morgan Fr6ling, Scott Paap, and Rocco Ciccolini. I would especially like to thank Rocco for his enthusiasm and for our many discussions that helped me appreciate chemical reactions from the perspective of a chemical engineer. I would also like to thank our other collaborators from across the Atlantic Ocean, Andy Holmes and his graduate students Melanie Tsang and Catherine Smith, for many helpful discussions and insights that shaped the direction of our research. During the course of our collaboration, I was very fortunate to make two separate trips to England to work with Melanie and Catherine for a period of several days in the Cambridge laboratories. These overseas adventures were among the most exciting of my graduate career. I wish Melanie and Catherine the best of luck as they continue their professional careers. I consider myself lucky to have worked alongside so many wonderful lab mates who became friends. Martin Hayes deserves a special acknowledgment for being my graduate student mentor and bay mate when I first joined the group. He helped me develop my skills as a chemist and was a constant source of patience and encouragement. He was also the senior member of "Club Enyne" for many years and the two of us had countless discussions late at night concerning the possible mechanisms of these remarkable enyne cycloadditions. I am sure vve will stay in contact throughout the years. During my early years in the group, I also turned to 3 senior group members Jason Diffendal and Dave Amos for help in lab, and I appreciate the way they taught me to think about my chemistry with their special brand of tough love. Special thanks also go to Dave for making me the manager of Toxic Waste for two years, and although we did not win any championships during my tenure as captain, we made the playoffs one year and I think we all had a lot of fun on the softball diamond. I would also like to acknowledge Aimee Crombie, who sat across from me for three years in the desk area and added some excitement and humor to the atmosphere of the lab. In addition, Aimee deserves credit for the preparation of ynamide 294 according to our N-alkynylation procedure (Table 5, "A" conditions). Javier Horta and I have worked at adjacent hoods since we moved into the renovated labs in 2002, and I will miss our jokes and camaraderie. Javier is now the final member of "Club Enyne" and I think he will hold down the fort just fine. I would like to thank Wesley Austin fbr being an encyclopedia of chemistry knowledge - he is a very helpful guy to have around. I wish the best of luck to Kevin Maloney as he starts his fourth year of graduate school. We had a lot of fun together learning at the Philadelphia ACS meeting and winning the Toxic Waste championship. I am going to miss talking baseball with Kevin and will now have to buy my own Friends DVDs. I also wish the best of luck to Xiao Yin Mak and Tammy Lam with their research projects which use ynamides for the synthesis of various nitrogen heterocycles. I wish special success to Xiao Yin as she continues the "green" chemistry collaboration with the Tester and Holmes laboratories. I wish to acknowledge the efforts of rising second-year Lucy Kohnen, who brings an exuberance to the group that is both refreshing and invigorating. We have worked closely together to develop a procedure for Organic Synthesis involving the preparation of diynamide ,296, and she deserves special credit for exploring ways to further optimize our N-alkynylation procedure. Lucy also deserves credit for the preparation of ynamides 291 and 292 using our protocol (Table 5, "A" conditions) and ynamide 296 using our protocol and Hsung's second- generation protocol (Table 5, "A" and "B" conditions). Lucy, I will miss your energy and enthusiasm and wish you the best of luck! During my time at MIT, I have been blessed with some very close friends. First, I would like to acknowledge Graham Wright, who was my lab mate for a couple of years and a very fun guy to have around. I would like to thank Graham for his levity and humor, and also for introducing me to some wonderful operas and musicals. Best of luck to him as he pursues his singing career. One day it will be a honor to tell people that I knew the great Graham Wright before he shaved his head. I am going to miss all the smiles and hugs from Diana Hunt, who was a constant support during graduate school. Asides from little things that Diana does, such as make the absolute best chocolate pudding ever and organize field trips to movies I might not have otherwise seen (such as annual excursions from lab to see Lord of the Rings), I have come to admire Diana for her energy and optimism, her smiles and hugs, and I will miss her dearly. She will always be my #1 Swattie and I wish her the best of luck as she finishes up her graduate career. I am also going to miss my fellow lab mate Charnsak "Touch" Thongsornkleeb. Although we never worked on the same side of the lab, Touch and I became close friends while bonding over Thai food at Rod-Dee, Mexican food at the Border Cafe, Thanksgiving in Long Island... what can I say, the guy is an eating machine! He is also a genuine friend and a confidant, and I appreciate all our talks and his help both in and out of lab. Touch is not just a smart and excellent chemist but also a good person who will undoubtedly be a big success back 4 home in Thailand. We have to make sure geography does not put distance between us in the coming years. Spotlight on Betsy Colby! Graduate school would have been much tougher without her in my life. Between the cat sitting, the apple orchards, the whale experts at Fanueil Hall, the Adarn Sandler movies, and the ballroom dancing at Wonderland, we had some fun adventures together that I will remember always. I will miss the lunches, the soda breaks, and even the movie naps. We were roommates, teammates, TA partners, Outreach buddies, and most of all friends.
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