ANNULATION STRATEGIES FOR THE SYNTHESIS OF AZULENES AND POLYCYCLIC NITROGEN HETEROCYCLES By Aimee Lynn Crombie B.S., Chemistry University of Pittsburgh, 1999 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 June 2004 © 2004 Massachusetts Institute of Technology All Rights Reserved Signatureof Author.. ........................................................................... Department of Chemistry May 12, 2004 Certifiedby .............. ..... ............................................. Rick L. Danheiser Thesis Supervisor A ccepted by ........ ... .../ .... ........................................................... Robert W. Field Departmental Committee on Graduate Studies MASSACHUSMS INSTI iI OF TECHNOLOGY SCIENCE I LI a lnnL I JUN L o uul LIBRARIES 1 This doctoral thesis has been examined by a committee of the Department of Chemistry as follows: ProfessorTimothy F. Jamison........ ..... .. ................................ Chairman Professor Rick L. Danheiser .......... ..... .................... Thesis Supervisor Professor Timothy M. Swager........... ...... 2 Acknowledgments I would first like to thank my advisor, Rick Danheiser. I am grateful for having the opportunity to be a member of his outstanding research group. Rick has been a wonderful mentor and teacher throughout my five years at MIT. I greatly appreciate his persistent efforts to help develop my skills as a chemist and my ability to communicate scientific knowledge. I would also like to thank Rick for all of the time and effort that he devoted to the completion of this thesis. I am grateful to Professor Timothy Jamison and Professor Timothy Swager for their helpful suggestions and comments pertaining to this thesis. I would like to thank Tim Jamison for his support and useful advice throughout my time at MIT. I would not have had the opportunity to enter the Ph.D. program at MIT without the guidance and support I received at the University of Pittsburgh. I am thankful to several outstanding professors and mentors, including Dr. George Bandik, Dr. David Waldeck, and Dr. Toby Chapman, who all encouraged me to pursue a higher degree of education in chemistry. Above all, I am graciously indebted to Dr. Dennis Curran for allowing me to be a member of his research group and introducing me to synthetic chemistry. Dr. Curran was particularly influential in my decision to enter graduate school and has been supportive throughout my academic career. I am also grateful to Dr. Greg McIntire and Dr. Ed Bacon for their guidance and support and I am thankful to have had the opportunity to work with these two outstanding supervisors at Nycomed Amersham. Several people at MIT have contributed to the research described in this thesis. The pioneering work performed by John Kane made my azulene project possible. Kevin Shea made important contributions to the study of azulenes in our laboratory and I am grateful for his efforts to properly introduce me to the azulene project. I am thankful for the thorough investigations of benzannulation reactions by Steve Gee, Kollol Pal, and other former group members. Their work was extremely helpful to my research in the area of ynamide benzannulations. I would also like to thank the members of the Buchwald, Fu, and Swager laboratories for their helpful suggestions and answers to my endless questions. I am particular grateful to Phoebe Kwan (Swager laboratory) for supplying a thienylstannane to support Stille cross-coupling studies. I would also like to thank Josh Dunetz for his helpful guidance in synthesizing ynamides and for supplying compounds to study these reactions. I am grateful to Tammy Lam and Xiao Yin Mak for also supplying compounds to support the ynamide benzannulation project. In addition, I would like to thank the members of the DCIF (Mark Wall, David Bray, Jeff Simpson, and Li Li) for their support and guidance in obtaining spectral data. I am fortunate to have known so many wonderful people here at MIT. I remain thankful to Kevin Shea for his support and mentoring as I entered the Danheiser lab five years ago. I would like to thank other former members of the Danheiser lab for their guidance and good humor, including Hiroshi Shinokubo, Greg Dudley, Jason Diffendal, and Dave Amos. I am grateful to all of the current members of the Danheiser lab for creating such an enjoyable working environment. It was my pleasure to have known and worked with Chris Davie, Charnsak Thongsornkleeb, and Josh Dunetz. I wish them all the best as they complete their graduate careers and pursue future endeavors. Javier 3 Horta, Kevin Maloney, and Wes Austin have all been terrific labmates and I wish them well and much success in their years to come at MIT. It was a joy to have three new members of the Danheiser lab this year: Xiao Yin Mak, Hui Won Choi, and Tammy Lam. I am confident that these talented women will find success here at MIT. I am particularly thankful to Martin Hayes, who has been a valued classmate, labmate, and friend throughout my time at MIT. He has been a constant source of ideas, support, and laughs. I wish Martin and his wife, Toni, all the best in the years to come. I am thankful to the many friends that I have made here at MIT. Most of all, I am grateful to have the friendship of Karen Villazor. I would like to thank Karen for all of her support and for helping me to realize what is truly valuable in life. I know Karen will be successful with her new career and I hope that she finds much happiness in life with her husband, Chris. I must acknowledge my dearest friends, Rachel, Melissa, Leslie, and Megan who have supported me through the years and brought many laughs and good times when they were needed the most. I am particularly thankful to have had the wonderful and supportive friendship of Melissa during my time at MIT. I cannot express how grateful I am to my family. Mom and Dad, thank you for your endless support and love and for all of that you have done to provide us with the opportunity to reach our goals. I would not be where I am today without you. Kara and Katie, thank you for being the most wonderful and amazing sisters. I am grateful for your laughter, especially at inappropriate times. Finally, I would like to thank Michael for his support, understanding, and love. It has been the encouragement and support you give to me everyday that has made all of this possible. Thank you for always being there. 4 To my beloved parents, my wonderful sisters, and Michael 5 Annulation Strategies for the Synthesis of Azulenes and Polycyclic Nitrogen Heterocycles by Aimee Lynn Crombie Submitted to the Department of Chemistry on May 12, 2004 in partial fulfillment of the requirements for the Degree of Doctor of Philosophy ABSTRACT Highly convergent annulation strategies have been developed for the synthesis of azulenes and polycyclic nitrogen heterocycles. Specifically, substituted azulenes have been synthesized via a ring expansion-annulation strategy based on P-halo diazo ketones. The method employs the use of readily available benzenoid starting materials and achieves the synthesis of azulenes substituted on both the five- and seven-membered rings regioselectively. The synthetic utility of the ring expansion annulation products, in particular azulenyl halides and triflates, has been demonstrated by their successful application in transition metal-mediated carbon-carbon bond forming reactions. These reactions have been used to further functionalize the five- and seven-membered rings and also in the synthesis of oligoazulenes and azulenylamino acid derivatives. In addition, polycyclic nitrogen heterocycles have been synthesized via a tandem ring forming strategy. The strategy employs a novel benzannulation reaction of substituted cyclobutenones with ynamides, which are synthesized via the strategy for the N- alkynylation of amides strategy developed in the Danheiser laboratory. The products of these benzannulation reactions, highly-substituted anilines, then participate in ring closing metathesis reactions to form various nitrogen heterocycles. In particular dihydroquinolines, hydrobenzoazepines, and hydrobenzoazocines were synthesized via this tandem ynamide benzannulation ring closing metathesis strategy. Thesis Supervisor: Rick L. Danheiser Title: Professor of Chemistry 6 Table of Contents Part I Ring Expansion-Annulation Strategy for the Synthesis of Azulenes and Oligoazulenes Chapter 1 Introduction and Background ................................................ 12 Properties and Applications of Azulenes .................................................. 13 Methods for the Synthesis of Azulenes ................................................. 18 Attempts to Synthesize Azulenes via an Intramolecular Biichner Reaction........26 Chapter 2 Synthesis of Azulenes via the -Halo Diazo Ketone Strategy .......... 34 Synthesis of Ring Expansion-Annulation Substrates................................. 35 Feasibility of the Ring Expansion-Annulation Reaction ......... ...............41 Scope of the Ring Expansion-Annulation Strategy .................................... 43 Chapter 3 Attempts to Synthesize Azulenes via Cycloheptafuranones............ 49 Attempts to Synthesize Cycloheptafuranones via Alkylidenecarbenes ............. 63 Recent Developments in the Synthesis of Azulenes via Alkylidenecarbenes ..... 69 Chapter 4 Transition Metal-Mediated Carbon-Carbon Bond Forming Reactions of Azulenyl Halides and Sulfonates