Development of New Domino Reactions of Alkylidene Meldrum’s Acids Involving Friedel-Crafts Chemistry and Catalytic Conjugate Allylation of Alkylidene Meldrum’s Acids by Aaron Michael Dumas A thesis presented to the University of Waterloo in fulfilment of the thesis requirement for the degree of Doctor of Philosophy in Chemistry Waterloo, Ontario, Canada, 2009 © Aaron Michael Dumas 2009 I hereby declare that I am the sole author of this thesis. This is a true copy of my thesis, including any required final revisions, as accepted by my examiners. I understand that my thesis may be made electronically available to the public. ii Abstract Alkylidene Meldrum’s acids are very reactive acceptors in conjugate additions, and are known to be significantly more electrophilic than other α,β-unsaturated carbonyl electrophiles. They also offer advantages in terms of ease of preparation, purification and storage. Despite this, they are relatively underused in organic synthesis, and have been treated as something of a curiousity in the literature. The goal of my research was to demonstrate the utility of these molecules in new reactions that are not readily available to other electrophiles. To facilitate this work, new conditions for the Knoevenagel condensation of aldehydes with Meldrum’s acid were developed. This allowed access to a broader range of monosubstituted alkylidenes than was previously possible from any single method. In a reaction that exploits the acylating ability of Meldrum’s acid, a domino addition of phenols to alkylidene Meldrum’s acids was developed. Here, Yb(OTf) 3 catalyzed the addition of a phenol to the alkylidene as well as acylation through activation of the electrophile. The unique properties of these acceptors permitted synthesis of 3,4-dihydrocoumarins and coumarins through C-alkylation/O-acylation, and also 4-chromanones and chromones through O-alkylation/C-acylation. The predictable and general reversal of chemoselectivity is dependent on the number of substituents on the alkylidene. The same properties that make alkylidene Meldrum’s acids strong electrophiles also make them excellent dienophiles. A one-pot Diels-Alder/Friedel-Crafts process was used as an entry into the 6-5-6-tricyclic skeleton of a family of natural products that have been of interest in our group. The modular nature of the reaction allowed structural variation at nearly every position around both 6-membered rings. An attempted extension of this work into the synthesis of ergot alkaloids provided insight into the factors affecting Friedel-Crafts acylation of 4-substituted indoles. These results provided a highly regioselective entry into 4,5-fused indole ring systems. iii The electrophilicity of alkylidene Meldrum’s acids was combined with Lewis acid activation for development of a mild conjugate allylation reaction. The use of allyltriphenyltin as nucleophile for addition to monosubstituted alkylidenes avoided many of the practical disadvantages of working with trialkylstannanes. By employing such a relatively weak allylating agent, functional group compatibility was maximized to include groups susceptible to nucleophilic allylation. Additions to chiral, non-racemic alkylidenes were highly diastereoselective. It was also shown that functionalized all-carbon quaternary stereocentres can be formed by this process. iv Acknowledgments I came to the University of Waterloo specifically to study with Prof. Eric Fillion. Over the last five years, I have never regretted this decision. The dedication he has shown to producing high-quality and interesting new chemistry is surpassed only by his dedication to the students in his group. He has always been willing to teach, guide, and motivate, while still allowing the independence to explore ideas on my own. He has also created an environment of cooperation, mutual respect, and friendship among the group, which has made working in his labs a pleasure from my first day. The lessons I take away from him in terms of being a scientist, a mentor, and a colleague are invaluable, and I cannot thank him enough. The members of my Ph.D. committee, Profs. Mike Chong, Gary Dmitrienko, and Adrian Schwan, are thanked for their suggestions and support. I especially thank Prof. Chong, from whom I took two very challenging graduate courses, and who was in the unfortunate position of having an office across from my lab. I have knocked on his door with more than a few questions, and have never been turned away, or left with anything other than a complete answer. I have collaborated with undergraduates on many projects, and have learned a lot about teaching chemistry from working with them. I particularly thank my co-authors Bryan Kuropatwa, Neil Malhotra, Tammy Sitler, Sylvia Hogg, Adam Seed, and my current, very hardworking and dedicated student Chan Lau, for their participation, interest, and patience. I have been incredibly fortunate to work with a large group of talented and fun- loving coworkers who have become wonderful friends as well. When I first arrived, Dan Fishlock helped me get settled and was a role model to me of how to be a successful grad student. His taste in movies and music was also greatly appreciated. Vince Trepanier and I worked together “in the other lab” for a long time, and he taught me the necessity of keeping a beer cabinet well-stocked for those long summer Saturdays. He and his wife Karine were always great to talk to, and I thank them both for helpful advice. When Sébastien Carret joined the group, he and Vince made our side of the lab a little piece of v francophonie which was a real pleasure for me. Seb’s constant good spirits and enthusiasm, and the hospitality he and Val showed to me meant a lot. I still have not had a better meal in Waterloo than confit au canard and foie (not to mention the wine and pastis) at their house. Jarkko Heikkinen was another great friend and colleague, whose work ethic and positive attitude were inspiring. Someday I will repay him the favour and bury his car in snow in the middle of a freezing parking lot. Alex Zorzitto, who first worked with me as an undergrad, has been incredibly fun to work with. He introduced me to the orange club, and I have also admired his well-rounded approach to graduate student life. His company on my walks to get coffee in the morning is also an appreciated daily ritual. In the other lab, Dave Moon was a great addition to our group. His terrible jokes notwithstanding, he and Kathleen threw good parties and were always ready to have some fun. Stuart Mahoney has been a generous and friendly collaborator, and anyone who gives beer in exchange for answers will always be appreciated. Between him and Yen Nguyen, the next generation of the Fillion group will be outstanding. I started graduate studies with an amazing group of fellow students. I thank Laura Ingram, Alla Darwish, and Jarrod Johnson for their friendship, support, and help over these last five years. Julie Goll has been around since those days as well, and she was as good a friend and coworker as she was a boss, even if she did make me hand in my labs on time. Thanks too for a lot of breaks. Of all the people I have worked with, Ash Wilsily deserves special mention. He and I started at nearly the same time, and over five years I have learned to respect him immensely. I have never worked with a more dedicated, hard-working, curious, honest, or trustworthy person. His example has pushed me to be a better chemist, and his friendship has made working in the group a constant pleasure. He is especially fun to work with now that he plays better music than the “Little Shop of Horrors” soundtrack. Our trip to Philadelphia and New York for the ACS meeting was one of the highlights of my grad studies, and Ash’s unflagging enthusiasm and energy were a big part of the reason for that. I know he will go on to be an incredibly successful chemist, and I wish him all the best as he moves on from UW. vi To my friends outside of chemistry, I can finally answer “I’m done” to the question “Hey Dumas when are you gonna finish school?”. Thanks to everyone in Waterloo, Toronto, Ottawa, and Sault Ste. Marie for way too many good times, laughs, and hangovers. My parents, Michael and Joan, have never been anything other than totally loving and supportive. I cannot repay the debt of gratitude I owe them for their academic, fiscal, and emotional support throughout my grad studies. I have worked hard to live up to the potential they have always seen in me, and I thank them for their constant encouragement (and a few labcoats too). I can only imagine where I would be now if they hadn’t bought me that chemistry set. I have been very fortunate to have family close to Waterloo, and I thank my uncle and aunt Hans and Mireille Dumas for inviting me to their home and providing me a very welcoming (and nourishing) place to visit. My aunt Linda has been incredibly supportive, and her house has been a second home which has meant a lot to me. That is not to mention her help with organizing my things during my constant moving, and an endless supply of peanut butter cakes. Between the three of them I may have been beaten at cards more than a few times, but I thank them for letting me win every now and then. For their technical help I thank Jan Venne, Dr. Richard Smith, the late Dr. Nick Taylor, and Dr. Jalil Assoud. Any errors in interpreting the data they’ve helped me collect are my own. I am also grateful for the rigorous training in organic chemistry I received at the University of Ottawa. I was lucky enough to learn the subject from Prof. Tito Scaiano, Prof. Bill Ogilvie, Prof. Louis Barriault, and especially Prof. Alex Fallis, whose passion for this science showed me that maybe a career in the field was something I should look into. vii Table of Contents LIST OF FIGURES ................................................................................................................................... ix  LIST OF ABBREVIATIONS ........................................................................................................................ x  LIST OF SCHEMES ................................................................................................................................ xiii  CHAPTER 1. PROPERTIES AND PREPARATION OF ALKYLIDENE MELDRUM’S ACIDS .................................. 1  1.1. STRUCTURE AND REACTIVITY OF MELDRUM’S ACID.......................................................................................... 1  1.1.2. FRIEDEL‐CRAFTS ACYLATIONS OF MELDRUM’S ACID DERIVATIVES ................................................................... 4  1.3 PROPERTIES OF ALKYLIDENE MELDRUM’S ACIDS .............................................................................................. 9  1.4 PREPARATION OF ALKYLIDENE MELDRUM’S ACIDS ..........................................................................................15  1.5. EXPERIMENTAL SECTION ...........................................................................................................................22  CHAPTER 2. REACTIONS OF ALKYLIDENE MELDRUM’S ACIDS WITH PHENOLS ....................................... 29  2.1. SYNTHESIS OF 3,4‐DIHYDROCOUMARINS, COUMARINS, CHROMANONES, AND CHROMONES .................................29  2.2. YB(OTF)3‐CATALYZED ADDITIONS OF PHENOLS TO ALKYLIDENE MELDRUM’S ACIDS. ...........................................34  2.3. EXPERIMENTAL SECTION ...........................................................................................................................41  CHAPTER 3. DIELS‐ALDER/FRIEDEL‐CRAFTS ACYLATION OF ALKYLIDENE MELDRUM’S ACIDS AND  INVESTIGATIONS INTO THE REGIOSELECTIVITY OF FRIEDEL‐CRAFTS ACYLATIONS OF 4‐SUBSTITUTED  INDOLES .............................................................................................................................................. 50  3.1. TAIWANIAQUINOL B AND RELATED NATURAL PRODUCTS ................................................................................50  3.2 DIELS‐ALDER REACTIONS OF ALKYLIDENE MELDRUM’S ACIDS ...........................................................................54  3.3. DIELS‐ALDER/FRIEDEL‐CRAFTS ACYLATION OF ALKYLIDENE MELDRUM’S ACIDS ..................................................59  3.4. REGIOSELECTIVE FRIEDEL‐CRAFTS ACYLATIONS OF 4‐SUBSTITUTED INDOLES .......................................................68  3.5. EXPERIMENTAL SECTION ...........................................................................................................................79  Part 1. Diels‐Alder/Friedel‐Crafts Acylation of Alkylidene Meldrum’s Acids .......................................79  Part 2. Investigations of the Friedel‐Crafts Acylation of 4‐Substituted Indoles .................................112  CHAPTER 4. CATALYTIC CONJUGATE ALLYLATION OF ALKYLIDENE MELDRUM’S ACIDS ........................ 133  4.1 NUCLEOPHILIC ALLYLATING AGENTS: GENERAL CONSIDERATIONS ....................................................................133  4.2 LEWIS ACID‐ACTIVATED CONJUGATE ALLYLATIONS .......................................................................................137  4.3. CATALYTIC CONJUGATE ALLYLATIONS ........................................................................................................143  4.4 SC(OTF)3‐CATALYZED CONJUGATE ALLYLATION OF ALKYLIDENE MELDRUM’S ACIDS ...........................................148  4.5. CATALYTIC, ENANTIOSELECTIVE CONJUGATE ALLYLATION OF ALKYLIDENE MELDRUM’S ACIDS ..............................156  4.6. EXPERIMENTAL SECTION .........................................................................................................................163  REFERENCES ...................................................................................................................................... 181  viii List of Figures Figure 1.1. pK of some common carbon acids in H O ...................................................... 2  a 2 Figure 1.2. Structure of alkylidene Meldrum’s acids ......................................................... 9  Figure 1.3. Absolute electrophilicities of alkylidene Meldrum’s acids ............................ 12  Figure 1.4. X-Ray crystal structure of a disubstituted alkylidene Meldrum’s acid .......... 13  Figure 1.5. Conformations of benzylidene acetylacetone ................................................. 14  Figure 1.6. Comparison of Lewis-acid activatived malonates to alkylidene Meldrum’s acids .......................................................................................................................... 14  Figure 3.1. Taiwanaiquinoid natural products .................................................................. 50  Figure 3.2. X-ray structures of Diels-Alder adducts 3.54 and 3.53 .................................. 66  Figure 3.3. Representative members of the ergot alkaloids .............................................. 69  ix List of Abbreviations Ac acetyl app apparent Ar aryl BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl BINOL 2,2′-dihydroxy-1,1′-binaphthyl Bn benzyl Br broad Bu butyl calc’d calculated cat catalytic d doublet DA Diels-Alder dba dibenzylidene acetone DCC dicyclohexylcarbodiimide DCE 1,2-dichloroethane DDQ 2,3-dichloro-5,6-dicyanobenzoquinone DEAD diethyl azodicarboxylate DEPT distortionless enhancement by polarization transfer DMAP 4-dimethylaminopyridine DME 1,2-dimethoxyethane DMF dimethylformamide DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (dimethyl propylene urea) DMS dimethylsulfide DMSO dimethylsulfoxide E+ electrophile ee enantiomeric excess EI electron impact Et ethyl equiv equivalents EWG electron withdrawing group FC Friedel-Crafts h hour HMPA hexamethylphosphoramide HPLC high performance liquid chromatography HRMS high resolution mass spectrometry Hz Hertz x