Palladium-Catalyzed Reactions of Enol Ethers THESIS Presented in Partial Fulfillment of the Requirements for the Degree Master of Science in the Graduate School of The Ohio State University By Amneh Awad Graduate Program in Chemistry The Ohio State University 2014 Master's Examination Committee: Professor Christopher M. Hadad, Advisor Professor James P. Stambuli Professor Jovica D. Badjic ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! Copyright by Amneh Awad 2014 ! ! ! ! ! ! Abstract Enals were accessed via a palladium-catalyzed oxidation of enol ethers using lower palladium loadings than traditional Saegusa oxidations of silyl enol ethers. In addition to functional group tolerance, the conditions allow the access of di-, tri-, and tetrasubstituted olefins. This methodology was extended to the intramolecular cyclization of 4-hydroxy- 1-enol ethers to give furans and dihydrofurans which are prevalent in biologically active compounds. The extension of the methodology to synthesize pyrroles from 4-amino-1- enol ethers was also successful. ii Dedication This document is dedicated to my friends and family. iii Acknowledgments I would like to thank Professor James P. Stambuli for accepting me into his group. His mentorship and guidance taught me to love chemistry and to become a better problem solver. He is driven when it comes to his work but, above all, he cares about his students. I would like to thank him for creating a group dynamic that fostered a good team spirit where everyone was always willing to assist each other however possible. More than anything else, I want to thank him for always having his door open for me and for always looking out for my best interest. All the Stambuli group members have my appreciation and gratitude for making work a fun and intellectually stimulating environment. Special thanks to Dr. Matt Lauer and Dr. William Henderson for serving as my mentors on the enol ether project and beyond. Luke A. Baldwin, Jon W. Crowe, and I joined the group at the same time and I would like to thank them for being my friends as well as co-workers. I would like to thank Professor Christopher M. Hadad for giving me a place in his group and mentoring me for the past year. Special thanks to Ryan K. McKenney, Ben R. Garrett, and Tom S. Corrigan from the Hadad group as well as Chi “Chip” Le from the Stambuli group for the work we did on the Hapten project. Finally, I would like to thank Professor Jovica Badjic for serving on my Examination Committee. iv Vita December 12, 1989.......................................Born – Detroit, Michigan May 2007 .....................................................Fordson High School May 2011 .....................................................B.S. Chemistry, Biochemistry, University of Michigan-Dearborn 2011 to present ............................................Graduate Teaching Associate, Department of Chemistry and Biochemistry, The Ohio State University Publications Lauer, M. G.; Henderson, W. H.; Awad, A.; Stambuli, J. P. “Palladium-Catalyzed Reactions of Enol Ethers: Access to Enals, Furans, and Dihydrofurans.” Org. Lett. 2012, 14, 6000-6003. Fields of Study Major Field: Chemistry v Table of Contents Abstract.......................................................................................................................... ii! Dedication.................................................................................................................... iiii! Acknowledgments..........................................................................................................iv! Vita .................................................................................................................................v Table of Contents ...........................................................................................................vi List of Tables .............................................................................................................. viii! List of Figures.................................................................................................................x List of Schemes..............................................................................................................xi! List of Abbreviations.....................................................................................................xii! Chapter 1: Enals from the Saegusa-Type Oxidations of Enol Ethers ...............................1 1.1 Abstract ................................................................................................................1! 1.2 Background...........................................................................................................1! 1.3 Introduction ..........................................................................................................5! 1.4 Results and Discussion .........................................................................................7 1.5 Conclusions........................................................................................................18 vi Chapter 2: Furans and Dihydrofurans from 4-Hydroxy Enol Ethers...............................19! 2.1 Abstract ..............................................................................................................19! 2.2 Background.........................................................................................................19! 2.3 Results and Discussion........................................................................................23! 2.4 Conclusions and Future Work ............................................................................38 Chapter 3: Pyrroles from 4-Amino Enol Ethers..............................................................39! 3.1 Abstract ..............................................................................................................39! 3.2 Background.........................................................................................................39! 3.3 Results and Discussion........................................................................................41! 3.4 Conclusions and Future Work ............................................................................46! Chapter 4: Experimental Details...................................................................................47! 4.1 General Methods.................................................................................................47! 4.2 Chapter 1 Experimental Details...........................................................................48! 4.3 Chapter 2 Experimental Details...........................................................................69! 4.4 Chapter 3 Experimental Detials...........................................................................86! References and Notes ....................................................................................................88 Appendix A: 1H NMR and 13C NMR Spectra for Selected Compounds .........................93 vii List of Tables Table 1.1 Larock Optimization Conditions 3 Table 1.2 Takayama Optimization Conditions 4 Table 1.3 Initial Reaction Optimization 9 Table 1.4 Enal Solvent Screen 10 Table 1.5 Enal Substrate Scope 12 Table 1.6 Greener Optimization Conditions 14 Table 1.7 Initial Enone Optimization 16 Table 2.1 Yields of 4-Hydroxy Methyl Enol Ethers Using Reissig’s Synthesis 24 Table 2.2 Optimization of 4-Hydroxy Methyl Enol Ether Synthesis 26 Table 2.3 Acetic Acid and Water Screen 27 Table 2.4 Effect of Alkyl Enol Ether of Furan Yield 30 Table 2.5 Furan Acetic Acid Screen 32 Table 2.6 Furan Solvent Screen 33 Table 2.7 Furan Ligand Screen 34 Table 2.8 Furan Substrate Scope 35 Table 2.9 Conversion of Enol Ethers to 2,5-Dihydrofurans 36 Table 3.1 General Pyrrole Cyclization Conditions Screen 43 Table 3.2 Pyrrole Solvent Screen 44 viii Table 3.3 Acetic Acid and Triphenylphosphine Screen 45 ix List of Figures Figure 1.1 Saegusa Oxidation Mechanism 2 Figure 1.2 Possible Oxidation Mechanisms 17 Figure 2.1 Proposed Oshima-Utimoto Reaction Mechanism 21 Figure 2.2 Furan % Yield vs Hydrolysis Rate of Alkyl Vinyl Ether 31 x List of Schemes Scheme 1.1 Oxidant Controlled Stereoselectivity 6 Scheme 1.2 Conversion of Vinyl Fluorides to !,"-Unsaturated Aldehydes 7 Scheme 1.3 Methods for Enol Ether Synthesis 8 Scheme 1.4 Stellettadine A Intermediate Synthesis 13 Scheme 2.1 Paal-Knorr Furan Synthesis 20 Scheme 2.2 Catalytic Oshima-Utimoto Reaction 21 Scheme 2.3 Reisigg’s Dihydrofuran Synthesis 22 Scheme 2.4 Allyl Methyl Ether Addition to Aldehydes and Ketones 25 Scheme 2.5 One-Pot Cyclization/Sakurai Allylation 28 Scheme 2.6 Conversion of 2,5-Dihydrofurans to Furans 28 Scheme 2.7 2,3-Disubstituted Furan Synthesis 37 Scheme 2.8 2,4-Diphenylfuran Substrate Synthesis 38 Scheme 3.1 Paal-Knorr Pyrrole Synthesis 40 Scheme 3.2 Synthesis of 1,2-Diarylpyrroles 40 Scheme 3.3 Possible Mechanism for the Formation of 1,2-Diarylpyrroles 41 Scheme 3.4 Pyrrole Substrate Synthesis Attempts 42 xi List of Abbreviations °C degrees Celsius ! alpha Å angstrom " beta # gamma $ heat (reflux) % chemical shift in parts per million µ micro 1H NMR proton nuclear magnetic resonance 13C NMR carbon 13 nuclear magnetic resonance Ac acetyl AcOH acetic acid aq aqueous atm atmosphere(s) Bn benzyl Bt benzotriazole BQ 1,4-benzoquinone xii br broad nBu normal-butyl sBu sec-butyl tBu tert-butyl Bz benzoyl c centi c concentration calcd calculated CAM ceric ammonium molybdate cat catalytic COSY correlation spectroscopy CSA camphorsulfonic acid D dextrorotatory d day(s); doublet