Investigations into the Frustrated Lewis Pair-Catalyzed Hydrogenation of Epoxides MASTERTHESIS Martine R. Tiddens 19-02-2016 Supervisor: Dr. Matthias Otte Organic Chemistry and Catalysis Debye Institute for Nanomaterials Science 2 Abstract Traditionally hydrogenation of unsaturated substrates is a transition metal (TM)-catalyzed or stoichiometric transformation. The report about heterolytic H2-activation via Frustrated Lewis Pairs (FLP) allows the performance of classic TM-catalyzed reactions in an organocatalytic fashion. In the last decade the substrate scope for FLP-catalyzed hydrogenation has grown steadily. However, to the best of our knowledge epoxides have not yet been successfully reduced. The epoxide motive is an important building block in organic synthesis or product in natural product synthesis. Currently, hydrogenation of epoxides to alcohols is a stoichiometric or a TM-complex catalyzed transformation. Here, attempts to FLP-catalyzed hydrogenations of epoxides to alcohols are described. The known FLPs B(C6F5)3/1,4-dioxane and B(C6F5)3/diethyl ether, which are used for the FLP-catalyzed hydrogenation of carbonyl moieties, were tested for possible hydrogenation of epoxides. Meinwald rearrangement of the epoxide to an aldehyde is observed. With this result a tandem isomerization-hydrogenation reaction was envisioned. Here an epoxide rearranges to an aldehyde, upon which it should be reduced to an alcohol. Unfortunately, this reaction was not successful. The reactivity of less electron-poor Lewis acids in FLP-catalyzed hydrogenation of epoxides was investigated. Upon investigations of adduct formation between the Lewis acids with trans- phenylpropane oxide, a Lewis acid dependent reactivity of the epoxide was found. trans-phenylpropane oxide dimerizes upon stoichiometric exposure to B(C6F5)3, but isomerizes to an aldehyde when exposed to B(C7H8)3. trans-phenylpropane oxide does not form a Lewis adduct with B(C6F5)2Mes. Therefore, it is proposed that a new FLP was found. Transfer hydrogenation (TH) of epoxides was attempted by B(C6F5)3-catalyzed hydride abstraction from a diene. However, hydride transfer was prevented most likely by the interaction of B(C6F5)3 with epoxides. The finding that B(C6F5)2Mes and trans-phenylpropane oxide form a FLP opens possibilities for future research, especially in combination with B(C6F5)2Mes -catalyzed TH. 3 List of Abbreviations H2 Dihydrogen TM transition metal FLP Frustrated Lewis Pair LA Lewis acid LB Lewis base HOMO highest occupied molecular orbital LUMO lowest unoccupied molecular orbital 1a Tris(pentafluorophenyl)borane TH transfer hydrogenation GB glove box ee enantiomeric excess EWG electron withdrawing group NMR nuclear magnetic resonance δ chemical shift ppm parts per million J coupling constant Hz Hertz s singlet d doublet qd quartet of doublets t triplet m multiplet ESI-MS Electron spray Ionization Mass spectroscopy GC-MS Gas chromatography-mass spectroscopy g gram mL milliliter rt room temperature h hour bp boiling point Å Ångström THF Tetrahydrofuran Et2O Diethyl ether CH2Cl2 Dichloromethane C6D6 deuterated Benzene m.s. molecular sieves 4 Table of Contents Abstract ......................................................................................................................................................... 3 List of Abbreviations ..................................................................................................................................... 4 1. Introduction .......................................................................................................................................... 7 1.1. Reduction and Hydrogenation ...................................................................................................... 7 1.1.1. Homolytic Cleavage of H2 by Transition Metal Complexes ................................................... 7 1.1.2. Catalytic hydrogenation based upon homolytic H2 cleavage ............................................... 7 1.1.3. Heterolytic Cleavage of H2 by Cooperative Interaction of Metal Centre and its Ligand ...... 8 1.1.4. Catalytic hydrogenation based upon heterolytic H2 cleavage .............................................. 8 1.1.5. Stoichiometric Hydrogenation based on Transfer Hydrogenation ....................................... 9 1.2. Frustrated Lewis Pair Chemistry ................................................................................................. 11 1.2.1 The Principle of Frustrated Lewis Pairs ...................................................................................... 11 1.2.2. FLPs of B(C6F5)3 in Combination with Different Lewis Bases ..................................................... 12 1.2.3. Metal – free Reduction of Carbonyl Moieties ........................................................................... 16 1.2.4. Lewis Acids for Frustrated Lewis Pair Catalysis ......................................................................... 19 1.2.5. Transfer Hydrogenation with FLPs ............................................................................................ 21 1.3. Epoxides ...................................................................................................................................... 22 1.3.1. Synthesis of Epoxides ................................................................................................................ 22 1.3.2. Transformation of Epoxides ...................................................................................................... 23 2. Project Aim .......................................................................................................................................... 28 3. Results and Discussion ........................................................................................................................ 29 3.1. Attempted FLP-catalyzed Hydrogenation of Epoxides .................................................................... 29 3.1.1. Attempts to Hydrogenate Epoxides Catalyzed by a FLP of 1a/1,4-dioxane ............................. 29 3.1.2. High-pressure Experiments Aiming for Hydrogenation of trans-Phenylpropane Oxide .......... 34 3.2. Investigation into the Reactivity between 1a and trans-Phenylpropane Oxide .............................. 37 3.3. Investigation into the Tandem Isomerization – Hydrogenation Reaction of Stilbene Oxide .......... 43 3.4. Investigation into the Use of Different Lewis Acids for the FLP-catalyzed Hydrogenation of trans- Phenylpropane Oxide .............................................................................................................................. 46 3.4.1. B(tol)3 ........................................................................................................................................ 46 3.4.2. B(C6F5)2Mes ............................................................................................................................... 49 3.5. Attempted Transfer Hydrogenation of Epoxides ............................................................................. 51 4. Conclusion ........................................................................................................................................... 55 5 5. Outlook ............................................................................................................................................... 57 6. Experimental section .......................................................................................................................... 58 6.1. General ............................................................................................................................................. 58 6.2. Epoxide Synthesis ............................................................................................................................. 59 6.3. General Procedures ......................................................................................................................... 60 6.4. Attempted FLP-catalyzed Hydrogenation of Epoxides .................................................................... 61 6.5.Dimerization of 29e to 2,5-dimethyl-3,6-diphenyl-1,4-dioxane ....................................................... 66 6.6. Attempted Tandem Isomerization – Hydrogenation of Stilbene Oxide .......................................... 66 6.7. Synthesis of tris-para-tolueneborane: B(tol)3 .................................................................................. 68 6.8. Hydrogenation attempts with B(tol)3 .............................................................................................. 69 6.9. Hydrogenation attempts with BMes(C6F5)2 ..................................................................................... 70 6.10. Attempted Transfer Hydrogenation of Epoxides ........................................................................... 71 7. Appendix ............................................................................................................................................. 74 8. References .......................................................................................................................................... 87 9. Acknowledgment ................................................................................................................................ 90 6 1. Introduction 1.1. Reduction and Hydrogenation In organic chemistry the term reduction, though technically referring to the overall gain of electrons, is often associated