To Erik, Frida, Oskar & Camilla List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Sävmarker, J., Lindh, J., Nilsson, P. Deoxybenzoins from Stille Carbonylative Cross-Couplings using Molybdenum Hexa- carbonyl. Tetrahedron Lett. 2010, 51, 6886-6889. II Odell, L., Sävmarker, J., Larhed, M. Microwave-Promoted Aminocarbonylation of Aryl Triflates using Mo(CO)6 as a Solid CO Source. Tetrahedron Lett. 2008, 49, 6115-6118. III Lindh, J., Sävmarker, J., Nilsson, P., Sjöberg, P. J. R., Larhed, M. Synthesis of Styrenes by Palladium(II)-Catalyzed Vinylation of Arylboronic Acids and Aryltrifluoroborates by Using Vinyl Acetate. Chem-Eur J. 2009, 15, 4630-4636. IV Sävmarker, J., Lindh, J., Nilsson, P., Sjöberg, P. J. R., Larhed, M. Oxidative Heck Reactions Using Aryltrifluoroborates and Aryl MIDA Boronates. Submitted. V Sävmarker, J., Rydfjord, J., Gising, J., Odell, L., Larhed, M. Direct Palladium(II)-Catalyzed Synthesis of Arylamidines from Aryltrifluoroborates. Submitted. VI Behrends, M., Sävmarker, J., Sjöberg, P. J. R., Larhed, M. Microwave-Assisted Palladium(II)-Catalyzed Synthesis Of Aryl Ketones from Aryl Sulfinates and Direct ESI-MS Studies Thereof. ACS Catal. 2011, 1, 1455-1459. Reprints were made with permission from the respective publishers. Related Publications and Manuscript Not Included in this Thesis Trejos, A., Sävmarker, J., Schlummer, S., Datta, G. K., Nilsson, P., Larhed, M. Stereoselective Heck Arylation of a Functionalized Cyclopentenyl Ether using (S)-N-Methyl-Pyrrolidine as the Stereochemical Controller. Tetrahed- ron 2008, 64, 8746-8751. Andaloussi, M., Lindh, J. Sävmarker, J., Sjöberg, P. J. R., Larhed, M. Microwave-Promoted Palladium(II)-Catalyzed C-P Bond Formation Using Arylboronic Acids or Aryltrifluoroborates. Chem. Eur. J. 2009, 15, 13069- 13074. Russo, F., Wångsell, F., Sävmarker, J., Jacobsson, M., Larhed, M. Synthesis and Evaluation of a New Class of Tertiary Alcohol Based BACE-1 Inhibitors. Tetrahedron 2009, 65, 10047-10059. Wångsell, F., Russo, F., Sävmarker, J., Rosenquist, Å., Samuelsson, B., Larhed, M. Design and Synthesis of BACE-1 Inhibitors Utilizing a Tertiary Hydroxyl Motif as the Transition State Mimic. Bioorg. Med. Chem. Lett. 2009, 19, 144-155. Wångsell, F., Nordeman, P., Sävmarker, J., Rosenquist, Å., Samuelsson, B., Larhed, M. Investigation of Alpha-Phenylnorstatine and Alpha- Benzylnorstatine as Transition State Isostere Motifs in the Search for New BACE-1 Inhibitors. Bioorg. Med. Chem. 2009, 19, 4711-4714. Sävmarker, J., Trejos, A., Russo, F., Rosenquist, Å., Samuelsson, B., Larhed, M. Synthesis and Evaluation of Stereopure Tertiary Alcohol Based -Secretase Inhibitors. Manuscript. Contents 1. Introduction ............................................................................................... 11 1.1 Palladium ............................................................................................ 11 1.2 Palladium Catalysis in C-C Bond Forming Reactions ....................... 11 1.3 Palladium Ligands .............................................................................. 13 1.4 Palladium(0) Catalysis ....................................................................... 14 1.4.1 Oxidative Addition ..................................................................... 14 1.4.2 CO Coordination and Insertion ................................................... 15 1.4.3 Transmetallation ......................................................................... 15 1.4.4 Reductive Elimination ................................................................ 15 1.5 Mo(CO)6-Mediated Carbonylation ..................................................... 15 1.5.1 Carbonylative Stille Coupling .................................................... 16 1.5.2 Aminocarbonylations .................................................................. 16 1.6 Palladium(II) Catalysis ....................................................................... 17 1.6.1 Transmetallation ......................................................................... 18 1.6.2 Desulfination............................................................................... 18 1.6.3 Insertion ...................................................................................... 19 1.6.4 Elimination ................................................................................. 20 1.6.5 Reoxidation ................................................................................. 21 1.6.6 The Aryl Source .......................................................................... 22 1.7 Styrene Synthesis ............................................................................... 26 1.8 The Oxidative Heck Reaction ............................................................ 26 1.9 Palladium-Catalyzed Nitrile Insertion ................................................ 28 1.10 Electrospray Ionization Mass Spectrometry ..................................... 29 2. Aims of the Present Study ......................................................................... 32 3. Mo(CO)6-Mediated Carbonylations (Paper I & II) .................................. 33 3.1 Synthesis of Deoxybenzoins under Gas-Free Conditions .................. 33 3.1.1 Vinyl and Allyl Halide Screening ............................................... 34 3.1.2 Benzyl Halide Screening ............................................................ 35 3.2 Aminocarbonylation of Aryl Triflates using Mo(CO)6 ...................... 37 3.2.1 Aryl Triflate Screen .................................................................... 38 3.2.2 Nucleophile Screen ..................................................................... 39 4. Palladium(II)-Catalyzed Heck-Type Reactions (Paper III & IV) ............. 42 4.1 Styrene Synthesis using Vinyl Acetate .............................................. 42 4.1.1 Solvent and Ligand Screen ......................................................... 42 4.1.2 Temperature and Vinyl Acetate Excess Screening ..................... 43 4.1.3 Screening of Arylborane Substrates ........................................... 44 4.1.4 Mechanistic Study ...................................................................... 46 4.2 Oxidative Heck Reactions using Aryltrifluoroborates and Aryl MIDA Boronates .................................................................................................. 50 4.2.1 Arylboronate Screening with an Electron-Poor Olefin ............... 51 4.2.2 Arylboronate Screening with an Electron-Rich Olefin ............... 53 4.2.3 ESI-MS Investigation ................................................................. 55 5. Palladium(II)-Catalyzed 1,2-Carbopalladation of Nitriles (Paper V & VI) ...................................................................................................................... 57 5.1 Synthesis of Arylamidines from Aryltrifluoroborates ........................ 57 5.1.1 Ligand Screen ............................................................................. 58 5.1.2 Screen of Aryltrifluoroborates .................................................... 58 5.1.3 Screen of Cyanamides with Different Aryltrifluoroborates ........ 61 5.1.4 Mechanism .................................................................................. 61 5.2 Synthesis of Aryl Ketones from Aryl Sulfinates ................................ 62 5.2.1 Ligand Screens............................................................................ 63 5.2.2 Screen of Aryl Sulfinates ............................................................ 64 5.2.3 Variation of Nitriles .................................................................... 65 5.2.4 ESI-MS Investigation ................................................................. 66 6. Concluding Remarks ................................................................................. 69 Acknowledgements ....................................................................................... 70 References ..................................................................................................... 72 Abbreviations Ac acetyl aq aqueous Ar aryl Bdpp 2,4-bis(diphenylphosphino)pentane Bn benzyl Bu butyl CID collision induced dissociation dba dibenzylideneacetone DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DFT density functional theory DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide dmphen 2,9-dimethyl-1,10-phenathroline dppb 1,3-bis(diphenylphosphino)butane dppp 1,3-bis(diphenylphosphino)propane dppf 1,1'-bis(diphenylphosphino)ferrocene EDG electron-donating group ESI electrospray ionization Et ethyl EWG electron-withdrawing group GC gas chromatography HTFA trifluoroacetic acid LC liquid chromatography Nu nucleophile Me methyl MeCN acetonitrile MS(+) mass spectrometry in positive mode MS(-) mass spectrometry in negative mode MS/MS tandem mass spectrometry OAc acetate p-BQ para-benzoquinone Pd palladium Phen 1,10-phenanthroline Ph phenyl Q Quadrupole RP reversed phase rt room temperature TEMPO 2,2,6,6-tetramethylpiperidine-1-oxyl TFA trifluoroacetate THF tetrahydrofuran XPhos 2-dicyclohexylphosphino-2 1. Introduction 1.1 Palladium Most of the palladium produced today is used in catalytic converters, which transform exhaust gases into less harmful substances.1 Other everyday appli- cations of palladium include jewelry, fuel cells, electronic components, pho- tography2 and the production of pharmaceuticals.3 Pd is a late transition- metal located at position 46 in the periodic table. It was discovered