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Palladium(II)-Catalysed Heck and Addition Reactions Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 221 Palladium(II)-Catalysed Heck and Addition Reactions Exploring Decarboxylative and Desulfitative Processes BOBO SKILLINGHAUG ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6192 ISBN 978-91-554-9717-0 UPPSALA urn:nbn:se:uu:diva-304746 2016 Dissertation presented at Uppsala University to be publicly examined in B21, BMC, Husargatan 3, Uppsala, Friday, 25 November 2016 at 09:15 for the degree of Doctor of Philosophy (Faculty of Pharmacy). The examination will be conducted in English. Faculty examiner: Professor Antonio de la Hoz Ayuso (Universidad de Castilla-La Mancha). Abstract Skillinghaug, B. 2016. Palladium(II)-Catalysed Heck and Addition Reactions. Exploring Decarboxylative and Desulfitative Processes. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 221. 100 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-554-9717-0. Palladium complexes have the ability to catalyse cross-coupling of two organic moieties through the formation of transient metal-carbon bonds, thus bringing them closer to each other to facilitate the formation of a new bond. Palladium-catalysed coupling reactions are one of the most important carbon-carbon forming reactions available to organic chemists and many of these reactions rely on the reactivity of aryl-palladium complexes. The investigation of new aryl-palladium precursors is thus of great interest, especially as more sustainable and economic methods can be developed. This thesis describes the use of carboxylic acids and sodium arylsulfinates as such new arylating agents. Protocols for microwave-assisted palladium(II)-catalysed decarboxylative synthesis of electron-rich styrenes and 1,1-diarylethenes were developed. However, these transformations had very limited substrate scopes which prompted the investigation of sodium arylsulfinates as alternative arylating agents. These substrates were employed in the microwave- assisted palladium(II)-catalysed desulfitative addition to nitriles, and the substrate scope was demonstrated by combining a wide array of sodium arylsulfinates and nitriles to yield the corresponding aryl ketones. The application of the desulfitative reaction in a continuous flow setup was demonstrated, and aluminium oxide was identified as safe alternative to borosilicate glass as a reactor material. The mechanisms of the decarboxylative and desulfitative transformations were investigated by density functional theory (DFT) calculations. The desulfitative reaction was also investigated by direct electrospray ionization mass spectrometry (ESI-MS), providing further mechanistic insight. Finally, a protocol for the safe and convenient synthesis of a wide range of sodium arylsulfinates was developed. Keywords: Palladium, catalysis, palladium(II) catalysis, synthesis, Heck, carboxylic acid, sulfinic acid, sodium sulfinate, nitrile, styrene, ketone, aryl ketone, electrospray ionization mass spectrometry, density functional theory, microwave heating, continuous flow Bobo Skillinghaug, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Box 574, Uppsala University, SE-75123 Uppsala, Sweden. © Bobo Skillinghaug 2016 ISSN 1651-6192 ISBN 978-91-554-9717-0 urn:nbn:se:uu:diva-304746 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-304746) May you live in interesting times List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Fardost, A.,† Skillinghaug, B.,† Svensson, F.,† Wakchaure, P., Wejdemar, M., Larhed, M., Sköld. C. (2016) Mechanistic In- vestigation of Palladium(II)-Catalyzed Decarboxylative Synthe- sis of Electron-Rich Styrenes and 1,1-Diarylethenes. Manu- script. II Skillinghaug, B., Sköld., C., Rydfjord, J., Svensson, F., Beh- rends, M., Sävmarker, J., Sjöberg, P. J. R., Larhed, M. (2014) Palladium(II)-Catalyzed Desulfitative Synthesis of Aryl Ke- tones from Sodium Arylsulfinates and Nitriles: Scope, Limita- tions, and Mechanistic Studies. J. Org. Chem., 79, 12018−12032. III Skillinghaug, B., Rydfjord, J., Sävmarker, J., Larhed, M. (2016) Microwave Heated Continuous Flow Palladium(II)- Catalyzed Desulfitative Synthesis of Aryl Ketones. Org. Pro- cess Res. Dev., Under revision. IV Skillinghaug, B., Rydfjord, J., Odell, L. (2016) Synthesis of Sodium Aryl Sulfinates from Aryl Bromides Employing 1,4- Diazabicyclo[2.2.2]octane Bis(sulfur dioxide) Adduct (DAB- SO) as a Bench-stable, Gas-free Alternative to SO2. Tetrahe- dron Lett., 57, 533-536. †These authors contributed equally. Reprints were made with permission from the respective publishers. Author Contribution Statement The following contributions to the papers included in this thesis were made by the author: I Performed preparative work and characterisation of compounds, performed single point energy calculations, collated experi- mental data and contributed significantly during the manuscript preparation. II Performed the majority of the preparative work and characteri- sation of compounds, aided in the design of and participated in the electrospray ionisation mass spectrometry (ESI-MS) study, collated experimental data and drafted the manuscript. III Performed the optimisation work and synthesised the majority of the compounds, collated experimental data and contributed significantly during the manuscript preparation. IV Performed the optimization work, the majority of the prepara- tive work and characterisation of compounds, collated experi- mental data and drafted the manuscript. Contents Introduction ................................................................................................... 11 Synthetic Organic Chemistry ................................................................... 11 Catalysis ................................................................................................... 13 Palladium Catalysis .................................................................................. 14 Palladium-Catalysed Cross-Coupling Reactions ................................. 16 The Mizoroki-Heck reaction ................................................................ 19 Palladium(II) Catalysis ............................................................................. 21 The Oxidative Heck Reaction .............................................................. 22 Palladium-Catalysed Addition Reactions ............................................ 25 Metal-Catalysed Decarboxylative Reactions ....................................... 26 Sulfinic Acids and Metal-Catalysed Desulfitative Reactions .............. 28 Density Functional Theory ....................................................................... 31 Microwave-Assisted Organic Synthesis ................................................... 32 Continuous Flow Chemistry ..................................................................... 34 Electrospray Ionisation Mass Spectrometry ............................................. 35 Research Aims .............................................................................................. 37 Palladium(II)-Catalysed Decarboxylative Synthesis of Electron-Rich Styrenes and 1,1-Diarylethenes (Paper I) ..................................................... 38 Background .............................................................................................. 38 Optimisation of Reaction Conditions for the Synthesis of Styrenes ........ 39 Investigation of the Scope of the Palladium(II)-Catalysed Decarboxylative Synthesis of Styrenes .................................................... 44 Investigation of the Reaction Mechanism using Density Functional Theory ...................................................................................................... 45 Palladium(II)-Catalysed Decarboxylative Synthesis of 1,1- Diarylethenes ............................................................................................ 48 Palladium(II)-Catalysed Desulfitative Addition of Sodium Arylsulfinates to Nitriles (Paper II-III) ................................................................................. 51 Background .............................................................................................. 51 Initial Investigation .................................................................................. 51 Optimisation of Reaction Conditions for the Synthesis of Aryl Ketones ..................................................................................................... 53 Investigation of the Reaction Mechanism using Electrospray Ionisation Mass Spectrometry ................................................................................... 55 Investigation of the Reaction Mechanism using Density Functional Theory ...................................................................................................... 56 Investigation of the Scope of the Microwave-Assisted Organic Synthesis of Aryl Ketones ........................................................................ 60 Continuous Flow Microwave-Assisted Organic Synthesis of Aryl Ketones ..................................................................................................... 65 Synthesis of Sodium Arylsulfinates Using a Solid Source of Sulphur Dioxide (Paper IV) ........................................................................................ 72 Background .............................................................................................. 72 Development of the Protocol ...................................................................
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