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Palladium(II)-Catalyzed Addition Reactions Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 233 Palladium(II)-Catalyzed Addition Reactions Synthesis of Aryl Amidines and Aryl Ketones JONAS RYDFJORD ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6192 ISBN 978-91-513-0012-2 UPPSALA urn:nbn:se:uu:diva-326816 2017 Dissertation presented at Uppsala University to be publicly examined in B22, BMC, Husargatan 3, Uppsala, Friday, 15 September 2017 at 09:15 for the degree of Doctor of Philosophy (Faculty of Pharmacy). The examination will be conducted in English. Faculty examiner: Professor Adriaan Minnaard (University of Groningen). Abstract Rydfjord, J. 2017. Palladium(II)-Catalyzed Addition Reactions. Synthesis of Aryl Amidines and Aryl Ketones. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 233. 97 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-513-0012-2. Palladium-catalyzed reactions have become one of the most important tools in modern organic chemistry due to its ability to catalyze the formation of new carbon-carbon bonds. The aim of the work presented in this thesis was to develop new palladium(II)-catalyzed addition reactions. In this work, cyanamides were investigated as a new substrate to give aryl amidines as products. The first protocol developed employed aryltrifluoroborates as the aryl partner, and the insertion of the aryl group into un-, mono-, and di-substituted cyanamides was successful for a wide variety of aryltrifluoroborates. An alternative method of generating the necessary intermediate for insertion into the cyanamide is the decarboxylative formation of aryl-palladium from aryl carboxylic acids. A protocol was developed for this reaction, but was unfortunately limited to a small number of ortho-substituted electron-rich aryl carboxylic acids. The mechanism was investigated by the means of DFT calculations and ESI-MS studies, and the rate-determining step was suggested to be the 1,2-carbopalladation based upon those results. A translation of the batch protocol to continuous-flow conditions was also demonstrated. The ideal method of generating the aryl-palladium species is by C-H bond activation, and this approach was demonstrated with indoles, giving a variety of 3-amidinoindoles as products. The mechanism was investigated by DFT calculations and a plausible catalytic cycle was proposed. A continuous-flow application of a desulfitative palladium(II)-catalyzed addition to nitriles to give ketones was developed. In addition, different reactor materials were evaluated in the microwave heated reactor cavity. Thus the reaction was shown to proceed with microwave heating in a borosilicate glass and an aluminum oxide reactor, and also in conditions mimicking conventional heating in a silicon carbide reactor. Finally, a protocol was developed for the convenient synthesis of sodium aryl sulfinates from Grignard and lithium reagents using a solid sulfur dioxide source as a safe alternative to the gas. The products of this protocol can be used as aryl-palladium precursors by a desulfitative process. Keywords: Palladium, Catalysis, Palladium(II) catalysis, Synthesis, Addition Reactions, Cyanamide, Amidine, Aryl Amidine, Nitrile, Ketone, Aryl Ketone, Carbopalladation, Continuous-flow, Continuous flow, Microwave heating Jonas Rydfjord, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Box 574, Uppsala University, SE-75123 Uppsala, Sweden. © Jonas Rydfjord 2017 ISSN 1651-6192 ISBN 978-91-513-0012-2 urn:nbn:se:uu:diva-326816 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-326816) Till min familj 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., Rydfjord, J., Gising, J., Odell, L. R., Larhed, M. (2012) Direct Palladium(II)-Catalyzed Synthesis of Arylamidines from Aryltrifluoroborates. Organic Letters, 14(9):2394-2397 II Rydfjord, J., Svensson, F., Trejos, A., Sjöberg, P.J.R., Sköld, C., Sävmarker, J., Odell, L.R., Larhed, M. (2013) Decarboxylative Palladium(II)-Catalyzed Synthesis of Aryl Amidines from Aryl Carboxylic Acids: Development and Mechanistic Investigation. Chemistry – A European Journal, 19(41):13803-13810 III Rydfjord, J., Skillinghaug, B., Brandt, P., Odell, L.R., Larhed, M. Route to 3-Amidino Indoles via Pd(II)-Catalyzed C-H Bond Activation. Organic Letters, 19(15):4066-4069 IV Skillinghaug, B., Rydfjord, J., Sävmarker, J., Larhed, M. (2016) Microwave Heated Continuous Flow Palladium(II)-Catalyzed Desulfitative Synthesis of Aryl Ketones. Organic Process Research & Development, 20(11):2005-2011 V Skillinghaug, B., Rydfjord, J., Odell, L.R. (2016) Synthesis of sodium aryl sulfinates from aryl bromides employing 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO) as a bench-stable, gas-free alternative to SO2. Tetrahedron Letters, 57 (5):533-536 Reprints were made with permission from the respective publishers. Papers Not Included in This Thesis 2014 Konda, V., Rydfjord, J., Sävmarker, J., Larhed, M. Safe Palladium-Catalyzed Cross-Couplings with Microwave Heating Using Continuous-Flow Silicon Carbide Reactors. Organic Process Research & Development, 18(11):1413-1418 2014 Skillinghaug, B., Sköld, C., Rydfjord, J., Svensson, F., Behrends, M., Sävmarker, J., Sjöberg, P.J.R., Larhed, M. Palladium(II)-Catalyzed Desulfitative Synthesis of Aryl Ketones from Sodium Arylsulfinates and Nitriles: Scope, Limitations, and Mechanistic Studies. The Journal of Organic Chemistry, 79(24):12018-12032 2013 Rydfjord, J., Svensson, F., Fagrell, M., Sävmarker, J., Thulin, M., Larhed, M. Temperature measurements with two different IR sensors in a continuous-flow microwave heated system. Beilstein Journal of Organic Chemistry, 9(1):2079-2087 Contents 1. Introduction ............................................................................................... 11 1.1 Catalysis ............................................................................................. 11 1.1.1 Palladium Catalysis .................................................................... 13 1.2 Palladium(II)-Catalysis ...................................................................... 15 1.2.1 Aryl-Palladium Precursors .......................................................... 16 1.2.2 Palladium(II)-Catalyzed Addition Reactions .............................. 19 1.2.3 Palladium(II)-Catalyzed Addition to Nitriles ............................. 20 1.3 Mechanistic Investigations ................................................................. 24 1.3.1 Density Functional Theory Calculations .................................... 24 1.3.2 Electrospray Ionization Mass Spectrometry for Investigation of Live Reaction Mixtures ................................................................... 25 1.4 Amidines ............................................................................................ 27 1.4.1 Synthesis of amidines ................................................................. 29 1.5 Continuous-flow Chemistry ............................................................... 30 1.5.1 Heating by a Non-Resonant Microwave Applicator ................... 31 2. Aims of the Present Study ......................................................................... 35 3. Palladium(II)-Catalyzed Synthesis of Aryl Amidines from Cyanamides and Aryltrifluoroborates (Paper I)................................................................. 36 3.1 Background ........................................................................................ 36 3.2 Optimization of Reaction Conditions ................................................. 36 3.3 Investigation of the Scope of the Reaction ......................................... 38 3.4 Suggested Mechanism ........................................................................ 41 4. Palladium(II)-Catalyzed Synthesis of Aryl Amidines from Cyanamides and Aryl Carboxylic Acids (Paper II) ........................................................... 42 4.1 Background ........................................................................................ 42 4.2 Optimization of Reaction Conditions ................................................. 43 4.3 Investigation of the Scope of the Reaction ......................................... 45 4.4 Continuous-Flow Scale-Out ............................................................... 48 4.5 Mechanistic Investigation................................................................... 49 4.5.1 DFT Calculations ........................................................................ 50 4.5.2 Live Reaction Studies Using ESI-MS ........................................ 52 5. Palladium(II)-Catalyzed Synthesis of 3-Amidino Indoles from Cyanamides and Indoles (Paper III) .............................................................. 54 5.1 Background ........................................................................................ 54 5.2 Optimization of Reaction Conditions ................................................. 55 5.3 Investigation of the Scope of the Reaction ......................................... 56 5.4 Mechanistic Investigation................................................................... 59 5.4.1 DFT Calculations ........................................................................ 60 6. Continuous-Flow Palladium(II)-Catalyzed Desulfitative Synthesis of Aryl Ketones (Paper IV) ............................................................................... 64 6.1 Background .......................................................................................
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