Method development for the synthesis of organosulfur compounds and their functionalization by C–H activation and reductive borylation Von der Fakultät für Mathematik, Informatik und Naturwissenschaften der RWTH Aachen University zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigte Dissertation vorgelegt von Master of Science (M. Sc.) Carl Albrecht Dannenberg aus Gummersbach, Deutschland Berichter: Universitätsprofessor Dr. rer. nat. Carsten Bolm Universitätsprofessor Dr. rer. nat. Dieter Enders Tag der mündlichen Prüfung: 02.03.2017 Diese Dissertation ist auf den Internetseiten der Universitätsbibliothek online verfügbar. The work presented in this thesis was carried out from April 2014 until November 2016 at the Institute of Organic Chemistry, RWTH Aachen University, Aachen (Germany) under the supervision of Professor Dr. Carsten Bolm. I would like to thank Professor Dr. Carsten Bolm for the opportunity to work in his group, the scientific freedom, excellent working conditions and his guidance throughout this thesis. Parts of this work have already been published: C. A. Dannenberg, V. Bizet, C. Bolm, Synthesis 2015, 47, 1λ51‒1λ5λ. C. A. Dannenberg, L. Fritze, F. Krauskopf, C. Bolm, Org. Biomol. Chem. 2017, 15, 1086‒ 1090. Für meine Familie Table of contents 1. Theoretical Background ................................................................................................1 1.1. Introduction to sulfoximines and sulfilimines ...........................................................1 1.1.1. Properties ........................................................................................................1 1.1.2. Synthetic pathways to sulfoximines and sulfilimines .........................................2 1.1.2.1. Oxidation of sulfides and sulfilimines .............................................................3 1.1.2.2. Imination of sulfides and sulfoxides ...............................................................4 1.1.3. Synthesis and applications of N-alkyl- and N-methylsulfoximines ...................13 1.1.4. Synthesis and applications of N-cyanosulfoximines .......................................16 1.1.5. Biological relevance of sulfoximines and sulfilimines ......................................19 1.2. Relevant reaction types ........................................................................................21 1.2.1. Suzuki–Miyaura cross-coupling .........................................................................21 1.2.2. Directing group-assisted C–H activation ............................................................23 1.2.2.1. Oxidative C–H olefination ............................................................................25 1.2.2.2. Borylation: From stoichiometric reactions to directed C–H borylation ..........29 1.2.3. Reductive borylation ..........................................................................................36 2. Results and Discussion ...............................................................................................41 2.1. Synthesis of N-alkylated sulfoximines ...................................................................41 2.1.1. Background and aim of the project .................................................................41 2.1.2. Project realization ..........................................................................................42 2.1.2.1. Previous results ..........................................................................................42 2.1.2.2. Continuation of the project ..........................................................................43 2.1.3. Summary and outlook ....................................................................................48 2.2. Synthesis of N-cyanosulfoximines ........................................................................49 2.2.1. Background and aim of the project .................................................................49 2.2.2. Project realization ..........................................................................................50 2.2.3. Summary and outlook ....................................................................................58 2.3. Reductive borylation of sulfoximines .....................................................................59 2.3.1. Background and aim of the project .................................................................59 2.3.2. Project realization ..........................................................................................60 2.3.3. Summary and outlook ....................................................................................73 2.4. C–H borylation of sulfoximines and their use in Suzuki–Miyaura couplings ..........74 2.4.1. Background and aim of the project .................................................................74 2.4.2. Project realization ..........................................................................................75 2.4.2.1. Iridium-catalyzed ortho-borylation of sulfoximines .......................................75 2.4.2.2. Suzuki–Miyaura couplings of ortho-borylated sulfoximines ......................... 87 2.4.3. Summary and outlook .................................................................................... 92 2.5. Scope extension of N-acetylsulfilimines and their C–H olefination........................ 94 2.5.1. Background and aim of the project ................................................................ 94 2.5.2. Project realization .......................................................................................... 95 2.5.2.1. Synthesis of starting materials .................................................................... 95 2.5.2.2. C–H olefination of N-acetylsulfilimines ........................................................ 96 2.5.3. Summary and outlook .................................................................................. 103 3. Conclusion ............................................................................................................... 105 4. Experimental Section ................................................................................................ 107 4.1. General methods and chemicals ........................................................................ 107 4.2. Determination of physical data ........................................................................... 108 4.3. Synthesis and analytical data of compounds ...................................................... 110 4.3.1. Synthesis of substrates................................................................................ 110 4.3.2. Synthesis of N-alkylsulfoximines 31 and N-methylsulfoximines 30 .............. 113 4.3.3. Synthesis and characterisation data of N,S-dimethyl-S-phenylsulfiliminium bromide (119a) ...................................................................................................... 128 4.3.4. Synthesis of N-cyanosulfoximines 35 .......................................................... 129 4.3.5. One-pot synthesis of N-cyano-S-methyl-S-phenylsulfoximine (35a)............. 139 4.3.6. Synthesis of enantioenriched starting material and product ......................... 140 4.3.7. Synthesis of boronic acid pinacol esters ...................................................... 141 4.3.8. Isolation of N-methylbenzenesulfinamide (132a) as by-product ................... 143 4.3.9. Synthesis of boronic acid neopentyl ester 113a ........................................... 143 4.3.10. Synthesis of ortho-borylated N-protected sulfoximines 133........................ 144 4.3.11. Isolation of N-methylbenzenesulfinamide (132a) as side product .............. 155 4.3.12. Synthesis of N-methyl-S-methyl-S-((1,1'-biphenyl)-2-yl)sulfoximine (136a) 155 4.3.13. Synthesis of N-acetylsulfilimines ................................................................ 157 4.3.14. Synthesis of N-acetylsulfilimineacrylates ................................................... 167 5. Abbreviations............................................................................................................ 177 6. References ............................................................................................................... 183 7. Acknowledgments .................................................................................................... 191 8. Curriculum Vitae ....................................................................................................... 193 Introduction 1. Theoretical Background 1.1. Introduction to sulfoximines and sulfilimines 1.1.1. Properties Sulfoximines and sulfilimines represent the aza-analogs of sulfones and sulfoxides (Figure 1). In case of sulfoximines, the formal exchange of an oxygen atom by a nitrogen atom, leads to a tetracoordinated sulfur compound, which in contrast to sulfones bears a stereogenic center (if R1 and R2 are not equal). Sulfilimines are tricoordinated sulfur compounds, which are also generated by replacement of oxygen with nitrogen. Due to their free electron pair, chirality is existent if different substituents are present. Figure 1: Relevant sulfur compounds for this thesis. Sulfoximines are spatially structured as a contorted tetrahedron. Using both X-ray crystallography and spectroscopic data, sulfoximines could be shown to have a high double bond character of the S–N bond (Figure 2).[1] The nitrogen atom of NH-sulfoximines is usually mildly basic and nucleophilic. In contrast, the proton displays weakly acidic properties