Sulfoxide-Directed Metal-Free Aromatic C-H Functionalisation: Application to Heterocycle Synthesis and Derivatisation. A thesis submitted to the University of Manchester for the degree of Doctor of Philosophy in the Faculty of Science and Engineering 2017 Harry J. Shrives School of Chemistry Harry J. Shrives Ph.D Thesis Contents List of Abbreviations 4 Abstract. 7 Declaration 8 Copyright Statement 9 Acknowledgments 10 Chapter 1: Introduction 12 1.1 Pummerer and Pummerer-type Reactions 12 1.1.1 The Classical Pummerer Rearrangement 12 1.1.2 Additive and Vinylogous Pummerer Reactions 14 1.1.3 Aromatic and Hetero-aromatic Pummerer-type Reactions 20 1.1.4 Interrupted Pummerer Reactions 29 1.2 Functionalisation of Aromatics Through Charge Accelerated Rearrangements 32 1.2.1 Charge Accelerated [3,3]-Sigmatropic Rearrangments 32 1.2.2 Ortho Alkylations of Aromatic and Heteroaromatic Systems 39 1.3 Proposed Work 46 Chapter 2: Results and Discussion 49 2.1 Propargylations with Branched Propargyl Silanes 49 2.2 Synthesis of Benzothiophenes 58 2.2.1 Acid-Mediated Cyclisations to Give Alkyl Benzothiophenes 59 2.2.2 Iodine-Mediated Cyclisations to Give Carbonyl-Substituted Benzothiophenes 60 2.2.3 Iodine-Mediated Cyclisations to Give Alkyl-Substituted Benzothiophenes 62 2.2.4 Iodine-Mediated Cyclisations to Give Alkenes 64 2.2.5 Cyclisations to Give Highly Conjugated Benzothiophene-Containing Scaffolds 67 2.2.6 Iodine-Mediated Cyclisations: Mechanisms 71 2.2.7 Access to Benzodithiophene Scaffolds: A Novel Dimerisation 72 2.3 Selective Functionalisation of Benzothiophenes 80 2.3.1 Benzothiophene S-Oxides: Synthesis and Reactivity 81 2.3.2 Selective Arylation of Benzothiophenes Using Phenols 82 2 Harry J. Shrives Ph.D Thesis 2.3.3 Selective Alkylation of Benzothiophenes 89 2.3.4 Conclusion and Future Work 96 Chapter 3: Experimental 102 3.1 General Eperimental 102 3.2 Experimental Data 103 3.2.1 General Procedure A: Preparation of 1,3-Bispropargyl Silanes 103 3.2.2 General Procedure B: Propargylation of Aryl Sulfoxides 104 3.2.3 General Procedure C: Preparation of Propargyl Silanes 106 3.2.4 General Procedure D: Propargylation of Heterocycles 110 3.2.5 Gerenal Procedure E: Acid-Mediated Cyclisations 114 3.2.6 General Procedure F: Deprotections 116 3.2.7 General Procedure G: Iodine-Mediated Cyclisations to Give Alkyl Subsitution 118 3.2.8 General Procedure H: Iodine-Mediated Cyclisations to Give Alkenes 121 3.2.9 General Procedure I: Two-Directional Propargylations 126 3.2.10 General Procedure J: Oxidation to bis-sulfoxide 128 3.2.11 General procedure K: Bis-sulfide Formation 129 3.2.12 General Procedure L: Two-Directional Eliminative Cyclisation 130 3.2.13 General Procedure M: Iodine-Mediated Dimerisations 132 3.2.14 General Procedure N: Oxidation of Benzothiophenes 136 3.2.15 General Procedure O: Arylation of Benzothiophene S-Oxides 141 3.2.16 General Procedure P: Arylation of Benzothiophenes with in-situ Oxidation 146 3.2.17 General Procedure Q: Propargylation/Allyation of Benzothiophene S-Oxides 153 3.2.18 General Procedure R: Propargylation of Benzothiophenes with in-situ Oxidation 162 3.2.19 General Procedure S: C2 Propargylation of Benzothiophene S-Oxides 170 3.2.20 General Procedure T: C2 Allylations of Benzothiophene S-Oxides 172 3.3 Appendix: X-Ray Crystal Structures 179 Chapter 4: References 186 3 Harry J. Shrives Ph.D Thesis List of Abbreviations Ac acyl AIBN 2,2’-azo bisisobutyronitrile aq. aqueous Ar aryl BDT benzodithiophene BINAP 2,2’-bis(diphenylphosphino-1,1’-binaphthyl) Bn benzyl Boc t-butoxycarbonyl br. broad (NMR) Bu butyl Bz benzoyl CAN cerium(IV) ammonium nitrate cat. catalytic CI chemical ionisation C celsius Cy cyclohexyl d doublet (NMR) δ chemical shift (NMR) DCE 1,2-dichloroethane DDQ 2,3-dichloro-5,6-dicyano-p-benzoquinone DMF N,N-dimethylformamide DMSO dimethylsulfoxide DMTSF dimethyl(methylthio)sulfonium tetrafluoroborate DPPE ethylenebis(diphenylphosphine) dr diasteroisomeric ratio DTBP di-tert-butylpyridine E electrophile ee enantiomeric excess EDG electron donating group EG ethylene glycol EI electron ionisation equiv equivalent 4 Harry J. Shrives Ph.D Thesis ES+/ES- positive/negative ion electrospray (MS) Et ethyl EWG electron withdrawing group FSPE fluorous solid phase extraction g gram h hour HFIP 1,1,1,3,3,3-hexafluoroisopropanol HMPA hexamethylphosphoramide HRMS high resolution mass spectrometry Hz hertz IBX o-iodoxybenzoic acid i-Pr isopropyl IR infrared J coupling constant (NMR) μ electron mobility M Molar m multiplet (NMR) m-CPBA m-chloroperbenzoic acid Me methyl mg miligram MHz megahertz min minutes ml millilitre mmol millimole MOM methoxymethyl mp melting point MS mass spectrum MW micro wave m/z mass/charge ratio (MS) NDT naphthodithiophene NCS N-chlorosuccinimide Nf nonafluorobutanesulfonic NMR nuclear magnetic resonance 5 Harry J. Shrives Ph.D Thesis Nu nucleophile PCE Power Conversion Efficiency Ph phenyl PIFA iodobenzene-I,I-bis(trifluoroacetate) PMB p-methoxybenzyl ppm parts per million Pr propyl PTSA p-toluenesulfonic acid Pyr. pyridine q quartet (NMR) quin quintet (NMR) RF perfluoroalkyl rt room temperature s singlet (NMR) sxt sextet (NMR) SEM 2-(trimethylsilyl)ethoxymethyl t triplet (NMR) TBAF tetrabutylammonium fluoride TBS tert-butyldimethylsilyl TFA trifluoroacetic acid TFAA trifluoroacetic anhydride Tf trifluoromethanesulfonic THF tetrahydrofuran TIPS triisopropylsilyl TMEDA N,N,N’,N’-tetramethylethylenediamine TMS trimethylsilyl Tol tolyl Ts tosyl 6 Harry J. Shrives Ph.D Thesis Abstract. University of Manchester Harry J. Shrives Degree of Doctor of Philosophy. Sulfoxide-Directed Metal-Free Aromatic C-H Functionalisation: Application to Heterocycle Synthesis and Derivatisation. March 2017. Selective metal-free functionalisation of aromatic C-H bonds is a valuable goal in organic synthetic chemistry. Recently it has been shown that Pummerer-type reactions, for example interrupted Pummerer reactions, can be used to trap nucleophiles and deliver them selectively to aromatic rings via [3,3]-sigmatropic rearrangements. This thesis investigates the utility of sulfoxide-directed metal-free C-H functionalisations in the synthesis and derivatisation of a range of benzothiophene scaffolds. Through a sequence involving metal-free aromatic propargylation reactions and novel, diversity introducing heterocyclisations, benzothiophenes possessing a range of functionality, namely ketone, alkane or alkene substituents, can be synthesised. The value of this new cyclisation protocol is demonstrated through the sysnthesis of different highly conjugated benzothiophene motifs, molecules of particular interest in organic electronics. Using alkene substituted benzothiophenes; a new, iodine-mediated route to highly conjugated benzodithiophene cores is reported along with the application of two-directional heterocyclisations allowing the synthesis of naphthodithiophene scaffolds. Finally, selective C3 arylation and alkylation of benzothiophenes is reported through the use of benzothiophene S-oxides, an underexplored class of organic compound. Oxidation of the sulfur atom intrinsic to benzothiophene molecules allows the capture of phenol, propargyl silane and allyl silane coupling partners, which are delivered with complete regio-selectivity to the C3 position of the benzothiophene. 7 Harry J. Shrives Ph.D Thesis Declaration No portion of the work referred to in the thesis has been submitted in support of an application for another degree or qualification of this or any other university or other institute of learning. Portions of the work refered to in this thesis have been published in: Eberhart, A. J.; Shrives, H. J.; Álvarez, E.; Carrër, A.; Zhang, Y.; Procter, D. J. Chem. -Eur. J., 2015, 21, 7428. Eberhart, A. J.; Shrives, H.; Zhang, Y.; Carrër, A.; Parry, A. V. S.; Tate, D. J.; Turner, M. L.; Procter, D. J. Chem. Sci., 2016, 7, 1281. Shrives, H. J.; Fernández-Salas, J. A.; Hedtke, C; Pulis, A. P.; Procter, D. J. Nat. Commun., 2017, 8, 14801, doi: 10.1038/ncomms14801 8 Harry J. Shrives Ph.D Thesis Copyright Statement 1. The author of this thesis (including any appendices and/or schedules to this thesis) owns certain copyright or related rights in it (the “Copyright”) and s/he has given The University of Manchester certain rights to use such Copyright, including for administrative purposes. 2. Copies of this thesis, either in full or in extracts and whether in hard or electronic copy, may be made only in accordance with the Copyright, Designs and Patents Act 1988 (as amended) and regulations issued under it or, where appropriate, in accordance with licensing agreements which the University has from time to time. This page must form part of any such copies made. 3. The ownership of certain Copyright, patents, designs, trade marks and other intellectual property (the “Intellectual Property”) and any reproductions of copyright works in the thesis, for example graphs and tables (“Reproductions”), which may be described in this thesis, may not be owned by the author and may be owned by third parties. Such Intellectual Property and Reproductions cannot and must not be made available for use without the prior written permission of the owner(s) of the relevant Intellectual Property and/or Reproductions. 4. Further information on the conditions under which disclosure, publication and commercialisation of this thesis, the Copyright and any Intellectual Property and/or Reproductions described in it may take place is available in the University IP Policy (see http://documents.manchester.ac.uk/DocuInfo.aspx?DocID=487), in any relevant Thesis restriction declarations deposited in the University Library, The University Library’s regulations (see http://www.manchester.ac.uk/library/aboutus/regulations) and in The University’s policy on Presentation of Theses 9 Harry J. Shrives Ph.D Thesis Acknowledgments I would like to thank, first and foremost, my supervisor Professor David J. Procter for the invaluable continued support and mentoring he has provided over the last four years. The chance to contribute to the chemistry going on in his group has been an irreplaceable experience in which I have learnt in incredible amount. Also, I must thank Novartis for funding my Ph.D studentship. Thanks must also go to all the current and past members of the Procter group who have made my time so enjoyable; Craig, Irem, Miles, Matezeus, Nico, Becky, Huanming, Kay, Charlotte and the many others that have been a pleasure to work with. Special thanks should be given Andrew, Yuntong, Jose and Kristen all of whom, at one point or another, have been involved in my project and have therefore played a significant role in my development as a researcher, chemist and individual. I would like to dedicate this thesis to my mother, Liz, for her unwavering support and encouragement throughout the duration of my undergraduate and Ph.D. studies, her experience and guidance has been unbelievably helpful over the years. Last, but not least, I would like to thank Amy for putting up with me day-to-day and for keeping me sane, happy and motivated throughout my studies. 10