New Methods for the Synthesis of Functionalised Arenes A thesis submitted to the University of Manchester for the degree of Doctor of Philosophy in the Faculty of Science and Engineering Danielle L. Bunting School of Chemistry Faculty of Science & Engineering 2018 2 Contents List of abbreviations5 Abstract . 10 Declaration . 11 Copyright statement . 11 Acknowledgements . 12 1 Ruthenium catalysed C{H activation 13 1.1 Introduction . 13 1.1.1 Background: C{H activation . 13 1.1.2 ortho-Functionalisation . 14 1.1.3 meta-Functionalisation . 34 1.2 Investigations into meta-functionalisation . 48 1.2.1 Aims and objectives . 48 1.2.2 Results and discussion . 48 1.2.3 Conclusions . 65 1.3 Ruthenium catalysed ortho-halogenation . 67 1.3.1 Aims and objectives . 67 1.3.2 Results and discussion . 67 1.3.3 Conclusions and future work . 96 1.4 Tandem N,C-diarylation of pyrazole . 99 1.4.1 Background: Diaryliodonium salts . 99 1.4.2 Aims and objectives . 112 1.4.3 Results and discussion . 113 1.4.4 Conclusions and future work . 131 2 Arynes for the synthesis of substituted arenes 133 2.1 Introduction . 133 2.2 Hexadehydro-Diels{Alder (HDDA) reaction . 137 2.2.1 Background: HDDA . 137 2.2.2 Aims and objectives . 143 2.2.3 Results and discussion . 144 2.2.4 Conclusions . 151 2.3 Benzyne Truce{Smiles rearrangement . 154 2.3.1 Background . 154 2.3.2 Aims and objectives . 163 2.3.3 Results and discussion . 164 2.3.4 Conclusions and future work . 182 3 3 Experimental 184 3.1 General . 184 3.2 meta-Functionalisation experimental . 186 3.3 ICl experimental . 190 3.3.1 General procedures . 190 3.3.2 Preparation of starting materials . 191 3.3.3 ortho-Halogenation products . 198 3.3.4 Kinetic isotope experiments . 214 3.4 Tandem N,C-diarylation of pyrazole experimental . 221 3.4.1 Preparation of iodonium salts . 221 3.4.2 N{H/C{H arylation of pyrazoles . 226 3.4.3 Screening of other heterocycles . 232 3.5 HHDDA experimental . 237 3.6 Benzyne{Smiles experimental . 244 3.6.1 Synthesis of starting materials . 244 3.6.2 Screening of conditions . 258 Bibliography 267 4 List of abbreviations δ Chemical shift (in ppm) 1,10-phen 1,10-Phenanthroline 1,2-DCE 1,2-Dichloroethane A˚ Angstr¨om˚ µL microlitre(s) J NMR coupling constant k Rate constant k rel Relative rate of reaction mCPBA meta-Chloroperoxybenzoic acid o-DCB 1,2-Dichlorobenzene AdCO2H 1-Adamantanecarboxylic acid AIBN Azobisisobutyronitrile APCI Atmospheric Pressure Chemical Ionisation app. apparent aq. Aqueous Ar Aryl ATRA Atom transfer radical addition BHT 2,6-Di-tert-butyl-4-methylphenol BNDHP 1,1'-Binaphthyl-2,2'-diylhydrogen phosphate Boc tert-Butyloxycarbonyl bpy 2,2'-Bipyridyl br Broad calcd Calculated cat. Catalyst/catalytic cm centimetre(s) cm−1 wavenumbers CMD Concerted metallation deprotonation COD 1,5-Cyclooctadiene Conc. Concentration 5 Cp* Pentamethyl cyclopentadiene d doublet DABCO 1,4-Diazabicyclo[2.2.2]octane dap 2,9-Bis(4-methoxyphenyl)-1,10-phenanthroline DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCM Dichloromethane dF-ppy 2-(2,4-Difluorophenyl)pyridine DFT Density functional theory DG Directing group DIPA Diisopropylamine DIPEA N,N -Diisopropylethylamine DMEDA N,N '-Dimethylethane-1,2-diamine DMF N,N -Dimethylformamide DMSO Dimethylsulfoxide DPPB Butane-1,3-diylbis(diphenylphosphine) DPPE Ethane-1,2-diylbis(diphenylphosphine) dppf 1,1'-Ferrocenediyl-bis(diphenylphosphine) DPPH Di(phenyl)-(2,4,6-trinitrophenyl)iminoazanium DPPP Propane-1,3-diylbis(diphenylphosphine) DTBP Di-tert-butyl peroxide dtbpy 4,4'-Di-tert-butyl-2,2'-dipyridyl e− Electron EAS Electrophilic aromatic substitution EI Electron Ionisation Eosin Y 2-(2,4,5,7-Tetrabromo-6-oxido-3-oxo-3H -xanthen-9-yl)benzoate eq. Equivalents ESI Electrospray Ionisation EWG Electron withdrawing group Fluorescein 3',6'-Dihydroxyspiro[isobenzofuran-1(3H ),9'-[9H ]xanthen]-3-one g gram(s) Galvinoxyl 2,6-Di-tert-butyl-α-(3,5-di-tert-butyl-4-oxo-2,5-cyclohexadien-1- ylidene)-p-tolyloxy, free radical GCMS Gas Chromatography Mass Spectrometry 6 h hour(s) HDDA Hexadehydro-Diels{Alder HHDDA Hetero-Hexadehydro-Diels{Alder HMDS Bis(trimethylsilyl)amine Hz Hertz IR Infra-Red kcal/mol kilocalories per mole KIE Kinetic isotope effect L Ligand LDA Lithium diisopropylamide LED Light emitting diode LG Leaving group LR Low resolution M Molecular mass (in mass spectrometry) M mol dm−3 m medium (IR absorbance) m multiplet (NMR peak) m.p. Melting point mA milliamp Mes Mesityl mg milligram(s) MHz megahertz MIDA N -Methyliminodiacetic acid min minute(s) mL millilitre(s) MLCT Metal to Ligand Charge Transfer mmol millimole(s) mol% molar percentage MPAA Mono-protected amino acid MS Mass Spectrometry MS Molecular sieves MW Microwave NBE Norbornene 7 NBS N -Bromosuccinimide NCS N -Chlorosuccinimide NIS N -Iodosuccinimide nm nanometre(s) NMP N -Methyl-2-pyrrolidone NMR Nuclear Magnetic Resonance NR No reaction Nu Nucleophile PE Petroleum ether pin Pinacolato Piv Pivaloyl PMP para-Methoxyphenyl ppm parts per million PPTS pyridinium p-toluenesulfonate ppy 2-Phenylpyridine PRC Photoredox Catalyst psi Pound per square inch PTFE Poly(tetrafluoroethylene) q quartet quant. Quantitative yield RDS Rate determining step rt Room temperature s second(s) s singlet (NMR peak) s strong (IR absorbance) sat. saturated sept septet SET Single electron transfer SM Starting material soln. solution t triplet t1=2 Half life TBA-OAc Tetra-n-butylammonium acetate 8 TBAF Tetra-n-butylammonium fluoride TBAT Tetra-n-butylammonium difluorotriphenylsilicate TBATB Tetra-n-butylammonium tribromide TBHP tert-Butyl hydroperoxide temp Temperature TEMPO (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl Tf Triflyl TFA Trifluoroacetic acid THF Tetrahydrofuran THP 2-Tetrahydropyranyl TLC Thin Layer Chromatography TM Transition metal TMEDA N,N,N ',N '-Tetramethylethylenediamine Ts Tosyl UPLC Ultra Performance Liquid Chromatography UV Ultraviolet Val Valine vis Visible w weak w/u Work-up w/w weight/weight Xyl 3,5-(Dimethyl)phenyl 9 Abstract The University of Manchester Danielle L. Bunting School of Chemistry Doctor of Philosophy 2018 New methods for the synthesis of functionalised arenes Arenes are a cornerstone of organic chemistry, and new methods for their functionali- sation, whether with improved efficiency, or for the synthesis of novel, highly function- alised skeletons remain crucial. The methods available for achieving such transforma- tions are diverse. This thesis is comprised of two chapters, one investigating the use of ruthenium catalysis for directed C{H functionalisation of arenes possessing a strongly coordinating directing group. The second concerns the use of arynes for the construction of highly functionalised pyridines (via a hexadehydro-Diels{Alder (HDDA) reaction) and ortho- hydroxy biaryls (via a tandem benzyne-Truce{Smiles rearrangement). Ruthenium catalysis has successfully been used to introduce a number of functional groups by C{H activation. Combined with halocarbons, it could be used to introduce novel functionalities such as tetrasubstituted alkenes, or a formyl group in the meta- position of phenylpyridine. Pleasingly, the use of iodine monochloride as a halogenating agent allowed catalyst dependent ortho-halogenation of phenylpyridine substrates. Use of Ru3(CO)12 catalysis resulted in selective iodination, whereas RuCl2(PPh3)3 enabled chlorination. The substrate scope, as well as the reasons behind this intriguing change in selectivity were investigated. Ruthenium catalysis has also been used to achieve a one-pot tandem N,C-arylation of pyrazoles, using both aryl components of diaryliodonium salts, avoiding the waste of one equivalent of aryl iodide. Effective for both symmetrical and unsymmetrical di- aryliodoniums in good yields, this could also be extended to the use of styrylphenyliodo- niums for synthesis of trisubstituted alkenes. The use of arynes also provides a powerful method for the synthesis of functionalised arynes. Attempts to achieve a pyridyne synthesis and subsequent trapping in a HDDA cascade were unsuccessful. However, generation of benzyne from ortho-trimethylsilyl aryl triflate, followed by nucleophilic attack, and subsequent Truce{Smiles rearrange- ment of an aryl sulfonate ester was successful in the synthesis of ortho-functionalised biaryls. Word count: 56627 10 Declaration Work towards Sections 1.2 & 1.3 has been submitted in support of an application for a degree of PhD at this university: Christopher J. Teskey, Strategic use of transition metals for selective C{H bond func- tionalisation. Ph.D. thesis, University of Manchester, 2016. Part of this work (Section 1.4) has been published in a peer reviewed journal: Christopher J. Teskey, Shariar M. A. Sohel, Danielle L. Bunting, Sachin G. Modha and Michael F. Greaney, Domino N-/C-Arylation via In Situ Generation of a Directing Group: Atom-Efficient Arylation Using Diaryliodonium Salts, Angew. Chem. Int. Ed. 2017, 56, 5263{5266. Copyright statement i 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 she has given The University of Manchester certain rights to use such Copyright, including for administrative purposes. ii 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. 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