ARYNES IN SYNTHESIS; NEW REACTION AND PRECURSOR DEVELOPMENT A thesis submitted to the University of Manchester for the degree of Doctor of Philosophy in the Faculty of Engineering and Physical Sciences 2014 By Donald McAusland School of Chemistry 2 Contents Abstract 11 Declaration 12 Copyright 13 Acknowledgements 14 1 Introduction 15 1.1 Generationofbenzyne ............................ 17 1.2 Reactionsofbenzyne............................. 19 1.2.1 Pericyclicreactions. 19 1.2.2 Nucleophilicadditiontoarynes . 21 1.2.3 Transition-metal-catalysed reactions . 26 1.3 Selectivitywithsubstitutedarynes . ..... 28 1.4 (Trimethylsilyl)phenyl triflates and related aryne precursors . 32 1.4.1 ortho-Lithiation ........................... 33 1.4.2 [4+2]Cycloaddition . 34 1.4.3 Oxidative para-triflation of acetanilides . 34 1.4.4 Commerciallyavailableprecursors . 35 1.4.5 Precursors for the synthesis of polyaromatic structures...... 35 1.4.6 Other functionalised Kobayashi precursors . ..... 37 1.4.7 Relatedaryneprecursors. 39 1.5 Arynesinsynthesis.............................. 41 1.5.1 Indolesyntheses ........................... 42 2 The Benzyne Fischer Indole Reaction 46 2.1 Introduction.................................. 46 2.1.1 Buchwaldmodification. 47 Contents 3 2.1.2 The arylation of hydrazones with benzyne . 52 2.2 Application of aryne electrophiles to the Fischer indole synthesis . 52 2.2.1 Aryne reactions of other hydrazones . 55 2.2.2 BenzyneFischerindolescope . 58 2.2.3 Substitutedarynes . 60 2.2.4 Miscellaneoustosylhydrazones. 66 2.3 Conclusions .................................. 67 3 Synthesis and Applications of New Aryne Precursors 68 3.1 Introduction.................................. 68 3.1.1 Palladium cross-coupling chemistry . 68 3.1.2 TheSuzukireaction ......................... 69 3.1.3 Organoboronreagents . 71 3.1.4 Chemoselectivity in Suzuki couplings . 74 3.2 Aims...................................... 78 3.3 Optimisation ................................. 79 3.3.1 distal-Bromoaryneprecursor . 80 3.3.2 ortho-Bromoaryneprecursor . 82 3.3.3 Controlreactions ........................... 86 3.4 ScopeoftheselectiveSuzukicoupling . 88 3.4.1 Alternativecouplingreagents . 90 3.5 Reactions of substituted aryne precursors . ...... 92 3.5.1 ortho-Nucleophilicgroups . 93 3.5.2 Reactivityatanitrilegroup. 94 3.5.3 Metalcatalysed[2+2+2]reactions . 97 3.6 Furtherattemptsandleads . 101 3.6.1 Benzyne–furanreactions . 101 3.6.2 Further reactions on the 2′-ring................... 102 3.6.3 Sonogashiracoupling. 102 3.6.4 Boryl-substituted aryne precursors . 104 3.6.5 More highly functionalised aryne precursors . 105 3.6.6 Conclusions .............................. 105 4 Benzyne σ-Insertions 106 4.1 Introduction.................................. 106 4.2 Aryneynamideinsertions . 109 4.2.1 Insertions with oxazolidinone–acetylene . 109 4 Contents 4.2.2 Insertions with N -ethynyl sulfonamides . 111 4.3 Conclusionsandfurtherwork . 114 5 Conclusions 116 6 Experimental 118 6.1 ThebenzyneFischerindolereaction . 119 6.1.1 Hydrazoneprecursorsyntheses . 119 6.1.2 Arylationofprotectedhydrazones . 123 6.1.3 N -Tosylindolesynthesis. 124 6.2 Biphenyl aryne precursors via palladium-mediated cross-coupling . 129 6.2.1 Startingmaterialsynthesis . 129 6.2.2 Biphenylsynthesis . 131 6.2.3 Reactions with substituted biphenyl aryne precursors....... 139 6.3 Benzyne σ-insertionreactions . 141 6.3.1 Ynamidesynthesis . 141 6.3.2 Insertionreactionproducts . 144 References 146 Appendices 157 Listofabbreviations ................................ 157 Crystallographicdata ............................... 159 Word Count: 57947 5 List of Tables 2.1 Benzyne-mediated N -arylation and Fischer cyclisation. 58 2.2 N -Arylation and Fischer cyclisation with substituted arynes. ...... 61 3.1 Control reactions for Suzuki coupling of 216 and phenyl boronic acid . 87 3.2 Suzuki coupling of boronic acids and 216.................. 89 3.3 Suzuki coupling of boronic acid precursors with 216............ 91 4.1 Conditions for C–N insertion with 311 ................... 113 A1 Crystal data and structure refinement for 283. .............. 159 A2 Atomic coordinates and equivalent isotropic displacement parameters for 283 ...................................... 160 A3 Bond lengths and angles for 306....................... 167 A4 Anisotropic displacement parameters for 283................ 184 A5 Hydrogen coordinates and isotropic displacement parameters for 283. 191 A6 Torsion angles for 283............................. 197 A7 Crystal data and structure refinement for 306. .............. 205 A8 Atomic coordinates and equivalent isotropic displacement parameters for 306 ...................................... 206 A9 Bond lengths and angles for 306....................... 207 A10 Anisotropic displacement parameters for 306................ 208 A11 Hydrogen coordinates and isotropic displacement parameters for 306. 208 A12 Torsion angles for 306............................. 209 6 List of Figures 1.1 Representationsofbenzyne. 15 1.2 Benzyne–transition metal complexation. ...... 26 1.3 Selectivity in nucleophilic addition to an aryne. ......... 29 1.4 Commercially availble ortho-(trimethylsilyl)aryl triflates . 36 1.5 Larger polycyclic ortho-(trimethylsilyl)aryl triflates. 36 1.6 Alkoxy-substituted Kobayashi aryne precursors. ........ 39 1.7 Alternative fluoride activated aryne precursors. ......... 40 2.1 Indole-containing compounds. 46 2.2 Buchwald–Hartwig catalytic cycle for a 2° amine. ....... 48 2.3 Arylationofprotectedhydrazones. 56 2.4 Three possible isomers of 168 and 169. .................. 62 2.5 Two of the three possible isomers of phenylindole 170........... 63 3.1 The catalytic cycle of the Suzuki reaction. ...... 70 3.2 Prominent organoboron cross-coupling reagents. ........ 73 3.3 Halo-aryneprecursors. 80 3.4 Initial screen of conditions for coupling 220 and PhB(OH)2 ....... 81 3.5 Screen of bases for coupling 216 and PhB(OH)2 .............. 83 3.6 Screen of solvent for coupling 216 and PhB(OH)2 ............. 84 3.7 Optimised Suzuki coupling conditions. ..... 85 3.8 Potassium trifluoroborate salts attempted. ....... 92 3.9 1H NMR spectra for purification of 275 .................. 96 3.10 X-ray crystal structure of triphenylene 283................. 99 3.11 Triphenylenes synthesised by P˜ena et al. .................. 101 4.1 The molecular structure of 306 with displacement ellipsoids at the 50 % probabilitylevel. ............................... 111 4.2 Possible substrates for further aryne–ynamide insertion reactions. 114 7 List of Schemes 1.1 Early 14C labelling experiment to demonstrate the existence of benzyne. 15 1.2 Routes to generate benzyne from stable precursors. ........ 17 1.3 Reactionsofaryneprecursors.. 18 1.4 Diels–Alderreactionwithfuran. 19 1.5 [3+2] cycloaddition with diazoalkanes. ...... 19 1.6 Enamine–benzynereactions.. 20 1.7 Enereactionofaryneswithalkynes. 20 1.8 Nucleophilicadditiontobenzyne. 21 1.9 Arylation reactions under mild conditions. ....... 22 1.10 Three-component couplings with electrophilic CO2............. 22 1.11 Self-quenching three-component couplings. ....... 23 1.12 N–C(sp2)aryneinsertion. .......................... 24 1.13 Organolithium–aryne C–CN insertion . 24 1.14 σ-Insertionreactionsatnitrile. 25 1.15 Addition of C(sp) nucleophiles to benzyne. ....... 25 1.16 Palladium-catalysed triphenylene synthesis. ......... 27 1.17 Benzyne–alkyne [2+2+2] cycloaddition. ...... 27 1.18 Palladium-catalysed Sn–C(sp) benzyne insertion. ......... 27 1.19 C(sp)–Br bond fission in aryne reactions. ..... 28 1.20 ortho-Biphenylarynereactions. 28 1.21 Reactions with ortho-phenyl Kobayashi aryne precursor. 29 1.22 Fluoride induced selectivity in ortho-(trimethylsilyl)arynes. 30 1.23 Boryl group controlled selectivity. ....... 31 1.24 ortho-Selective addition to (triethylsilyl)benzyne. 32 1.25 Other effects that may influence regiomeric outcome of aryne reactions. 32 1.26 (Trimethylsilyl)phenyl triflate synthesis from ortho-halophenols. 33 1.27 Aryne precursors via ortho-lithiation..................... 34 8 List of Schemes 1.28 Preparation on substituted aryne precursors by a [4+2] cycloaddition– decarboxylationapproach . 35 1.29 Oxidative para-triflationofacetanilides. 35 1.30 Introduction of ortho-difunctionality via cobalt-catalysed cycloaddition. 37 1.31 Diaryne precursors for acene and helicene extension. .......... 37 1.32 Aryne precursor with pendant furan. 38 1.33 Aryne precursors for intramolecular [4+2] reactions. ........... 38 1.34 Tethered acetylene precursors for benzofuran syntheses. ......... 39 1.35 Nonafluorobutanesulfonyl fluoride-induced aryne formation. 40 1.36 Arynesbyanionrelayroute.. 41 1.37 (-)-Curvularin synthesis from polysubstituted benzyne........... 41 1.38 Indolyne indolactam V synthesis. 42 1.39 Intramolecular cyclisation indole aryne syntheses. ............ 42 1.40 Aziridine–aryne indole synthesis. ...... 43 1.41 Jamart-Grégoire and Kudzma indole syntheses. ...... 43 1.42 Benzyne–titanocene indole synthesis. ....... 44 1.43 4-Substituted indoles by cyclisation/trapping. .......... 44 1.44 2-azidoacrylate benzyne indole synthesis. ........ 44 1.45 Benzyne Bischler–Möhlau indole synthesis. ........ 45 1.46 Benzynecarbazolesyntheses. 45 2.1 The Fischer indole reaction from an N -phenylhydrazone. 47 2.2 Traditional and C–N routes to arylhydrazones. ...... 48 2.3 Buchwald’s palladium catalysed synthesis of arylhydrazones and sub- sequent transformation into indoles. 49 2.4 C–N bond forming cross-couplings with hydrazines. ....... 50 2.5 Fischer indole syntheses