Sulfoxide Directed Metal-free Cross Coupling: Propargylation of Aromatic and Heteroaromatic Systems A dissertation submitted to The University of Manchester for the degree of Master of Science by Research in the Faculty of Engineering and Physical Science. 2015 Yuntong Zhang School of Chemistry Contents List of Tables: ............................................................................... 4 List of Abbreviations ..................................................................... 5 Abstract ......................................................................................... 9 Declaration .................................................................................. 10 Copyright Statement .................................................................... 11 Acknowledgement ....................................................................... 12 Chapter 1: Introduction ............................................................... 13 1.1 Pummerer and Pummerer-type Reactions............................ 13 1.1.1 The Classical Pummerer Rearrangement .................... 13 1.1.2 Additive and Vinylogous Pummerer Reactions .......... 14 1.1.3 Interrupted Pummerer Reactions ................................ 18 1.2 Pummerer-Type Reactions Extended to Aromatic Systems . 24 1.2.1 Aromatic and Hetero-aromatic Pummerer-type Reactions ................................................................................. 24 1.2.2 Ortho Alkylations of Aryl and Heteroaryl Systems .... 29 1.3 Beyond Classical Pummerer Reaction Electrophiles ........... 35 1.4 Application of Pummerer-type Reactions in Total Synthesis ………………………………………………………………………………………….36 1.5 Previous Work and Proposed Work .................................... 38 Chapter 2: Results and Discussion............................................... 39 2.1 Synthesis of Starting Materials ............................................ 39 2.1.1 Synthesis of Sulfoxides .............................................. 39 2.1.2 Synthesis of Silanes ................................................... 40 2.1.3 Sulfoxide-directed Metal-free Propargylation of Arenes …………………………………………………………………………………41 2.2 Propargylation of Thiophene ............................................... 42 2.3 Cyclisation of the Products of Metal-free Propargylation .... 44 2.4 Cyclisation of Propargyl Thiophenyl Sulfide ...................... 51 2.5 Conclusions and Future Work ............................................. 53 Chapter 3: Experimental .............................................................. 55 3.1 General Procedure 1: bis-sulfide formation ......................... 56 2 3.2 General Procedure 2: bis-sulfide oxidation .......................... 57 3.3 General Procedure 3: sulfide oxidation ................................ 58 3.4 General Procedure 4: alkynyl silane synthesis ..................... 60 3.5 General Procedure 5: propargylation of aromatic systems ... 61 3.6 General Procedure 6: propargylation of thiophenes ............. 63 3.7 General Procedure 7: iodine mediated cyclization to vinyl benzothiophene ........................................................................... 69 3.8 General Procedure 8: iodine mediated two directional cyclisation ................................................................................... 73 3.9 General Procedure 9: iodine mediated cyclisation to vinyl iodide .......................................................................................... 76 References ....................................................................................... 77 3 List of Tables: Table 1: NMR experiments of propargylation reaction process ....... 44 Table 2: Optimising of iodine mediated cyclisation ......................... 47 Table 3: Optimisation of two directional heterocyclisation .............. 50 4 List of Abbreviations Ac acyl AIBN 2,2’-bis(isobutyronitrile) aq. aqueous Ar aryl 2,2’-bis(diphenylphosphino-1,1’- BINAP binaphthyl) Bn benzyl Boc t-butoxycarbonyl br. broad (NMR) Bu butyl Bz benzoyl cerium(IV) ammonium CAN nitrate cat. catalytic CI chemical ionisation C celsius d doublet (NMR) δ chemical shift (NMR) DCE 1,2-dichloroethane 2,3-dichloro-5,6-dicyano-p- DDQ benzoquinone DMF N,N-dimethylformamide DMSO dimethylsulfoxide dimethyl(methylthio)sulfonium DMTSF tetrafluoroborate 5 DPPE ethylenebis(diphenylphosphine) dr diastereoisomeric ratio DTBP di-tert-butylpyridine DTBB 4,4-di-tert-butylbiphenyl E electrophile ee enantiomeric excess EDG electron donating group EG ethylene glycol EI electron ionisation equiv. equivalent positive/negative ion electrospray ES+/ES- (MS) Et ethyl EWG electron withdrawing group fluorous solid phase FSPE extraction g gram h hour HFIP 1,1,1,3,3,3-hexafluoroisopropanol HMPA hexamethylphosphoramide high resolution mass HRMS spectrum Hz hertz IBX o-iodoxybenzoic acid i-Pr isopropyl IR infrared 6 J coupling constant (NMR) M Molar m multiplet (NMR) m-CPBA m-chloroperbenzoic acid Me methyl mg milligram 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) NCS N-chlorosuccinimide Nf2O nonafluorobutanesulfonic anhydride NMR nuclear magnetic resonance Nu nucleophile Ph phenyl PIFA iodobenzene-I,I-bis(trifluoroacetate) PMB p-methoxybenzyl ppm parts per million 7 Pr propyl PTSA p-toluenesulfonic acid Pyr. pyridine q quartet (NMR) quin quintet (NMR) F R perfluoroalkyl rt room temperature s singlet (NMR) sxt sextet (NMR) 2- SEM (trimethylsilyl)ethoxymethyl t triplet (NMR) tetrabutylammonium TBAF fluoride TBS tert-butyldimethylsilyl TFA trifluoroacetic acid TFAA trifluoroacetic anhydride Tf trifluoromethanesulfonyl THF tetrahydrofuran TIPS triisopropylsilyl N,N,N’,N’- TMEDA tetramethylethylenediamine TMS trimethylsilyl Tol tolyl Ts tosyl 8 Abstract This thesis describes the development of an interrupted Pummerer reaction and its application in aromatic and hereroaromatic carbon-hydrogen substitution. During the development of the approach, a wide range of aryl and heteroaryl sulfoxides has been synthesised in order to investigate the scope of ortho-propargylation. Good to excellent yields of propargyl aromatic and heteroaromatic products have been obtained. Moreover, propargylated substrates can be treated with iodine undergoing 5-exo-dig cyclisation leading to benzothiophenes and thienylthiophenes, which have industrially-significant applications in organic materials, pharmaceuticals and chemosensors. Under different conditions, different functionalised benzothiophenes can be obtained. Further extending this reaction in two directional cyclisation of propargyl naphthalene sulfides gives napthodithiophenes motif found in organic materials. 9 Declaration No portion of the work referred to in the dissertation has been submitted in support of an application for another degree or qualification of this or any other university or other institute of learning. Part of this work has been published in peer reviewed journals: A. J. Eberhart, H. J. Shrives, E. Álvarez, A. Carrër, Y. Zhang and D. J. Procter, ‘Sulfoxide-directed metal-free ortho-propargylation of aromatics and heteroaromatics.’ Chem. Eur. J. 2015, 21, 7428-7434. A. J. Eberhart, H. Shrives, Y. Zhang, A. Carrër, A. Parry, D. Tate, M. J. Turner, D. J. Procter ‘Sulfoxide-directed metal-free cross-couplings in the expedient synthesis of benzothiophene-based organic materials’ Chem. Sci. 2015, DOI: 10.1039/C5SC03823E. 10 Copyright Statement The author of this dissertation (including any appendices and/or schedules to this dissertation) owns any copyright in it (the “Copyright”) and s/he has given The University of Manchester the right to use such Copyright for any administrative, promotional, educational and/or teaching purposes. Copies of this dissertation, either in full or in extracts, may be made only in accordance with the regulations of the John Rylands University Library of Manchester. Details of these regulations may be obtained from the Librarian. This page must form part of any such copies made. The ownership of any patents, designs, trade marks and any and all other intellectual property rights except for the Copyright (the “Intellectual Property Rights”) and any reproductions of copyright works, for example graphs and tables (“Reproductions”), which may be described in this dissertation, may not be owned by the author and may be owned by third parties. Such Intellectual Property Rights 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 Rights and/or Reproductions. Further information on the conditions under which disclosure, publication and exploitation of this dissertation, the Copyright and any Intellectual Property Rights and/or Reproductions described in it may take place is available from the Head of the School of Chemistry. 11 Acknowledgement At the beginning, I am very grateful for my supervisor Prof. David Procter giving me chance study in the University of Manchester and I really appreciate his help on my study and life. Sincere thanks to my lab work and English supervisor Harry Shrives. He is very patient with my work and gives me a lot of help apart from chemistry. His optimism towards life and encouragement definitely helped me a lot in my one year study here. I would also like to say thanks to Dr. Alex Pulis, Dr. Nicolas Kern, Dr Xavier Just Baringo, Dr Jose Antonio Fernandez Salas, Dr Jie An, Mateusz Plesniak, Craig Cavanagh, Huanming Huang and the rest