Iron-Mediated C–H Coupling of Arylsulfides and Simple Terminal Alkenes

Iron-mediated C–H coupling of arylsulfides and simple terminal alkenes

A thesis submitted to the University of Manchester for the degree of Doctor of Philosophy (PhD) in the Faculty of Engineering and Physical Sciences

2016

Craig W. Cavanagh

School of Chemistry

Contents Index of Figures ...... 6

Index of Schemes ...... 7

Index of Tables ...... 10

Abstract ...... 11

Declaration ...... 12

Acknowledgements ...... 15

Abbreviations and Definitions ...... 16

1. Organoiron Chemistry ...... 20

1.1 Introduction ...... 20

1.2 Cross-Coupling Reactions...... 20

1.2.1 Coupling of Alkyl Electrophiles ...... 22

1.2.2 Couplings of Aryl Electrophiles ...... 26

1.2.3 Coupling of Heteroaromatic Compounds ...... 29

1.3 C–H Bond Activation ...... 30

1.3.1 Activation of sp2 C–H bonds ...... 31

1.3.2 Activation of sp3 C–H bonds...... 35

1.4 Cross Dehydrogenative Coupling ...... 38

1.4.1 CDC of two sp3 C–H bonds ...... 38

1.4.2 CDC between sp2 and sp3 C–H bonds ...... 40

1.4.3 CDC in Domino Processes ...... 42

1.5 Summary ...... 44

2. Iron-mediated Coupling of Arylsulfides with Silanes ...... 45

2.1 Introduction to Pummerer and Pummerer-Type Reactions ...... 45

2.1.1 Classical Pummerer Rearrangement ...... 45

2.1.2 Aromatic Pummerer-Type Reactions ...... 46

2.2 Results and Discussion ...... 48

2.2.1 Proposed Project ...... 48

2.2.2 Preliminary Reaction ...... 49

2.2.3 Synthesis of Biarylsulfide Starting Materials ...... 50

2.2.4 Solvent Screen ...... 50

2.2.5 Oxidant Screen ...... 51

2.2.6 Changing The Addition Rate of Allyl Silane ...... 53

2.2.7 Changing Reagent Stoichiometry ...... 54

2.2.8 Other Biaryl Sulfides ...... 55

2.2.9 Reaction with an unfunctionalised alkene ...... 56

3. Metal-catalysed Reactions of Arenes and Alkenes ...... 57

3.1 Oxidative Coupling of Arenes and Alkenes ...... 57

3.1.1 Examples of Directing Groups ...... 58

3.1.2 Sulfur Directing Groups in Oxidative Alkenylations ...... 61

3.2 Hydroarylation of Alkenes ...... 65

3.3 Iron-mediated Functionalisation of Alkenes...... 68

3.4 Summary ...... 70

4. Iron-mediated Chloroarylation of Alkenes ...... 71

4.1 This Work ...... 71

4.2 Optimisation Studies ...... 71

4.2.1 Solvent Screen ...... 71

4.2.2 Oxidant Screen ...... 72

4.2.3 Investigation of Bases and Additives...... 74

4.2.4 Further Optimisation Studies ...... 75

4.2.5 Controlled Addition of Reagents ...... 77

4.3 Substrate Scope ...... 78

4.3.1 Variation of Alkene Coupling Partners ...... 78

4.3.2 Variation of Arene Coupling Partners ...... 82

4.3.3 Use of Other Aryl Sulfides ...... 85

4.4 Mechanistic Studies ...... 87

4.4.1 Proposed Mechanism ...... 87

4.4.2 Cyclic Voltammetry ...... 90

4.4.3 Solvent Investigations ...... 91

4.4.4 Use of Other Oxidants ...... 91

4.4.5 Electron Paramagnetic Resonance ...... 93

4.4.6 Alternative Mechanisms ...... 94

4.5 Towards a Catalytic Process ...... 96

4.5.1 Iron Catalysis ...... 96

4.5.2 Photoredox Catalysis...... 97

4.6 Product Manipulation ...... 101

4.6.1 Formation of Dihydrobenzofuran Motifs ...... 104

4.7 Summary ...... 109

4.8 Future Work ...... 110

4.8.1 Iron-mediated Chloroarylation of Alkenes ...... 110

4.8.2 Manipulation of Allylation Products – The Truce-Smiles Rearrangement ...... 112

5. Experimental ...... 116

5.1 General Experimental ...... 116

5.2 Cyclic Voltammetry ...... 116

5.3 Sulfide Synthesis ...... 117

5.4 Synthesis of Other Arenes...... 134

5.5 Synthesis of Alkenes ...... 136

5.6 Iron-mediated Allylation of Arylsulfides ...... 139

5.7 Iron-mediated C-H Coupling of Arylsulfides and Terminal Alkenes ...... 141

5.8 Manipulation of Products ...... 164

5.9 Synthesis of Dihydrobenzofurans ...... 171

5.10 Cross-Coupling of Dihydrobenzofurans ...... 175

5.11 Towards the Truce-Smiles Rearrangement ...... 185

6. References ...... 189

Final word count: 53,930

Index of Figures

Figure 1 Activation of arene through interaction with t-BuOK and ligand ...... 34 Figure 2 Steric clash resulting from biaryl formation ...... 56 Figure 3 Unsuccessful coupling partners ...... 82 Figure 4 Proposed thioquinone-type radical cation intermediate ...... 86 Figure 5 Aromatic substrates that failed to undergo cross-coupling ...... 87 Figure 6 Alternative intermediate species in chloroarylation reaction ...... 88 Figure 7 Voltammogram for sulfides vs reference electrode ...... 90 Figure 8 Possible n-σ* interaction ...... 106

Index of Schemes

Scheme 1 Catalytic cycle for Pd(0)-catalysed cross-coupling reaction ...... 21 Scheme 2 Iron-catalysed Suzuki-Miyaura coupling of alkylhalides ...... 22 Scheme 3 Proposed cycle for Fe-catalysed Suzuki-Miyaura coupling of alkyl halides ...... 23 Scheme 4 FeCl2(SciOPP)-catalysed Sonogashia-type coupling ...... 23 Scheme 5 Suzuki-Miyaura coupling of alkyl halides and alkynyl borates ...... 24 Scheme 6 Fe-catalysed Kumada alkyl-alkyl cross-coupling ...... 24 Scheme 7 Fe-catalysed Kumada-type alkyl-alkyl cross-coupling using Fe-NHC ...... 24 Scheme 8 Proposed catalytic cycle for the alkyl-alkyl cross-coupling reaction ...... 26 Scheme 9 Fe-catalysed coupling of aryl chlorides with alkyl Grignard reagents ...... 27 Scheme 10 Selective Fe-catalysed biaryl cross-coupling ...... 27 Scheme 11 Proposed mechanism for biaryl coupling ...... 28 Scheme 12 Cross-coupling of aryl sulfamates and tosylates with aryl Grignard reagents .. 28 Scheme 13 Use of Fe(OTf)2/SIPr for selective biaryl cross-coupling ...... 29 Scheme 14 Fe-catalysed coupling of N-heterocyclic halides and arylmagnesium reagents 29 Scheme 15 Ligand accelerated iron-catalysed heteroaryl-heteroaryl cross-coupling ...... 30 Scheme 16 Radical clock studies showing formation of cyclised product ...... 30 Scheme 17 Fe-catalysed arylation through directed C–H bond activation ...... 31 Scheme 18 ortho-Arylation of aryl imines by directed C–H activation...... 31 Scheme 19 Fe-catalysed activation of olefinic C–H bond with Grignard reagent ...... 32 Scheme 20 Proposed mechanism of direct C–H activation ...... 32 Scheme 21 Fe-catalysed direct arylation of aryl iodides ...... 33 Scheme 22 Proposed mechanism for the iron-catalysed direct arylation of aryl iodides .... 33 Scheme 23 Iron-catalysed Suzuki-Miyaura-type C–H coupling ...... 34 Scheme 24 Proposed catalytic cycle for Suzuki-Miyaura-type C–H coupling ...... 35 Scheme 25 Fe-catalysed alkenylation of 2-substituted azaarenes...... 36 Scheme 26 Proposed intermediate in the direct-alkenylation reaction ...... 36 Scheme 27 Fe-catalysed amidation of C–H bonds ...... 37 Scheme 28 Proposed mechanism for Fe-catalysed amidation of benzylic sp3 C–H bonds . 38 Scheme 29 Iron-catalysed CDC of benzylic C–H and 1,3-diketones ...... 38 Scheme 30 Tentative mechanism for iron-catalysed CDC ...... 39 Scheme 31 Iron-catalysed CDC of cyclic alkanes and 1,3-dicarbonyl compounds ...... 40 Scheme 32 Iron-catalysed CDC α- to heteroatoms ...... 40 Scheme 33 Iron-catalysed CDA of benzylic C–H bonds ...... 41 Scheme 34 Proposed mechanism for the CDA reaction ...... 41 Scheme 35 Iron-catalysed direct functionalisation of benzylic C–H bonds ...... 42 Scheme 36 Iron-catalysed oxidative coupling of alkylamides with arenes ...... 42 Scheme 37 Vinylaromatic generation via iron-catalysed sp3 C–H functionalisation ...... 43 Scheme 38 Proposed mechanism for generation of vinylaromatics ...... 43 Scheme 39 Classical Pummerer Rearrangment ...... 45 Scheme 40 1,4 addition to p-sulfinylphenols to give dihydroxybenzofurans ...... 46 Scheme 41 Nucleophilic ortho-allylation of aryl sulfoxides ...... 47 Scheme 42 Mechanism of ortho-allylation of aryl sulfoxides ...... 47 Scheme 43 Proposed oxidative process for nucleophilic cross-coupling with aryl sulfides 48 Scheme 44 Iron-catalysed oxidative coupling of biaryl sulfides ...... 49 Scheme 45 Model reaction conditions ...... 50 Scheme 46 Pd- and Cu-catalysed formation of biaryl sulfides ...... 50 Scheme 47 Reaction of 91c under standard conditions ...... 55

Scheme 48 Reaction of 91a under standard reaction conditions ...... 55 Scheme 49 FeCl3-mediated chloroarylation of 1-octene ...... 56 Scheme 50 Catalytic Fujiwara-Moritani reaction ...... 57 Scheme 51 Mechanism for Fujiwara-Moritani reaction ...... 58 Scheme 52 Pd-catalysed ortho-alkenylation of phenylacetic acids ...... 58 Scheme 53 Use of amino acid ligands for increased A. reactivity and B. regioselectivity . 59 Scheme 54 Sequential olefination with different alkene partners ...... 60 Scheme 55 Ester-directed alkenylation of arenes by A. Ackermann and B. Jeganmohan .. 60 Scheme 56 Proposed catalytic cycle for Ru-catalysed oxidative alkenylation ...... 61 Scheme 57 Screen of S-containing directing groups ...... 62 Scheme 58 Pd-catalysed selective ortho-alkenylation with thioether directing groups ...... 62 Scheme 59 Controlled Rh-catalysed olefination using thioether directing groups ...... 63 Scheme 60 Rh-catalysed selective alkenylation of 2-aryl-1,3-dithianes ...... 63 Scheme 61 Proposed catalytic cycle for sulfur-directed oxidative C–H alkenylation ...... 64 Scheme 62 Use of sulfoxides as remote directing groups for arene C–H olefination ...... 65 Scheme 63 Ru-catalysed hydroarylation of olefins through direct C–H activation ...... 65 Scheme 64 Proposed mechanism for Ru-catalysed hydroarylation of olefins ...... 66 Scheme 65 Ni-catalysed hydroarylation of alkenes using electron-deficient arenes ...... 66 Scheme 66 Linear-selective hydroarylation of olefins with electron-deficient arenes ...... 67 Scheme 67 Proposed mechanism for Ni-catalysed linear-selective hydroarylation ...... 67 Scheme 68 Iron-mediated halo-nitration of alkenes ...... 68 Scheme 69 Iron(III)/NaBH4-mediated additions to unactivated alkenes ...... 68 Scheme 70 Fe-catalysed reductive olefin coupling ...... 69 Scheme 71 Mechanism for reductive olefin coupling ...... 69 Scheme 72 Variation of the alkene coupling partner ...... 79 Scheme 73 Proposed 5-exo-trig cyclisation of 1,6-heptadiene intermediate ...... 80 Scheme 74 Reaction of more substituted dienes ...... 80 Scheme 75 Reaction of 4,4-dimethyl-1-pentene ...... 81 Scheme 76 Variation of arylsulfide in the cross-coupling ...... 83 Scheme 77 Attempted second chloroarylation reaction ...... 84 Scheme 78 Competition experiment between 91b and 91d ...... 84 Scheme 79 Competition experiment between 91b and 91e ...... 85 Scheme 80 Proposed mechanism for coupling of biaryl sulfides and terminal olefins ...... 88 Scheme 81 Cu(II)-catalysed functionalisation directed by pyridyl group ...... 88 Scheme 82 Proposed mechanism for Cu-catalysed functionalisation of C–H bonds ...... 89 Scheme 83 Iron-catalysed oxidative coupling/cyclisation between phenols and styrenes .. 89 Scheme 84 Proposed mechanism of cross-coupling/cyclisation ...... 89 Scheme 85 Use of brominated solvent to investigate halide incorporation ...... 91 Scheme 86 Reaction of biaryl sulfide and octene with CAN ...... 91 Scheme 87 Fe-catalysed hydroarylation of styrenes ...... 94 Scheme 88 Alternative electrophilic metalation/carbometalation reaction ...... 95 Scheme 89 Standard photoredox catalysis cycle ...... 98 Scheme 90 mCPBA oxidation to the sulfone ...... 102 Scheme 91 Desulfurisation of products using Raney Ni ...... 102 Scheme 92 ortho-Directed metalation using various quenches ...... 102 Scheme 93 Elimination to give conjugated and non-conjugated alkenes ...... 103 Scheme 94 Manipulation of alkyl chloride moiety in cross-coupled products ...... 104 Scheme 95 Proposed cyclisation of coupling products to form dihydrobenzofuran ...... 104 Scheme 96 Deallylation/cyclisation sequence to form dihydrobenzofuran ...... 105 Scheme 97 Pd-catalysed deallylation ...... 105

Scheme 98 Substrate scope for dihydrobenzofuran formation ...... 107 Scheme 99 Triflation and Pd-catalysed couplings of dihydrobenzofuran ...... 108 Scheme 100 Desulfurisation of dihydrobenzofurans using Raney Ni ...... 108 Scheme 101 Ni-catalysed Kumada-Corriu cross-coupling ...... 109 Scheme 102 Use of vinylcyclopropane in radical clock studies ...... 110 Scheme 103 Preparation of vinyl cyclopropane via Wittig reaction ...... 111 Scheme 104 Proposed conversion of chloroarylation products to dibenzothiepines ...... 111 Scheme 105 Silver-mediated dehalogenation to form sulfonium salts ...... 112 Scheme 106 Proposed Truce-Smiles rearrangement of allylphenylsulfones ...... 112 Scheme 107 ortho-C–H Allylation of diphenylsulfoxide ...... 112 Scheme 108 Selective oxidation to the allylated sulfone ...... 113 Scheme 109 Preliminary studies on the Truce-Smiles rearrangement ...... 113 Scheme 110 Use of MeI as quench for intermediary metal sulfinate ...... 114 Scheme 111 Isomerisation of the allyl unit using NaNH2 ...... 114 Scheme 112 Potential further manipulations of metal sulfinate intermediates ...... 115

Index of Tables

Table 1 Solvent screen using FeCl3 oxidant ...... 51 Table 2 Oxidant screen carried out in MeNO2 ...... 52 Table 3 Slow addition of allyl TMS to mixture of 91b and FeCl3 ...... 53 Table 4 Changing the stoichiometry of the reaction ...... 54 Table 5 Solvent screen for FeCl3-mediated reaction of 91b with 1-octene ...... 72 Table 6 Oxidant screen for Fe(III)-mediated reaction with octene ...... 73 Table 7 Addition of base to reaction mixture ...... 75 Table 8 Effect of changing various parameters on the reaction ...... 76 Table 9 Changing the addition rate of reagents ...... 78 Table 10 Screen of Ce(IV) reagents/conditions for an analogous cross-coupling ...... 93 Table 11 Screen of Lewis acids ...... 95 Table 12 Attempts to perform the reaction with catalytic amounts of FeCl3 ...... 97 Table 13 Initial photocatalyst screen ...... 99 Table 14 Solvent screen with Ru(bpy)3Cl2 ...... 100 Table 15 Investigation of oxidative quenchers towards a photocatalytic process ...... 101 Table 16 Improved conditions for deallylation/cyclisation cascade ...... 106

Abstract

The University of Manchester Craig Cavanagh School of Chemistry Doctor of Philosophy

Iron-mediated C–H coupling of arylsulfides and simple terminal alkenes

The use of directing groups in C–H functionalisation reactions provides a means to control the regioselectivity of such processes. Previous work in the Procter group reported the sulfoxide-directed metal-free C–H alkylation of arenes with organosilane nucleophiles. Attempts to expand this work by carrying out a similar process directly from the sulfide oxidation level, utilising an Fe(III) oxidant, a diarylsulfide and an alkene are discussed herein. During these investigations, it was discovered that the use of simple, unfunctionalised olefins selectively gave linear products of formal chloroarylation, which represents a novel transformation. Following optimisation studies, the reaction proceeded in good to moderate yield under exceptionally mild conditions with a range of alkene and sulfide coupling partners, although sulfides do require a particular oxygenation pattern in the aryl ring undergoing coupling. Based on various experimental observations, a single electron oxidation process is believed to be responsible for the desired reactivity. A number of manipulations of the chlorinated products are demonstrated, including their use in an expedient synthesis of important dihydrobenzofuran motifs. The original sulfur directing-group has also been used as a handle for further elaboration of these interesting structures.

Declaration

No portion of the work referred to in this 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.

Part of this work has been published in peer reviewed journals:

Cavanagh, C. W.; Aukland, M. H.; Hennessy, A.; Procter, D. J., Chem. Commun. 2015, 51, 9272.

Cavanagh, C. W.; Aukland, M. H.; Laurent, Q.; Hennessy, A.; Procter, D. J., Org. Biomol. Chem. 2016, 14, 5286.

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 s/he 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. This page must form part of any such copies made. iii. The ownership of certain Copyright, patents, designs, trademarks 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. iv. Further information on the conditions under which disclosure, publication and commercialisation of this thesis, the Copyright and any Intellectual Property University IP Policy (see http://documents.manchester.ac.uk/display.aspx?DocID=24420), in any relevant Thesis restriction declarations deposited in the University Library, The University Library’s regulations (see http://www.library.manchester.ac.uk/about/regulations) and in The University’s policy on Presentation of Theses.

Finite to fail, but infinite to venture.

For the one ship that struts the shore

Many’s the gallant, overwhelmed creature

Nodding in navies nevermore.

Emily Dickinson

Acknowledgements

First and foremost, I would like to thank my supervisor David for giving me the opportunity to work in his group and for all the help and support that has been extended over the years. I would also like to thank Syngenta for funding my PhD and my industrial supervisor Alan for his continued input and for ensuring I was looked after during my placement. Thanks are also due to the University of Manchester for financial support and all of the technical staff for providing assistance when required. Of course boundless thanks go to the members of the Procter and Greaney research groups, past and present, who have provided companionship on this scientific journey. It has been a pleasure to work with many of you and your adherence to Rule #1 is greatly appreciated. Particular thanks are extended to everyone who proof-read parts of this thesis and helped make it moderately readable. To my compeers, Chris and Irem, I have (mostly) enjoyed our time together and am glad to have started this stint at your side. To The Plastics, thank you so much for being so welcoming when I first arrived and for being such good sources of laughter for the following years. The Crossword Compatriots, Harry and Becky, thank you for providing a link to the outside world and for the hours spent attempting ‘quick’ crosswords. Miles, I appreciate all the help you’ve given me in those tough times and hope that your future is a perfect shade of orange. The Syngenta Crew, your presence in the dark and lonely abyss that is Bracknell was most opportune and I can safely say that, thanks to you all, what could have been a major low became one of the highlights of my PhD. To our longstanding postdocs, Xavi and Jose, thanks for your help and for attempting to understand my lightning-fast chatter. Huanming and Kay, your patience in expanding my linguistic knowledge is much appreciated; I can only apologise for the horrendous ways I twisted said knowledge. Mateusz, your obsession with those born out of wedlock has provided much amusement in those long lab hours. I risk causing offence by attempting (and failing) to list everyone so I may as well just cause it; if you haven’t been mentioned already, assume you don’t matter (especially Nico!). Regardless, I wish you all luck in whatever future escapades you find yourselves. Finally I should thank my family. You will likely never read this but I appreciate the encouragement you have offered, even though you may not know what I am actually doing most of the time.

Abbreviations and Definitions

Å 10-10 metres Ac acetyl Acac acetylacetone AIBN azobisisobutyronitrile APCI atmospheric pressure chemical ionisation Ar aryl Asym asymmetric Aq. aqueous BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene Bipy 2,2-bipyridine B:L branched:linear ratio Bn benzyl Boc tert-butoxycarbonyl Bpz 2,2’-bipyrazine brsm based on recovered starting material Bu butyl BQ benzoquinone Bz benzoyl CAN ceric ammonium nitrate CAS ceric ammonium sulfate cat. catalyst/catalytic Cbz carboxybenzyl CDA cross dehydrogenative arylation CDC cross dehydrogenative coupling CI chemical ionisation cod 1,5-cyclooctadiene Cp* pentamethylcyclopentadiene CV cyclic voltammetry Cyp cyclopentane dba dibenzylideneacetone DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCE 1,2-dichloroethane DCIB 1,2-dichloroiso-butane DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone

DFT density functional theory DG directing group DMF dimethylformamide DMSO dimethylsulfoxide DTBP di-tert-butyl peroxide DTBPy 2-6-di-tert-butylpyridine dtbbpy 4,4′-di-tert-butyl-2,2′-bipyridyl EDG electron donating group EDTA ethylenediaminetetraacetic acid EI electron ionisation ES+/ES– positive/negative ion electrospray Et ethyl Eq. equivalent EWG electron withdrawing group FTIR Fourier transform infrared spectroscopy Gly glycine h hour/s HFIP hexafluoroisopropyl alcohol HRMS high resolution mass spectrometry i- iso- Ile isoleucine IMes 1,3-bis(2,4,6-trimethylphenyl)-imidazolium IR infrared JohnPhos (2-biphenyl)di-tert-butylphosphine KIE kinetic isotope effect LDA lithium diisopropylamide M metal/molar m meta m/z mass/charge ratio (MS) mCPBA meta-chloroperoxybenzoic acid Me methyl min. minutes m.p. melting point Ms mesyl MS molecular sieves/ mass spectrometry MW microwave/ molecular weight

17 n- normal NBS N-bromosuccinimide NHC N-heterocyclic carbene NMP N-methyl-2-pyrrolidone NMR nuclear magnetic resonance o ortho p para Ph phenyl Phen phenanthroline PI photoionisation Piv pivaloyl ppm parts per million Ppy phenylpyridine Pr propyl rt room temperature s-/sec- secondary Sat. saturated SciOPP spin-control-intended-ortho-phenylene biphosphine

SEAr electrophilic aromatic substitution SET single electron transfer SHE standard hydrogen electrode SM starting material

SN2 bimolecular nucleophilic substitution Sym symmetric t-/tert- tertiary T temperature t-AmOH tert-pentyl alcohol TBHP tert-butyl hydroperoxide TBAHFP tetrabutylammonium hexafluorophosphate TBS tert-butyldimethylsilyl TEMPO (2,2,6,6-tetramethylpiperidin-1-yl)oxyl Tf triflyl TFA trifluoroacetic acid TFAA trifluoroacetic anhydride THF tetrahydrofuran TLC thin layer chromatography

TMEDA tetramethylethylenediamine TMS trimethylsilyl Tol toluene Ts tosyl Val valine Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

Unit Abbreviations

M 106 m 10-3 µ 10-6 n 10-9

NMR Abbreviations

Singlet (s), broad singlet (br. s), apparent singlet (app. s), doublet (d), triplet (t), quartet (q), quintet (quin), septet (sept), doublet of doublets (dd), doublet of doublet of doublets (ddd), multiplet (m), quaternary carbon (Cq)

1. Organoiron Chemistry

1.1 Introduction Throughout organic synthesis, the late transition metals, such as Pd, Rh and Au, demonstrate powerful catalytic ability and play vital roles in many areas. Despite their synthetic utility, most of these metals are relatively rare and come from limited and rapidly depleting stocks. Their decreasing availability means that these reagents tend to be very expensive and prices will only continue to rise. Also, many compounds of these elements exhibit considerable toxicity in humans and in the environment, making their extensive use and disposal of some long lasting concern.1 Clearly the use of these late transitions metals is not sustainable; a worrying thought considering their utility and importance. If these elements were to run out, would it be possible to sufficiently replace their current role in synthesis? Thus, attention has turned toward the more readily available first row transition metals, such as Cu and Ni. Among these metals, particular attention has been drawn to Fe: the cheapest, most abundant, non-toxic and environmentally friendly transition metal.2 Iron can be converted into its salts and complexes with relative ease and many iron salts are commercially available.3 These properties make iron extremely attractive for synthesis and catalysis. Despite its advantages and ubiquity in many fundamental biological processes, iron was somewhat underdeveloped in the field of catalysis until only recently. Since then the use of iron has increased significantly and it has demonstrated some unique and novel reactivity. It has been widely used as a Lewis acid for the activation of organic substrates and the generation of radicals and carbocations.4 The ability of iron to play a role in many different reactions has led to its use in a number of areas and consequently the chemical literature surrounding iron is vast. This review will discuss recent advances in the use of iron in areas such as Fe-catalysed cross-coupling and C–H bond activation and will serve to demonstrate some key aspects of iron’s behaviour.

1.2 Cross-Coupling Reactions Transition metal-catalysed cross-coupling reactions are one of the most used C–C bond- forming reactions in many areas of organic chemistry. Indeed the late transition metals, Pd in particular, are employed extensively and couplings such as the Suzuki-Miyaura reaction are used far and wide.

A general catalytic cycle for a Pd-catalysed cross-coupling reaction is shown in Scheme 1. The first step is the oxidative addition of Pd(0) species I into a C–X bond (X can be a number of groups such as halides or a sulfonate). This forms an organopalladium(II) species II, which can undergo a transmetalation step with another metal species III. Reductive elimination from the resultant organopalladium species IV gives the cross- coupled product V and reforms the original Pd catalyst.5

Scheme 1 Catalytic cycle for Pd(0)-catalysed cross-coupling reaction

Alongside the widely used Suzuki-Miyaura reaction [where M = B(OR2)] many variations of this mode of coupling have been reported using different organometallics, such as M =

ZnX, SnR3, Cu and Mg. Traditionally, these types of cross-coupling reaction were limited to sp- or sp2-hybridised α-C atoms. This was due to the initial oxidative addition being slow with sp3 carbon and also β-H elimination competing with the desired transmetalation step in these systems, leading to unsaturated by-products.6 A lot of work has been carried out in this area and coupling of alkyl species is possible through the use of bulky trialkylphosphines7 or N- heterocyclic carbene (NHC) ligands.8 The application of these reactions on large scales has made them very popular in industrial processes, such as in the synthesis of pharmaceutical products and fine chemicals. However, it is in these areas that a push for more green processes and materials is most sought after. Thus, the use of iron as an alternative for the development of new catalysts is an attractive concept and its application in many cross-coupling reactions has been successfully realised with a range of substrates, such as alkenyl9 and aryl halides.10

1.2.1 Coupling of Alkyl Electrophiles The coupling of alkyl halides and other alkyl electrophiles has been investigated extensively. Nakamura recently reported an iron catalysed Suzuki-Miyaura coupling of alkyl halides 1 and arylborates 2 through the development of novel iron-phosphine complexes 3 (Scheme 2).11

Scheme 2 Iron-catalysed Suzuki-Miyaura coupling of alkyl halides These bisphosphine ligands were later dubbed ‘SciOPPs’ (spin-control-intended ortho- phenylene bisphosphine).12 The bulky substituents in these phosphine complexes prevent the formation of coordinatively saturated octahedral iron complexes and are easily synthesised from commercially available starting materials. The coupling reaction was shown to have a wide substrate scope, with a variety of different functional groups in 2 being tolerated, such as OMe, Cl and F. Interestingly, the reaction was also shown to be highly chemoselective, with the desired products still being observed in high yields in the presence of various ester and cyano moieties, which were untouched. A radical clock study was carried out to probe the mechanism by using bromomethylcyclopropane as the alkyl halide partner. The corresponding ring-opened product was observed in 99% yield, suggesting a radical mechanism was in effect (Scheme 3). The starting iron complex 3 first reacts with 2 equivalents of aryl borate to form the active species I. Lack of biaryl formation and various mechanistic studies suggested that iron is not reduced in this step and is still present as Fe(II). The first step in the cycle then involves homolytic cleavage of the sp3 C–X bond to give Fe(III) species II similar to in metal-catalysed living radical polymerisation reactions.13 II then reacts with the formed alkyl radical via either release of an aryl radical or, more likely, ipso attack of the alkyl radical at one of the aryl groups to yield the coupling product and Fe(II) species III. Transmetalation of III with an aryl borate 2 then regenerates the active species I. It is believed that the MgBr2 additive aids in this step by activating the Fe(II)–X bond. The steric bulk of 3 prevents formation of ferrate complexes, which often show low selectivity in coupling reactions.11

Scheme 3 Proposed cycle for Fe-catalysed Suzuki-Miyaura coupling of alkyl halides Nakamura et al. later reported a Sonogashira-type coupling of unactivated alkyl halides with alkynyl Grignard reagents using hindered Fe(SciOPP) complexes (Scheme 4).12 The proposed mechanism involved a similar SET process to that observed in Scheme 3.

Scheme 4 FeCl2(SciOPP)-catalysed Sonogashia-type coupling Whilst the couplings reported proceeded in high yields and, unusually, allowed for coupling of primary and secondary alkyl halides in the presence of alkenyl triflates, low functional group compatibility was observed and the reaction required slow addition of the Grignard reagents at reflux. This was later improved upon by carrying out a Suzuki- Miyaura-like coupling of alkynyl borate reagents, such as 10, similar to that discussed earlier (Scheme 5).14

Scheme 5 Suzuki-Miyaura coupling of alkyl halides and alkynyl borates These conditions allowed for a broader reaction scope and a simpler reaction procedure, with no slow addition being required. The reaction was able to tolerate the presence of reactive functional groups, such as nitriles and ketones, when carried out in toluene. It was reasoned that the low polarity of toluene prevented side reactions that may occur in more polar solvents, such as the formation of ferrate complexes. Despite a number of reports of alkyl halides being used as coupling partners in cross-coupling chemistry, the formation of C(sp3)-C(sp3) bonds is still underdeveloped. The first Fe-catalysed Kumada alkyl-alkyl cross-coupling reaction was published in 2007 by Chai et al., using Fe(OAc)2 and phosphine ligands (Scheme 6). The reaction gave reasonable yields for coupling of unactivated primary alkyl bromides and alkyl Grignard reagents; however, it seemed to be limited to unsubstituted long chain alkyl bromides as the starting material.15

Scheme 6 Fe-catalysed Kumada alkyl-alkyl cross-coupling Cárdenas et al. carried out further work on this reaction and reported the use of a novel Fe-NHC catalytic system to couple alkyl iodides and alkylmagnesium reagents in good to excellent yields (Scheme 7).16

Scheme 7 Fe-catalysed Kumada-type alkyl-alkyl cross-coupling using Fe-NHC An assortment of ligands were screened, including Xantphos, the ligand reported by Chai for the coupling of alkyl bromides, however only low yields were obtained. The use of

24 stronger σ-donor NHC ligands, generated in situ from deprotonation of imidazolium salts with 16, led to increased yields. The reaction itself is viable with both primary and secondary alkyl iodides; alkyl bromides and tosylates led to lower yield and chlorides gave no reaction. Substrates containing an ester functionality and N-Boc protected piperidines also successfully afforded cross- coupled products. However, a major limitation in this reaction was the Grignard reagent, with only 16 showing the desired reactivity. Several mechanisms had been previously proposed for the coupling, such as cycles involving Fe(I)/Fe(III),17 Fe(0)/Fe(II)18 or Fe(-II)/Fe(0).19 It has been found that the exact pathway is dependent upon the nature of the organohalide.20 Thus extensive mechanistic studies were carried out to attempt to elucidate the correct cycle operating. The reaction was carried out in the absence of an electrophile and no β-elimination products were detected, suggesting the absence of Fe hydride species. Also, by measuring the amount of homocoupling of the Grignard reagent, the change in oxidation state of the Fe complex by reduction of the starting salt could be deduced. The data obtained indicated that half of the starting Fe(II) was reduced to Fe(0), formally corresponding to reduction to Fe(I). This was confirmed by EPR spectroscopy. Finally, radical clock experiments indicated the presence of carbon radicals in the reactions, suggesting activation of the electrophile occurs through homolytic cleavage of the C–I bond. These results led to a proposed catalytic cycle (Scheme 8). The active metal complex I can evolve through either oxidative addition of the alkyl iodide (pathway A) or transmetalation with the Grignard reagent (pathway B), with the alternate step following in each case. It could not be stated with certainty which cycle was operating, however initial activation of the Fe salt required addition of an excess of the Grignard reagent compared to the amount necessary for reduction to Fe(I). This may suggest that transmetalation to an alkyl-Fe(I) II complex may be necessary prior to the oxidative addition. Nevertheless, reductive elimination from the Fe(III) complex IV yields cross-coupled product and the active complex.

Scheme 8 Proposed catalytic cycle for the alkyl-alkyl cross-coupling reaction Another pathway involves formation of an anionic dialkyl-Fe(I) species VII, which would likely give easier oxidative addition (pathway C). However the trialkyl-Fe(III) species VIII involved would give a mixture of cross-coupling and homocoupling compounds, including homocoupling of the electrophile. The absence of these products suggests this pathway is unlikely.16

1.2.2 Couplings of Aryl Electrophiles The previous examples have utilised an iron-mediated radical-based mechanism, using bromo- and iodoalkyl compounds. It has been shown that the coupling of aryl chlorides with alkyl Grignard reagents using iron salts in the presence of additives, such as N- methyl-2-pyrrolidone (NMP), can proceed via an ionic mechanism. These couplings were highly efficient for primary alkyl Grignard reagents with activated, electron poor aryl chlorides but failed for secondary Grignard reagents and more electron rich aryls.21 Recently Law et al. described the use of NHC’s as ligands in an iron-catalysed cross-coupling of non-activated aryl chlorides with primary and secondary alkyl Grignard reagents; expanding the scope of iron-catalysed couplings (Scheme 9).22

Scheme 9 Fe-catalysed coupling of aryl chlorides with alkyl Grignard reagents The reaction gave excellent yields for the coupling of primary Grignard reagents, such as 19; however secondary alkyl Grignard reagents were not as efficient and only gave moderate yields. The use of acyclic secondary Grignard reagents led to formation of n- alkyl isomers in various branched:linear ratios (B:L), suggesting reversible β-H elimination occurs in competition with desired reductive elimination. This indicates an ionic mechanism is operating rather than a radical-based one. Despite suffering lower yields for secondary alkyl Grignard reagents, these results are promising as such couplings were previously unreported and have only recently been carried out with reasonable yields and linear to branched ratios using Pd.23 Aryl-aryl cross couplings can often be challenging due to the formation of homocoupled products of the organometallic reagent.24 However significant developments have recently been reported in this area. In 2007 Nakamura was able to suppress this homocoupling and demonstrated that the use of iron fluoride salts in combination with NHC ligands helped to form the desired coupling products.25 Results indicated that the fluoride anion is key to suppressing unwanted side reactions. This ‘fluoride effect’ was further investigated and later reports were able to expand the scope of the reaction (Scheme 10).26

Scheme 10 Selective Fe-catalysed biaryl cross-coupling The ‘fluoride effect’ is believed to be due to strong coordination of the fluoride ion to the metal centre. This is believed to suppress reduction of the metal by the organometallic species and promotes formation of a metalate complex I. This complex can then catalyse

27 the desired biaryl cross-coupling (Scheme 11). Notably this proposed mechanism proceeds through an unusual high-valent Fe(IV) intermediate II. DFT calculations were carried out and this pathway was determined to be feasible. The instability of this intermediate results in a fast reductive elimination step, which disfavours alternate pathways that could lead to products of homocoupling. The resultant Fe(II) complex III then undergoes transmetalation with the Grignard reagent to return active species I.

Scheme 11 Proposed mechanism for biaryl coupling Cook et al. demonstrated a similar system for carrying out the coupling of aryl sulfamates and tosylates 24 with aryl Grignard reagents (Scheme 12). This procedure did not use an extra sacrificial Grignard reagent to deprotonate the NHC precursor, as was used in Nakamura’s protocol, and added an excess of the coupling Grignard reagent to do this in one step. A large array of aryl species were shown to successfully couple, with electron donating and electron withdrawing substituents all being tolerated, to afford the desired products 25.27

Scheme 12 Cross-coupling of aryl sulfamates and tosylates with aryl Grignard reagents Duong et al. later reported a similar reaction using iron alkoxide species to carry out selective cross-couplings. Alkoxides are known to form strong bonds to first row transition metals and it was found that Fe2(Ot-Bu)6 was effective at carrying out the reaction. It is

28 believed that, similar to fluoride, t-butoxide may hamper reduction of Fe(III) to Fe(0) by the Grignard reagent.28

During the investigation of different iron salts it was noticed that Fe(OTf)2 was somewhat resistant to reduction. Following further studies it was found that the combination of

Fe(OTf)2/SIPr as a catalyst was remarkably efficient at carrying out selective biaryl cross- coupling, in some cases surpassing previously described systems. With this method, a variety of aryl Grignard reagents could be coupled with aryl chlorides and tosylates 27 in good to excellent yields (Scheme 13).29

Scheme 13 Use of Fe(OTf)2/SIPr for selective biaryl cross-coupling 1.2.3 Coupling of Heteroaromatic Compounds Recently, Knochel has achieved the cross-coupling of N-heterocyclic halides 29 with 30 arylmagnesium reagents 30 using FeBr3 (Scheme 14).

Scheme 14 Fe-catalysed coupling of N-heterocyclic halides and arylmagnesium reagents The use of heterocycles can be difficult due to interaction of the heteroatom with the metal catalyst, which can deactivate the metal centre and prevent product formation. Nevertheless this reaction was highly efficient and a range of differently substituted partners 29 and 30 could be coupled. Both electron rich and electron poor substituents were tolerated in 30, however sterically hindered reagents led to much slower reaction times. Polar solvents appeared to hamper the reaction and apolar solvents were found to be vital to achieving high yields, mainly by avoiding the formation of homocoupled products. A recent serendipitous discovery demonstrated that addition of isoquinoline as a ligand can promote this cross-coupling, leading to better yields and shorter reaction times, thus

29 increasing the range of coupling partners available. This also allowed the smooth coupling of two heteroaryl species, such as 32 and 33 (Scheme 15).31

Scheme 15 Ligand accelerated iron-catalysed heteroaryl-heteroaryl cross-coupling The mechanism of these couplings was not determined, however Fe(II) and Fe(III) salts gave similar yields. Despite this, reduction of the Fe(III) catalyst in situ with i-PrMgCl prior to the reaction deactivated the catalytic system. Radical clock studies suggest the presence of radical intermediates, due to formation of cyclised product 35 upon reaction of 29a, and further mechanistic studies are underway (Scheme 16).31

Scheme 16 Radical clock studies showing formation of cyclised product The discussed examples demonstrate only a small sample of iron-catalysed cross-couplings and many more have been developed, incorporating a range of coupling partners, such as aryl carbamates,32 alkenyl carboxylates33 and alkyl sulfides/sulfones.34 The formation of carbon-heteroatom bonds has also been reported.35 Many of these reactions rival current discoveries involving late transition metals and express the possibility of iron replacing them in the future.

1.3 C–H Bond Activation Direct C–H transformation has attracted a great deal of interest as substrates need not be pre-functionalised to instil the necessary reactivity. This greatly increases the sustainability of a process by reducing the number of reaction steps required. It has been shown that the precious late transition metals are extremely useful in developing efficient C–H activation processes. The combination of the advantages of both iron chemistry and C–H transformation was an appealing concept and this area has recently been developed.36

1.3.1 Activation of sp2 C–H bonds In 2008, Nakamura reported an iron-catalysed direct arylation through directed activation of an aromatic C–H bond. This reaction required the use of a large excess of Grignard reagent in conjunction with a stoichiometric amount of Zn salts (Scheme 17).37

Scheme 17 Fe-catalysed arylation through directed C–H bond activation

The reaction required 2 equivalents of Ph2Zn (formed by transmetalation from the Grignard reagent) for reaction to occur, yet an excess was used due to a biphenyl-forming side reaction also consuming reagent. It was found that the TMEDA additive was vital and 1,2-dichloroiso-butane (DCIB) proved an effective oxidant for the iron catalyst. With this system a number of arylpyridines, aryl pyrimidines and arylpyrazoles were reacted. It was also later demonstrated that arylimines, such as 38, could be used as ortho- directing groups for this reaction to yield the corresponding ketones, such as 39 (Scheme 18).38 A range of ring substituents, such as halide, tosyl, nitrile and methoxy groups, were tolerated in this reaction. The expensive DCIB oxidant was also later replaced by oxygen.39

Scheme 18 ortho-Arylation of aryl imines by directed C–H activation The procedure could eventually be carried out without the need for stoichiometric Zn salts by introducing an aromatic co-solvent and through slow addition of Grignard reagent. This protocol allowed for increased yield of coupling compared to previous reactions.40 Nakamura et al. have also developed an iron-catalysed directed substitution reaction of an olefinic C–H bond with a Grignard reagent using a similar procedure (Scheme 19).41

Scheme 19 Fe-catalysed activation of olefinic C–H bond with Grignard reagent The reaction takes place in a syn-specific manner; however the product 41 may be allowed to isomerise to the more stable isomer, such as in the case of 41a which was obtained in an E:Z ratio of 96:4. This isomerisation can be suppressed by a substituent being present at the 1-position of the olefin (cf. 41b). The reaction was shown to occur for aryl Grignard reagents possessing electron- withdrawing or electron-donating groups, however ortho-substitution was shown to subdue the reaction. The reaction also did not occur for alkyl or alkenyl Grignard reagents. A variety of cyclic and acyclic olefins 40 with a 2-pyridyl directing group successfully participated in the reaction. Yield also increased with the steric bulk of groups at the 1- position of the olefin, however substituents at the 2-position hindered the reaction. Interestingly unsaturated imines also took part in the reaction and, following hydrolysis, could give the corresponding unsaturated ketones. The exact catalytic cycle was not fully investigated, however a number of observations led to a proposed mechanism (Scheme 20). Due to the necessary presence of a directing group and the favourable effects of a 1-substituent, it was believed that the reaction involved a five-membered metallacycle 42 resulting from C–H activation (vide infra, Section 3.1) and that this then undergoes reductive elimination to give the Z-olefin.

Scheme 20 Proposed mechanism of direct C–H activation

Charette et al. have demonstrated the iron catalysed direct arylation of unactivated arenes with aryl iodides, without the need for stoichiometric amounts of organometallic reagent or a directing group (Scheme 21).42 It had previously been reported that reactions catalysed by iron may be positively affected by trace amounts of other metals, particularly copper.43 The use of catalytic amounts of copper as a co-catalyst were tested however it was found that the reaction was actually adversely affected. Various derivatives of 43 with a range of functionality underwent this reaction. However, the use of aryl bromides gave much lower yields. Different arenes besides 44 were also applied to afford the corresponding biaryl products in moderate to good yields; however these arenes were used as the reaction solvent and thus were present in large excess. This chemistry is also only applicable to symmetrical arenes due to poor regioselectivity.

Scheme 21 Fe-catalysed direct arylation of aryl iodides The kinetic isotope effect (KIE) was determined to be 1.04, indicating that the C–H bond breaking event was not rate determining. The reaction was also completely inhibited by the addition of radical scavengers, such as TEMPO. Therefore, a radical-based pathway was proposed (Scheme 22).

Scheme 22 Proposed mechanism for the iron-catalysed direct arylation of aryl iodides

Activation of the aryl-halogen bond occurs via single electron oxidation of the metal centre, forming the initiating radical species and an oxidised metallo intermediate II. Radical addition onto an arene gives radical species III and proximal abstraction of a halogen from II forms the biaryl product and an equivalent of HI, as well as regenerating the active form of the catalyst. As is the case in metal-catalysed living radical polymerisation, the extremely high efficiency and selectivity of the reaction relies on creating a dynamic equilibrium between a low concentration of growing radicals and a large amount of dormant species, which cannot propagate and/or self-terminate. This leads to side reactions being limited and the efficient process of direct coupling.42 Initially it was believed that the t-BuOK base was simply required to quench HI to keep the required pH of the system. However Shi later proposed a more prominent role in which it interacts with benzene and promotes reactivity through π-π and ion-π stacking with the phenanthroline ligand (Fig. 1).44

Figure 1 Activation of arene through interaction with t-BuOK and ligand The same reaction was later carried out using a preformed Fe/phen catalyst system and various aryl iodides and bromides. This procedure did not require inert atmospheres or anhydrous solvents for successful reaction.45 It was also reported by Yu et al. that a Suzuki-Miyaura-type coupling between arylboronic 46 acids and benzene could be carried out using stoichiometric Fe2(SO4)3. Hayashi and

Shirakawa later reported a catalytic variant of this reaction using Fe(OTf)3, a substituted bathophenanthroline ligand 47 and DTBP as oxidant (Scheme 23).47

Scheme 23 Iron-catalysed Suzuki-Miyaura-type C–H coupling

As was reported previously, substitution on the benzene aryl partner led to mixtures of regioisomeric products. A mechanism consisting of a radical pathway was proposed

(Scheme 24). Interaction of the Lewis acidic Fe(OTf)3 with DTBP leads to C–O bond cleavage and formation of a peroxoiron(III) species II, which undergoes homolysis to give Fe(IV)-OH III and a t-BuO• radical IV. IV then oxidises the arylboronic acid to give an aryl radical V (this was confirmed in a separate experiment), which then undergoes radical substitution at the arene to give VI. Finally the Fe(IV) species III oxidises the resultant radical to give the coupled product and regenerate Fe(III).

Scheme 24 Proposed catalytic cycle for Suzuki-Miyaura-type C–H coupling

1.3.2 Activation of sp3 C–H bonds Recently the Cu-catalysed direct alkenylation of activated pyridines and quinolines has been demonstrated as an efficient approach to alkenylated azaarenes; important structures in many pharmaceutically active compounds. However, this process requires the use of alkenyl iodides and ‘nitrogen-activating’ groups to proceed.48 Building upon the idea of forgoing the need for an activating group, Huang and co-workers developed a novel iron-catalysed direct alkenylation of 2-substituted azaarenes 49 with easily accessible N-sulfonyl aldimines 50 (Scheme 25).49 Notably the use of Cu catalysts in this reaction resulted in relatively low yields.

Scheme 25 Fe-catalysed alkenylation of 2-substituted azaarenes The reaction was not significantly influenced by functionality on the aromatic ring of 50 and also tolerated heterocycles and alkenyl groups being present. Replacement of the tosyl group with a nosyl was also successful, yet Boc and Cbz protected aldimines gave very low yields. A range of quinolines and quinoxalines was also successfully reacted, as well as various 2-substituted pyridines, however these required the use of t-BuOK as a co- catalyst. The presence of radical scavengers did not affect the reaction, suggesting that a free radical process was not occurring. A large KIE of 7.6 also indicated that C–H cleavage was rate determining and, combined with the formation of solely E-alkene, it was proposed that a concerted E2-elimination step was involved (Scheme 26). Formation of amine products via either benzylic C–H activation or Lewis acid-catalysed deprotonation and subsequent Mannich addition of the formed metal enamide was previously reported by this group.50,51 Performing the iron-catalysed reaction at lower temperatures resulted in formation of the same amine products, suggesting that the reaction may proceed through intermediate 52. The alkenylated product was also obtained by preparing the amine resulting from the nucleophilic addition step and subjecting it to the reaction conditions, supporting its role as an intermediate in the reaction.49

Scheme 26 Proposed intermediate in the direct-alkenylation reaction Despite there being many examples of C–O bond formation via C–H activation, metal- mediated C–N bond formation from C–H activation seems more difficult and was only reported relatively recently. Many of these processes use nitrene derivatives as the primary nitrogen source and PhI=NTs and its analogues have been widely used. However, such

36 hypervalent iodine reagents are not commercially available, can be unstable and produce ArI as byproducts; leading to a number of practical limitations in their use. Thus the use of amines and amides as nitrogen sources is an attractive prospect.

In 2008, Fu et al. reported an efficient, inexpensive and air-stable FeCl2/NBS catalyst/oxidant system for the amidation of benzylic sp3 C–H bonds using carboxamides and sulfonamides 54 (Scheme 27).52 There was no significant difference in the reactivity of carboxamides and sulfonamides and various substitutions on the aryl ring were tolerated and products 55 were obtained in moderate to good yields. The activity of 53 decreased in the order: diphenylmethane > ethylbenzene > 4-bromoethylbenzene. The latter reagents sometimes required further heating to 80 ⁰C to successfully react.

Scheme 27 Fe-catalysed amidation of C–H bonds

The presence of NBS and FeCl2 were integral to the reaction, which was unsuccessful if either or both were not present. NBS acts as both an efficient oxidant and the free radical initiator in the proposed mechanism (Scheme 28). It was proposed that NBS reacts with 54 to form N-bromocarboxamide/N-bromosulfonamide 56 to initiate the reaction. Pre- preparing these species and adding the benzylic reagent and FeCl2 successfully provided the amidation product, supporting their presence as intermediates. 56 then reacts with the iron salt via ligand exchange, which leads to formation of an iron-nitrene complex III.53 This then undergoes the key C–H activation step with the benzylic substrate via transition structure IV. Removal of the iron salt then provides the desired product 55 and restarts the cycle.52

Scheme 28 Proposed mechanism for Fe-catalysed amidation of benzylic sp3 C–H bonds 1.4 Cross Dehydrogenative Coupling In addition to the C–H activation reactions discussed in the previous section, the direct coupling of two C–H bonds is the most efficient, environmentally benign and atom economic method of constructing C–C bonds. Clearly this avoids the use of organohalides or organometallic reagents and formally produces an equivalent of H2, reducing the waste of the reaction. Early work carried out in this area, named cross-dehydrogenative coupling (CDC), investigated the use of first row transition metals and copper salts were popular. Later, iron-catalysed CDC reactions were reported and much research has been carried out since.1

1.4.1 CDC of two sp3 C–H bonds Li and co-workers have made significant contributions to this field and reported the first iron-catalysed benzylic C–H bond activation in CDC with 1,3-dicarbonyl compounds, such as 58 (Scheme 29).54

Scheme 29 Iron-catalysed CDC of benzylic C–H and 1,3-diketones The main difficulty in this reaction was avoiding homocoupling of the starting materials.

FeCl2 was found to be the most effective catalyst, outperforming the previously used Cu

38 and Co. It was also found that the use of di-t-butylperoxide (DTBP) was better than t- butylhydroperoxide (TBHP) as an oxidant and that the reaction proceeded efficiently for a wider range of substrates at increased temperatures. A range of different benzylic compounds besides 57, both cyclic and acyclic, and various 1,3-dicarbonyl compounds, including diketones, β-ketoesters and ketoamides, were successfully coupled. A radical pathway was proposed for the reaction (Scheme 30). DTBP initially oxidises Fe(II) species I, producing Fe(III) species II and a t-butoxyl radical III. III can abstract the benzylic H atom to form radical IV, while Fe(III) reacts with the 1,3-dicarbonyl to form an iron(III) enolate V. The desired C–C coupled product is obtained following attack by the electrophilic radical IV.

Scheme 30 Tentative mechanism for iron-catalysed CDC Using the same approach, Li and co-workers have also shown that various cyclic alkanes can be oxidised to react with 1,3-dicarbonyl compounds (Scheme 31).55 For these examples high temperatures and an inert nitrogen atmosphere were required. The tetrahydrate of FeCl2 also proved an equally useful catalyst. The alkylation of different ring sizes and more complex structures, such as norbornane and adamantane, were also reported, while the use of n-hexane led to two regioisomeric products due to reaction at the C-2 and C-3 positions.

Scheme 31 Iron-catalysed CDC of cyclic alkanes and 1,3-dicarbonyl compounds Li et al. have also reported a similar reaction using predominantly ethers 62 and 1,3- dicarbonyl compounds 63 as the carbon nucleophile (Scheme 32).56 It was found that various iron salts were efficient in this process, including FeCl2, FeBr2, Fe(OAc)2 and

Fe2(CO)9, and that DTBP was the best oxidant. Using these conditions, a variety of cyclic and acyclic ethers were successfully reacted with 63. It was also found that sulfide and amine substrates were suitable coupling partners.

Scheme 32 Iron-catalysed CDC α- to heteroatoms The C–H bonds α- to the heteroatoms can be readily abstracted via single electron transfer pathways to yield the corresponding iminium, thionium or oxonium ions 64. These intermediates can then further react with a nucleophile to form the C–C bond.1

1.4.2 CDC between sp2 and sp3 C–H bonds Shi et al. have reported an iron-catalysed cross-dehydrogenative arylation (CDA) of a benzylic C–H bond (Scheme 33).57 It was found that DDQ was the most efficient oxidant for this reaction and its use more advantageous than peroxides for safety reasons. The use of DCE as a cosolvent also greatly reduced the amount of diarylmethane required to obtain good yields. A large number of electron rich arenes 66 and diarylmethanes 67 were coupled in this manner in good to excellent yields, with more electron rich arenes leading to double CDA. Excellent regioselectivity was observed; controlled by the electronic properties of the arenes (primarily an OMe or SMe group, demonstrated by formation of 68a and 68b respectively).

Scheme 33 Iron-catalysed CDA of benzylic C–H bonds A similar mechanism as previously proposed was invoked to explain this reaction (Scheme 34). The reaction is initiated by the iron-catalysed SET oxidation, forming the benzyl radical III which can be further oxidised to the benzyl cation IV by Fe(III). This can then be intercepted by the arene 66 in a Friedel-Crafts-type process to give V and subsequent abstraction of hydrogen by the reduced hydroquinone VI yields the product and reforms the catalyst.57

Scheme 34 Proposed mechanism for the CDA reaction Subsequently, Shi attempted to develop a Heck-type reaction using diarylmethanes. However this had an extremely limited scope, only tolerating unsubstituted styrene. Vinyl acetates, such as 69, on the other hand, yield phenylketone products 70 in good to excellent yields (Scheme 35).58 This reaction tolerated both electron-rich and electron-deficient substitution patterns on 57 (also giving a moderate yield for simple toluene) and various vinyl acetates.

Scheme 35 Iron-catalysed direct functionalisation of benzylic C–H bonds 1.4.3 CDC in Domino Processes As demonstrated, iron is able to catalyse a number of different reactions and promote a variety of processes. It has been shown that some of these roles can be combined in domino processes. Recently Hayashi et al. reported an iron-catalysed oxidative coupling of alkylamides 71 with arenes 72 (Scheme 36).59 The reaction involves two steps; oxidation of 71 to form 73, followed by Friedel-Crafts alkylation. The combination of these two processes is not easy as one catalyst must sequentially promote two mechanistically distinct reactions. It was believed that this could be accomplished by iron as it is known to catalyse oxidation of sp3

C–H bonds and have strong Lewis acidity to promote SEAr.

This reaction had previously been reported using Zr(OTf)4 with O2 oxidant however the scope was limited to γ-lactams and electron-rich heteroarenes. This was believed to be due to the low catalytic activity of the zirconium complex towards oxidation.60

Scheme 36 Iron-catalysed oxidative coupling of alkylamides with arenes During the investigation of this reaction, multiple metal salts, including Fe, Cu and Rh, were tested for their ability to promote the individual reaction steps. It was found that only iron (specifically FeCl3) showed high catalytic activity for both steps. Following this, optimal conditions for the tandem procedure were successfully developed and a range of electron-rich and electron-poor arenes 72 were reacted with different alkylamides 71 in good to excellent yield. It was necessary to add a small amount of Fe(OTf)3 (3 mol%) to the reactions of arenes with low nucleophilicities. Fe(OTf)3 is a better Lewis acid than 59 FeCl3 and so is more efficient in the SEAr step.

Similar to the reaction by Huang reported earlier, Xu et al. reported the iron-catalysed generation of 2-vinyl azaarenes 77 (Scheme 37).61 The reaction tolerated a range of different heteroarene starting materials. It proceeded with both electron-donating and electron-withdrawing aromatic rings at the C-3 position and the use of ortho-substituted rings did not give any noticeable steric effects. However derivatives of 75 without any substituents at the C-3 position failed to give the desired product.

Scheme 37 Vinylaromatic generation via iron-catalysed sp3 C–H functionalisation This reaction employs a single electron transfer (SET) oxidation of amide 76 by Fe(III) to give radical cation II, from which abstraction of an α-H leads to formation of iminium species III. This then reacts with in situ generated enamine IV to provide V. Elimination from this species ultimately yields the products 77 (Scheme 38).

Scheme 38 Proposed mechanism for generation of vinylaromatics

1.5 Summary As mentioned previously, the many potential benefits iron possesses over classically used metals for CH cross-coupling have resulted in an explosion of interest in this field in recent years; as such the examples discussed here only scratch the surface of the iron literature. Nevertheless they serve to show the range of transformations iron is capable of assisting in and the real possibility of these systems replacing the use of precious metals in the future. Despite the huge strides taken in this field, there remain a number of challenges that must be overcome before Fe becomes a true successor to metals such as Pd. Most notable is the lack of understanding in many catalytic cycles, with a range of different cycles often being proposed. Elucidating the exact species present in these systems will aid in overcoming limitations that may currently be present and allow the true potential of iron to be unlocked.

2. Iron-mediated Coupling of Arylsulfides with Silanes

2.1 Introduction to Pummerer and Pummerer-Type Reactions The Pummerer rearrangement was first discovered in 1909 and, since then, has received attention in a variety of studies, including mechanistic and synthetic investigations. A large amount of Pummerer-type reactions have been reported since its inception and this area has been reviewed extensively.62 This section will introduce the classical Pummerer rearrangement and briefly focus on the aromatic Pummerer-type reaction.

2.1.1 Classical Pummerer Rearrangement The classical Pummerer rearrangement uses an aryl sulfoxide 78 as the substrate (Scheme 39). O-acetylation occurs upon addition of acetic anhydride to give 79; this serves to activate the sulfoxide and elimination of the acyloxy group from 79 can occur on abstraction of the α-proton by the acetate counter ion. This forms a thionium ion 80, which can be attacked by a nucleophile, as it is highly electrophilic, to give 81a. If no external nucleophile is present, the acetate counter ion can attack 80 to give an α-acetoxysulfide 81b, which can then be hydrolysed to a thioacetal and, ultimately, the corresponding aldehyde 82.

Scheme 39 Classical Pummerer Rearrangment A number of different nucleophiles, such as arenes, alkenes and amines, can be used in this reaction. Alternative methods of activation have been developed, such as the use of trifluoroacetic anhydride (TFAA) or trifluoromethanesulfonic anhydride. This changes the leaving group in the elimination step and can make this step more facile. However, the activating agent must be compatible with the nucleophile. It has also been shown that addition of Lewis acids, silyl chlorides and silyl triflates can be beneficial to systems that exhibit low reactivity. This could be through further activation of the acyloxysulfonium salt 79 or extension of the thionium ion’s lifetime by sequestering the acetate counter ion. Furthermore, it has been shown that direct sulfide oxidation to the

45 desired thionium ion 80 is possible using reagents such as N-chlorosuccinimide or various 62 hypervalent iodine reagents such as PhI(OTFA)2.

2.1.2 Aromatic Pummerer-Type Reactions A number of reactions have been reported in aromatic systems that are related to the Pummerer reaction. An example of this would be the 1,4-addition to p-sulfinylphenols 83 to give dihydroxybenzofurans 86 developed by Kita et al. (Scheme 40).63 The mechanism involves activation of the sulfoxide 83 with TFAA and expulsion of the O-leaving group by donation of the hydroxyl lone pair into the aromatic system to form a thio-quinonium ion 84. 1,4-Addition of a styrene to 84 is then followed by a spontaneous cyclisation, quenching the benzylic cation 85 and forming the dihydroxybenzofuran product 86 as a single regio- and stereoisomer.

Scheme 40 1,4 addition to p-sulfinylphenols to give dihydroxybenzofurans This reaction proceeded quickly at low temperature to give the product in moderate to high yields and trans-products were observed with a high selectivity for a wide range of substrates. Inspired by the work of Kita, Procter et al. have reported the nucleophilic ortho-allylation of aryl and heteroaryl sulfoxides 87 by reaction with triflic anhydride and allyltrimethylsilanes (Scheme 41).64 This reaction complements the ability of sulfoxides to direct ortho-metalation, followed by quenching with electrophiles. It has been shown to have a wide substrate scope, with neutral and electron-rich systems being successfully allylated in moderate to excellent yield; however halogenated substrates gave lower yields. Both alkyl-aryl and biaryl sulfoxides could be reacted and substituted allyl and crotyl silanes could also be used as substrates.

Scheme 41 Nucleophilic ortho-allylation of aryl sulfoxides The reaction is proposed to occur through an interrupted Pummerer reaction (Scheme 42). In this mechanism the activated sulfoxide reacts with the nucleophile directly at sulfur. The resulting sulfonium salt 89 is proposed to undergo an in situ thio-Claisen rearrangement to deliver the allyl group to the ortho-position of the aromatic ring. A number of observations support this proposal, such as solely the ortho-substituted products 88 being obtained and double-allylic inversion being observed for unsymmetrical allyl silanes (such as crotyl TMS). Double-allylic inversion also suggests that attack of the nucleophile directly on the ring is not occurring, as this would involve only one inversion step. The sulfonium ion 89 was also isolated and characterised by 1H NMR spectroscopy and the postulated carbocation intermediate was intercepted using a sulfoxide with a heteroatom in the ortho-position.64

Scheme 42 Mechanism of ortho-allylation of aryl sulfoxides Further work by the Procter group has extended this reaction to use on heteroaryl sulfoxides such as pyrroles and pyrazoles.65 This reaction can also be carried out using propargyl silanes, to yield the corresponding ortho-propargyl arylsulfides via a similar interrupted-Pummerer/thio-Claisen rearrangement.66,67

2.2 Results and Discussion

2.2.1 Proposed Project As discussed in the preceding section, previous work within the Procter group has involved the cross-coupling of organosilane nucleophiles with aromatic and heteroaromatic rings that proceeds via an interrupted Pummerer reaction of aryl sulfoxides.64,67 This reaction was efficient and had a wide substrate scope; however synthesis of the aryl sulfoxide starting material usually required oxidation of the corresponding aryl sulfide, adding an extra step to a target synthesis. It was proposed that direct reaction of aryl sulfides 91 with nucleophiles and a SET oxidant could produce similar products in a single step through an oxidative process described in Scheme 43 with a phenyl sulfide and allyltrimethylsilane (allyl TMS).68 First, the sulfur atom is oxidised to a radical cation III, which can then react with the allylsilane to produce radical cation IV. Oxidation of IV and elimination of TMS will then give thionium ion V, which can rearomatise to give the desired product 88. It was expected that this process would give a mixture of ortho- and para-substituted products due to lack of selectivity in the attack on the silane by radical cation III. It should be noted that another pathway may be possible, involving oxidation of the nucleophile followed by reaction with the aryl sulfide in a Friedel-Crafts-type mechanism.69

Scheme 43 Proposed oxidative process for nucleophilic cross-coupling with aryl sulfides Previous work in other groups, such as Kamimura’s oxidative coupling of biaryl sulfide 91a (Scheme 44)68 and Li’s CDC reactions (Scheme 32),56 have used Fe sources as oxidants for various sulfides. FeCl3 is also a commonly used reagent for oxidative biphenyl

48 couplings through oxidation of arenes to form similar intermediates to those shown in Scheme 43.70 Hence it was thought that the use of iron(III) as the single electron oxidant could achieve the desired products.

Scheme 44 Iron-catalysed oxidative coupling of biaryl sulfides The products of this reaction could also be further functionalised using the organosulfanyl group in a number of transformations, such as oxidation to sulfoxides and sulfones, which can lead to sulfoxide-lithium exchange or nucleophilic aromatic substitution by displacement of the sulfone.71 The Ni(II)-catalysed Kumada-Corriu cross-couplings of organosulfanyl groups has also been carried out in previous investigations within the group and would be a viable option for further functionalisation in this project (vide infra, Section 4.6.1.1).72,73

2.2.2 Preliminary Reaction Initial studies to investigate the feasibility of the proposed process used (3,5-dimethoxy)(phenyl)sulfide 91b and allyl TMS (Scheme 45). These substrates were chosen as it was thought that the use of an electron-rich aryl sulfide and the highly nucleophilic allyl TMS would facilitate the oxidation step and addition to the radical cation respectively. Stoichiometric quantities of oxidant were initially used to determine whether the desired reaction was possible. It was thought that once the reaction was better understood, an investigation into the use of substoichiometric amounts could be carried out. Pleasingly, the adopted reaction conditions gave the desired allylated product 88a in 8% yield. Despite the hypothesised selectivity issues, only the ortho-allylated product was isolated.

Scheme 45 Model reaction conditions 2.2.3 Synthesis of Biarylsulfide Starting Materials Biaryl sulfides 91 can be easily synthesised via a number of methods. Previous methods adopted in the Procter group include couplings of aryl bromides/iodides and thiophenols 74,75 catalysed by Pd(PPh3)4/CuI respectively (Scheme 46). A variety of sulfides can be formed by altering the substitution on the arylhalide and thiophenol substrates.

Scheme 46 Pd- and Cu-catalysed formation of biaryl sulfides 2.2.4 Solvent Screen A solvent screen was carried out to assess its effect on the yield of the desired product.

Commonly used solvents for FeCl3-mediated oxidative couplings were investigated (Table 1).70,3,4 Interestingly, changing the reaction solvent dramatically affected the amount of products observed and, in some cases, led to the observation of both the para- and bis- allylated products (96 and 97 respectively) in addition to 88a. Aromatic solvents, such as toluene and benzene, did not improve the yield over MeCN and the use of solvents such as THF and DMSO resulted in no reactivity (Entries 2-6). This is likely due to coordination to the metal centre inhibiting the desired reactivity.

It appeared that chlorinated solvents, such as CH2Cl2 (Entry 7) and CHCl3 (Entry 8), improved the observed yield, giving a combined yield of 30% and 22% respectively. As expected statistically, 88a and 96 were usually obtained in an approximately 2:1 ratio. The formation of the desired products was more favourable in nitromethane (Entry 9) and a combined yield of 49% was obtained, but a large amount of bis-allylated product 97 was also obtained in this solvent. Perhaps unsurprisingly, this suggested that 88a could further 50 react and may prove problematic during optimisation of the reaction. This issue of over- reaction is commonly reported in the alkylation of arenes using directing groups.76 Interestingly very little of 96 was observed in this solvent, possibly indicating that the SPh group directed the reaction to favour attack at the ortho-position. It could also indicate a different mechanism is operating compared to that followed in CH2Cl2, leading to different product ratios.77

Table 1 Solvent screen using FeCl3 oxidant Entry Solvent 91b (%)a 88a (%)a 96 (%)a 97 (%)a 1 MeCN 68 8 - - 2 Toluene 73 7 3 - 3 Benzene 59 10 4 - 4 THF 92 - - - 5 DMSO 95 - - - 6 1,4-dioxane 93 - - -

7 CH2Cl2 65 20 8 2

8 CHCl3 48 15 6 1

9 MeNO2 30 35 3 11 a 1 Determined by H NMR spectroscopy using MeNO2 standard (see Section 5.1)

It was decided that further experiments would be carried out in MeNO2, in the hope that the amount of over-oxidation leading to 97 could be reduced. If this proved difficult, then

CH2Cl2 appeared a viable alternative, as a smaller amount of 97 was obtained in this reaction. Interestingly, it was found that by submitting the crude reaction mixture obtained in CH2Cl2 to the standard reaction conditions, 88a and 96 could be obtained in 45% and

25% respectively, with <5% 97 observed. These results rival those obtained using MeNO2, however the lack of ortho-/para-selectivity made this option less attractive.

2.2.5 Oxidant Screen An oxidant screen was carried out to determine whether alternative oxidants could yield the desired products in a more efficient manner (Table 2).

Table 2 Oxidant screen carried out in MeNO2

Entry Oxidant 91b (%)a 88a (%)a 96 (%)a 97 (%)a

1 FeCl3 30 35 3 11 b 2 FeCl3 26 39 3 13

3 FeBr3 45 23 2 5

4 Fe(acac)3 90 - - -

5 Cu(OAc)2 90 - - -

6 CuCl2 86 - - -

7 Cu(OTf)2 67 11 - -

8 MnO2 85 - - -

9 Mn(OAc)3 87 - - - c 10 Mn(OAc)3 89 - - - a 1 b c Determined by H NMR spectroscopy using MeNO2 standard >99.9% Fe AcOH solvent

FeCl3 was the best oxidant out of those tested in terms of overall yield of products (Entry 1). The reaction gave similar results when using a >99.9% Fe source, suggesting that the observed reaction was not due to trace metal impurities (Entry 2).43 However, despite giving a lower yield of 88a, FeBr3 also yielded a comparatively smaller amount of 97 and thus had a better ratio of mono-:di-allylated products (Entry 3). If the overall reaction could be improved upon then this could be a potential oxidant to attempt to decrease over- oxidation. Other iron(III) salts (Fe(acac)3) proved unsuccessful in this oxidant screen, merely returning starting material 91b (Entry 4). Cu(II) and Mn(III) salts may also be used as single electron oxidants and so were also tested in this screen to determine whether they could carry out the same chemistry. Neither

Cu(OAc)2 nor CuCl2 yielded any of the desired product (Entries 5 and 6), however a small 78 amount of 88a was observed using Cu(OTf)2 (Entry 7). Interestingly 96 and 97 were not observed in this reaction. No reaction was observed upon use of either MnO2 or Mn(OAc)3 (Entries 8 and 9).79,80

2.2.6 Changing The Addition Rate of Allyl Silane Following investigation into the solvent and oxidant, the reaction still suffered from a high percentage of unreacted starting material being recovered. It was postulated that this could be due to FeCl3 reacting competitively with allyl TMS and producing a polymeric by- product instead of the desired product.81 In an attempt to combat this, slow addition of allyl

TMS to a mixture of 91b and FeCl3 was investigated (Table 3).

Table 3 Slow addition of allyl TMS to mixture of 91b and FeCl3

Entry Addition 91b (%)a 88a (%)a 96 (%)a 97 (%)a Time (min.)

1 30 13 5 - 2 2 10 19 15 1 6 3b 10 18 20 2 3 4c 10 7 6 1 1 a 1 b c Determined by H NMR spectroscopy using MeNO2 standard −25 ⁰C CH2Cl2 solvent

Adoption of a slow addition protocol of allyl TMS indeed reduced the amount of recovered starting material; however this also resulted in a decrease in reaction efficiency (Entry 1). Surprisingly no other noticeable peaks were observed in the 1H NMR spectrum to account for this missing mass. It was thought that this could be due to FeCl3 quickly reacting with 91b before allyl TMS is available for reaction. This could lead to a side reaction that results in material being lost in some way, possibly by formation of a polymer, degradation of the radical intermediate/starting material or the formation of highly polar by-products that were lost during workup. The addition time of allyl TMS was reduced to 10 minutes to try to reduce these side reactions (Entry 2). This seemed to be relatively successful and increased amounts of 88a and 96 were observed following the reaction. Lowering the temperature to −25 ⁰C gave a slightly greater amount of 88a (Entry 3), however the mass balance still remained low (57% of starting material was unaccounted for). Therefore, it was decided that the original

53 addition procedure would be retained as it provided better mass balances (80% starting material accounted for).

2.2.7 Changing Reagent Stoichiometry The next set of experiments investigated the effect of changing the amounts of allyl TMS and FeCl3 present in the reaction (Table 4). Decreasing the equivalents of allyl TMS with respect to 91b from 10 to 5 led to a slightly lower yield (Entry 2). However the mass balance also decreased from 79% to 64%, possibly due to the lower amount of allyl TMS making decomposition pathways of the starting material more likely. Although 5 equivalents gave similar yields, the use of 1 equivalent of allyl TMS only gave a trace of 88a and poor mass balance (Entry 3). The yield could be increased slightly by running the reaction at −25 ⁰C; however the most notable effect of this reduced temperature was to increase the mass balance (Entry 4). This suggests that the deleterious reactions responsible for a low mass balance are reduced at low temperature. Reducing the amount of FeCl3 present also gave a correspondingly lower yield (Entry 5) and, importantly, the absence of FeCl3 led to no observable product formation (Entry 6).

Table 4 Changing the stoichiometry of the reaction

Entry x y 91b 88a 96 97 (eq.) (eq.) (%)a (%)a (%)a (%)a

1 2.2 10 31 41 2 13 2 2.2 5 24 29 2 9 3 2.2 1 30 1 - - 4b 2.2 1 59 6 trace - 5 1 10 71 13 trace 4 6 - 10 98 - - - a 1 b Determined by H NMR spectroscopy using MeNO2 standard −25 ⁰C

2.2.8 Other Biaryl Sulfides Next, it was decided to use other biaryl sulfides in the currently optimal conditions to determine the effect of this reaction partner. The use of a mono-substituted sulfide, (4-methoxyphenyl)(phenyl)sulfide 91c, gave only a trace of allylation product 88b, but predominantly returned starting material (Scheme 47). This could be due to the fact that sulfur is less electron rich and thus less easily oxidised, favouring the side reaction of

FeCl3 with allyl TMS instead.

Scheme 47 Reaction of 91c under standard conditions

Scheme 48 Reaction of 91a under standard reaction conditions It was thought that Kamimura’s unsymmetrical biaryl sulfide 91a would successfully give allylated product since the required radical cation was suggested to be responsible for the biaryl coupling observed in Scheme 44. Surprisingly, no allylated product was seen; instead the reaction gave the same symmetrical dimer 92 that Kamimura obtained (Scheme 48).68 It is not known why this homocoupling is more favourable than the desired reaction with allyl TMS. Kamimura suggested that reaction occurs exclusively at the para-position (with respect to sulfur) due to steric effects; however previous results have shown that the ortho-position is more favoured in the allylation reaction. Therefore, it is possible that the desired o-allylation pathway is disfavoured due to these steric effects and this allows for the biaryl coupling to occur. A similar dimer is not observed in the reaction of 91b, which could be due to the fact that the arene is more hindered and any dimer would experience severe steric clashes (Fig. 2).

Figure 2 Steric clash resulting from biaryl formation 2.2.9 Reaction with an unfunctionalised alkene It was reasoned that the problems with conversion may be due to side reactions associated 81 with the reactivity of allyl TMS and FeCl3. The prevalence of over-oxidation using

MeNO2 was likely also due to the reactivity of allyl TMS under these conditions. Thus, the use of less reactive alkene coupling partners was investigated. Surprisingly, reaction with 1-octene 98 (a simple, unfunctionalised alkene) cleanly gave 99a, which was chlorinated β to the aryl ring (Scheme 49). Overall this can be viewed as a formal ‘chloroarylation’ across the double bond. Notably the mass balance of the reaction was again quite poor; however only the linear product was observed, with no corresponding branched products being formed. Due to the potential interest of this reaction, work on the allylation was put aside and focus was turned towards investigating the chloroarylation process. A literature search was carried out to determine the novelty and standing of this reaction and will be discussed in the following section.

Scheme 49 FeCl3-mediated chloroarylation of 1-octene

3. Metal-catalysed Reactions of Arenes and Alkenes

3.1 Oxidative Coupling of Arenes and Alkenes As has been stated earlier, the desire for more green and sustainable chemistry has led to increased interest in the direct reaction of two C–H bonds, without the need for pre- functionalisation. This would lead to lower costs, due to fewer steps being required, and less waste being produced compared to more standard metal-catalysed coupling reactions.82 However this endeavour poses a number of issues when compared to traditional cross-coupling; most notable are the need for a stoichiometric amount of sacrificial oxidant and the difficulty of regioselective functionalisation of ubiquitous C–H bonds.83 Olefins find many uses across organic synthesis and are present in a number of target molecules. The idea of forming these motifs through an oxidative Heck-type process is an attractive concept. Pioneering work in this area was carried out by Fujiwara and Moritani, who in 1967 reported the coupling of arenes and olefins.84 The reaction required the use of stoichiometric PdII-styrene complexes and a large excess of arene (which was used as the solvent). AcOH co-solvent was also deemed vital for reactivity.85

Following further work, Pd(OAc)2 was found to be most effective for carrying out this transformation and a range of simple arenes, such as toluene and anisole, could be coupled to mono-, di- and tri-phenyl styrenes. Most interestingly, the authors found that the reaction could be performed using catalytic amounts of Pd by using Cu(OAc)2 or AgOAc 86 and O2/air as stoichiometric oxidants (Scheme 50).

Scheme 50 Catalytic Fujiwara-Moritani reaction A mechanistic pathway was also proposed (Scheme 51). The cycle begins with electrophilic metalation by Pd(II) complex I to give an aryl-Pd(II) species II, followed by co-ordination and carbometalation of the alkene resulting in alkyl palladium IV. Subsequent β-H elimination gives the coupled product and Pd(0) species V, which then reacts with the stoichiometric oxidant to return Pd(II). This remains the currently accepted mechanism for this reaction, which was later named the Fujiwara-Moritani reaction.87

Scheme 51 Mechanism for Fujiwara-Moritani reaction While the Fujiwara-Moritani reaction was a seminal contribution to this field, it possessed many limitations compared to the general Heck reaction (which was reported around the same time). These include lower yields and the inability to control regioselective functionalisation of the arene C–H bonds; product distribution was dependent upon the electronics of the aromatic ring, with electron-donating substituents affording ortho- and para-reactivity and electron-withdrawing substituents giving the meta-products.86 The identification of groups that can coordinate to the metal catalyst and direct reaction, ostensibly to the ortho-position, dramatically increased the efficiency of this reaction and led to a renewed interest in the field.88 Various directing groups have been reported and some recent examples of directed oxidative-Heck reactions will be discussed herein.

3.1.1 Examples of Directing Groups Stemming from earlier reports, Pd has been the most widely used metal in directed C–H alkenylation reactions.89 In 2010 Yu and co-workers developed the reaction of synthetically useful phenylacetic acids, such as 102, and acrylates using catalytic Pd(OAc)2 and benzoquinone (BQ), with O2 as the terminal oxidant (Scheme 52). The selectivity is believed to arise from a weak interaction between the metal centre and the carbonyl of the carboxylic acid.90

Scheme 52 Pd-catalysed ortho-alkenylation of phenylacetic acids

This reaction was tolerant of a range of functional groups on the aromatic ring, with substrates containing fluoride, chloride, ketone and methoxy groups all proceeding in good to excellent yields. Functionalisation of some drug molecules, such as ibuprofen and naproxen, was also possible, demonstrating the utility of this reaction in late stage manipulation of pharmaceutically relevant compounds. Substitution α to the carboxylic acid moiety was also tolerated and higher substitution at this position led to increased efficiency. Remarkably, through extensive screening of ligands, it was found that the use of N-protected amino acids allowed for increased reactivity in difficult substrates (Scheme 53a) and also control of regioselectivity between two ortho-positions on the ring (Scheme 53b).90 It was found that this olefination reaction could be carried out with as little as 0.2 mol% catalyst loading.91

Scheme 53 Use of amino acid ligands for increased A. reactivity and B. regioselectivity It was also reported that use of these amino acid ligands allowed the formation of dialkenylation products 109 in excellent yields. By carrying out sequential olefination reactions, first without and then with amino acid ligand, it was also possible to form bis- alkenyl products with different alkene substituents (Scheme 54).92 The reaction was subsequently extended to allow for olefination of phenylethyl alcohols93 and ethers.94

Scheme 54 Sequential olefination with different alkene partners In addition to Pd, efforts towards the use of Ru complexes for directed cross- dehydrogenative alkenylations of arenes have recently been realised. The groups of Ackermann and Jeganmohan have been particularly prevalent in this area and have reported a range of directing groups, such as aldehydes,95 ketones,96 anilides and benzamides.97 In 2012 both groups reported the use of weakly co-ordinating aryl esters as directing groups for alkenylation with electron-deficient alkenes (Scheme 55).98,99

Scheme 55 Ester-directed alkenylation of arenes by A. Ackermann and B. Jeganmohan

Similar conditions were adopted by both groups, with the use of [RuCl2(p-cymene)]2 and co-catalytic amounts of AgSbF6. The silver salt reacts to give a cationic complex, [Ru(p- cymene)(OAc)][SbF6], which leads to a more facile C–H metalation step. Jeganmohan was able to use catalytic amounts of a Cu salt with O2 as terminal oxidant; however stoichiometric amounts of Cu were used by Ackermann. Despite slight differences, similar yields and substrate scope were reported; the reaction generally required electron-rich aromatics for efficient alkenylation and the use of electron-withdrawing groups, such as nitro and trifluoromethyl, were incompatible with this system.98

Mechanistic studies suggest that the cycle involves a reversible, acetate-assisted cycloruthenation by the cationic metal species to give a five-membered ruthenacycle II. Migratory insertion then provides a seven-membered metallacycle III which undergoes β-H elimination to yield the alkenylated product and, following oxidation by the Cu salt, the starting metal species I (Scheme 56).99

Scheme 56 Proposed catalytic cycle for Ru-catalysed oxidative alkenylation 3.1.2 Sulfur Directing Groups in Oxidative Alkenylations Despite a plethora of directing groups having been developed containing N or O atoms, the use of sulfur to direct oxidative alkenylations is quite rare and has only recently been established, with only a handful of examples demonstrated. Sulfur is known to bind strongly to many transition metals and has classically been viewed as a poison in many reactions by halting reactivity. However sulfur is an important motif in many natural and industrially useful compounds and its use as a directing group would be beneficial for product manipulation as it can be easily removed or used in further transformations.100,101 In 2012, Zhang and co-workers reported the first Pd-catalysed selective oxidative Heck reaction of arenes and acrylates using a thioether directing group.100 A number of S- containing groups were investigated (Scheme 57).

Scheme 57 Screen of S-containing directing groups It was found that benzyl thioethers were the most efficient directing groups. Benzyl(phenyl)sulfide 113d exhibited good reactivity, however a large amount of dialkenylation product was observed (shown in parentheses); replacing this with benzyl(methyl)sulfide 113e reduced the reactivity slightly but gave no diolefination. It was established that the properties of the sulfur centre are integral to the reaction as the use of sulfoxides 113a, sulfones 113b and thioesters 113c proved unsuccessful. Interestingly no reaction was observed when sulfur was replaced by oxygen in 113f. The alkenylation was shown to be tolerant of a range of functional groups; however electron deficient arenes gave lower yields, which may suggest an electrophilic metalation pathway (Scheme 58). The p-tolyl thioether group gave good yields of mono-olefinated products for ortho- and meta-substituted arenes but, as was observed during screening, a large amount of di-alkenylation was seen for para-substituted or unsubstituted rings. For these examples the methyl thioether was the best directing group for mono-olefination, obtaining the desired product in moderate yields.

Scheme 58 Pd-catalysed selective ortho-alkenylation with thioether directing groups

In the following year Shi et al. developed a variant of this reaction using a cationic Rh complex.102 A screen of S-containing groups was also carried out for this reaction and similar results as those observed previously by Zhang were reported. Interestingly it was found that mono- and di-olefination could be controlled by carrying out the reaction in either MeOH or t-BuOH (Scheme 59). This also led to a semi-one-pot dialkenylation reaction with two different alkenes by performing a solvent swap following the first coupling.

Scheme 59 Controlled Rh-catalysed olefination using thioether directing groups Contrary to the Pd-catalysed reaction, electron-deficient arenes performed better in this reaction. This suggested that the C–H activation may occur through a concerted metalation deprotonation pathway rather than the electrophilic metalation process proposed for Pd. Recently the same catalyst has been described by Satoh and Miura to carry out selective olefination of 2-aryl-1,3-dithianes, such as 121, under mild conditions (Scheme 60).103

Scheme 60 Rh-catalysed selective alkenylation of 2-aryl-1,3-dithianes The reaction mechanism is believed to occur similarly to that discussed earlier, in which chelation of the dithiane moiety directs C–H bond cleavage at the ortho-position to form five-membered rhodacycle II. Alkene insertion then occurs to give intermediate III, from which β-H elimination provides the alkenylated product 122 and, following reoxidation, the initial form of the catalyst I (Scheme 61).

Scheme 61 Proposed catalytic cycle for sulfur-directed oxidative C–H alkenylation The products of this reaction can be easily converted to the corresponding aldehydes or toluenes by using Dess-Martin periodinane or Raney Ni, respectively. This is beneficial as, while the use of aldehydes as directing groups in this reaction is known, the scope is limited to electron rich arenes.95 These research groups have also reported the use of benzothioamides in a Rh-catalysed coupling with electron deficient alkenes and styrenes.104 Sulfoxides have also been developed for use as directing groups in these reactions since the original report by Zhang. Phenyl sulfoxides were shown to direct coupling with acrylates to the ortho-position in combination with a Rh catalyst, however chelation was proposed to occur through the O atom to provide a 5-membered rhodacycle following C–H activation.105 Interestingly Zhang et al. have demonstrated that benzyl and phenylethyl sulfoxides 123 can promote selective olefination under Pd catalysis (Scheme 62).106 X-ray crystal structures of the corresponding five- and six-membered palladacycles were obtained and show that chelation occurs through sulfur. Impressively, phenylpropyl sulfoxides were also found to be highly efficient remote directing groups. The binding mode of the sulfoxide in this reaction is unknown.

Scheme 62 Use of sulfoxides as remote directing groups for arene C–H olefination An interesting use of sulfoxides as both directing group and chiral auxiliary has also been demonstrated by Colobert et al. for the atropodiastereoselective Pd-catalysed olefination of biphenyls using enantiopure p-tolylsulfoxides.107

3.2 Hydroarylation of Alkenes Another seminal piece of work in the field of C–H activation came in 1993 when Murai et al. reported a directed activation of aryl C–H bonds and subsequent hydroarylation catalysed by a low valent Ru complex (Scheme 63).108

Scheme 63 Ru-catalysed hydroarylation of olefins through direct C–H activation This reaction was shown to be highly efficient, with excellent yields achieved in the reported examples. However it proved limited to terminal, non-isomerisable alkenes and issues with overalkylation were encountered in the absence of ortho-substituents. The reaction mechanism involves chelation with the carbonyl as observed earlier with directed alkenylations, however the C–H insertion pathway is believed to occur via oxidative addition, resulting in a metal hydride species II being formed. Migratory insertion onto the alkene then provides an alkyl metal IV which can undergo reductive elimination to form the alkylated arene and the starting metal species I (Scheme 64). Notably no external oxidant is required in this reaction.109

Scheme 64 Proposed mechanism for Ru-catalysed hydroarylation of olefins Since the first reports of this reaction a number of investigations have been reported, including other metals such as Re, Rh and Ir.110 While investigating the alkenylation of fluoroarenes by Ni-catalysed hydroarylation of alkynes, Nakao and co-workers discovered alkylation using vinyl naphthalene 129 and 1-phenyl-1,3-butadiene 131 was also possible (Scheme 65).111 The reaction gave branched products 130 and 132 respectively, rather than the linear ones shown earlier. It was postulated that the reaction required these alkenes as the formation of benzylnickel and π-allyl intermediates, 133 and 134 respectively, following insertion into the Ni-H bond may make this step more facile.

Scheme 65 Ni-catalysed hydroarylation of alkenes using electron-deficient arenes More recently this reaction was further developed by Hartwig et al. and the Ni-catalysed, linear-selective hydroarylation of olefins without directing groups was reported (Scheme 66).112

Scheme 66 Linear-selective hydroarylation of olefins with electron-deficient arenes The procedure was limited to electron deficient arenes, such as 135, but a number of olefins were successfully reacted. Due to the absence of a chelating group the reaction was generally governed by sterics, with reaction at the least sterically hindered position being most favourable, although mixtures of regioisomers were observed. In depth experimental and computational studies suggested that the mechanism does not involve oxidative addition to form a nickel hydride species but rather proton transfer from the σ-C–H bond of the co-ordinated arene to the alkene (Scheme 67). This mechanism is similar to Ni- catalysed hydroarylation of alkynes.113 This step is reversible and a lower barrier for the subsequent rate determining reductive elimination gives rise to the observed high selectivity for the linear products.

Scheme 67 Proposed mechanism for Ni-catalysed linear-selective hydroarylation Interestingly the reaction could also be performed on internal alkenes and gave the same products obtained from terminal olefins. Rather than a chain walking process involving multiple proton transfers it is believed that the olefin isomerises through a mechanism unrelated to the hydroarylation reaction. This isomerisation would lead to a range of isomers being present from which Ni selectively co-ordinates to the terminal olefin. This

67 was supported by lack of D incorporation in the chain when deuterated arenes were reacted with internal olefins. The exact details of this isomerisation mechanism were not disclosed.

3.3 Iron-mediated Functionalisation of Alkenes Notably the previous section focused on hydroarylation of alkenes; however some examples of iron-mediated difunctionalisations of olefins have recently been reported. These occur via a radical pathway and the resultant radical species formed after the initial addition can be quenched to form a range of compounds.

Scheme 68 Iron-mediated halo-nitration of alkenes The iron-mediated radical chloro-nitration of alkenes, such as 137, was developed by

Taniguchi et al. using stoichiometric iron(III) nitrate nonahydrate and FeCl3 as chloride 114 source (Scheme 68). The heating of Fe(NO3)3.9H2O is known to produce NO2 gas (a free radical). It was proposed that radical addition of NO2 onto the double bond gives a radical intermediate 139 that can be trapped by the chlorine atom of FeCl3. It is notable that this reaction gives linear addition of NO2 onto the alkene; this is expected of a radical process due to the formation of the more stable secondary radical species.115 It was also noted that the chlorinated product may arise from oxidation of the radical intermediate to a carbocation, which is then quenched by Cl-.

Scheme 69 Iron(III)/NaBH4-mediated additions to unactivated alkenes

Interestingly, Boger et al. have reported reductive iron(III)/NaBH4-mediated additions to unactivated alkenes, such as 140, with the use of several radical traps giving anti-Markovnikov products (Scheme 69).116 A range of functionality could be introduced by varying the trap used, for example TsCN gave the corresponding cyano product, 117 SELECTFLUOR® gave fluorine products and using O2 gave the alcohol in good yield.

It is believed that this reaction occurs through an Fe(I)-H species which adds to the double bond, resulting in the most stabilised radical which is then quenched. A catalytic variant of this reaction was later utilised by Baran et al. to couple two olefins by quenching the radical intermediate with an electron deficient alkene (Scheme 70).118,119

Scheme 70 Fe-catalysed reductive olefin coupling The proposed reaction mechanism occurs via formation of Fe(III)-H species II from

PhSiH3 and the metal catalyst I. The more electron-rich alkene 142 can then abstract a hydrogen atom from this species to give the more stable tertiary radical IV and Fe(II). Notably this step may occur through hydrometalation of the olefin and subsequent homolysis of the metal-carbon bond.120 The radical IV then undergoes conjugate addition onto the electron deficient alkene 111 to give a second radical species V that is reduced by the Fe(II) species III. The resultant carbanion VI then undergoes protonation to give the observed products 143 (Scheme 71).

Scheme 71 Mechanism for reductive olefin coupling

3.4 Summary Some examples of directed Fujiwara-Moritani reactions have been examined, demonstrating the vast improvement this now well-established area has undergone since those early reports. A large portion of this discipline is governed by Pd catalysis; however the use of other metals, such as Rh and Ru, has increased in recent years. Despite the huge array of reaction systems developed, the vast majority require the use of functionalised alkenes, such as acrylates or styrenes. While some examples exist of simple, unactivated olefins being used as coupling partners, these remain outliers in the field.121,122 Also, despite their synthetic utility, the use of sulfur-containing groups for oxidative Heck reactions has been shown to be relatively underdeveloped. This was likely due to the belief that they bind metal centres too strongly and suppress catalytic activity. However recent reports of thioethers and sulfoxides partaking in successful couplings will hopefully lead to this area being expanded in the future. It has also been demonstrated that metals can carry out hydroarylation reactions by performing C–H activation and addition into alkenes. Contrary to the oxidative alkenylation reactions, a β-H elimination step is not involved in this mechanism, rather reductive elimination occurs to give alkyl products. The iron-mediated functionalisation of alkenes has also been developed. These occur through a radical pathway and a range of different quenches can be utilised to give various products. Notably many of these systems require stoichiometric amounts of metal; however some examples of catalytic reductive systems have been reported.

4. Iron-mediated Chloroarylation of Alkenes

4.1 This Work When compared with the transformations discussed in the preceding section, the current Fe-mediated chloroarylation reaction poses some interest; it bears some similarity to both the oxidative alkenylation (elimination of HCl would give the products of such a process) and the hydroarylation (reductive elimination installing a chlorine rather than a hydrogen). Notably this process makes use of a cheap metal, as opposed to the noble metals generally required in the other procedures, the reaction works with 1-octene (a simple, unactivated olefin) and it appears to be directed by the sulfur moiety. The complete regioselectivity with respect to the olefin is also similar to the iron-mediated alkene functionalisations shown, with complete selectivity for the linear product 99a. The reaction appeared to represent a novel transformation and thus attempts to optimise it were undertaken.

4.2 Optimisation Studies

4.2.1 Solvent Screen As solvent effects appeared to have a large influence on the allylation reaction, a screen was carried out for the reaction with 1-octene (Table 5). In contrast to the previously investigated reaction, CH2Cl2 (Entry 2) proved a much better reaction solvent than MeNO2 (Entry 1). This could be due to a number of reasons, including solubility of the reagents and solvent polarity. Interestingly, the reaction mixture was heterogeneous in the more efficient CH2Cl2 system, while the use of MeNO2 led to a homogeneous system. The use of a two-solvent system was consequently investigated to determine its effects (Entry 3).

Using a 1:1 mixture of CH2Cl2/MeNO2 gave a lower yield than just using CH2Cl2; however the mass balance was slightly improved. The higher boiling solvents 1,2-dichloroethane (DCE) and chlorobenzene gave comparable results to CH2Cl2 (Entries 4 and 5). These solvents would allow higher temperatures to be investigated during optimisation. As was observed in the previous allylation studies, the use of more nucleophilic/coordinating solvents resulted in lower activity; MeCN showed product formation in a low yield (Entry 6) and no reaction was observed using H2O, a biphasic 1:1 CH2Cl2/H2O system, THF, toluene or dimethyl carbonate (Entries 7-11). Intriguingly, running the reaction in a vast excess of 1-octene also led to a decrease in

71 product formation but high mass recovery, potentially suggesting 1-octene can inhibit the reactivity of FeCl3 (Entry 12).

Table 5 Solvent screen for FeCl3-mediated reaction of 91b with 1-octene

Entry Solvent 91b (%)a 99a (%)a

1 MeNO2 40 14

2 CH2Cl2 9 36

3 CH2Cl2/MeNO2 29 31 4 DCE 10 34

5 C6H5Cl 9 34 6 MeCN 45 10

7 H2O 89 -

8 CH2Cl2/H2O 91 - 9 THF 89 - 10 Toluene 34 - 11 Dimethyl carbonate 94 - 12 98 (60 eq.) 52 15 a 1 Determined by H NMR spectroscopy using MeNO2 standard

4.2.2 Oxidant Screen An oxidant screen was carried out with a wide selection of available Fe(III) salts (Table 6).

This screen demonstrated that FeCl3 was the most effective oxidant tested (Entry 1) and use of a >99.9% Fe sample made the reaction marginally better, suggesting that iron is indeed responsible for the reaction, rather than the presence of an impurity (Entry 2).43 The use of the hydrate of FeCl3 only gave a small amount of product (Entry 3). A similar, brominated product 144 was observed using FeBr3, although it was isolated in lower yield (Entry 4).

Table 6 Oxidant screen for Fe(III)-mediated reaction with octene

Entry Oxidant 91b (%)a 99 (%)a

1 FeCl3 9 36

2 FeCl3 (>99.9% Fe) 15 42

3 FeCl3.6H2O 87 4 b 4 FeBr3 36 22

5 FeF3 95 -

6 Fe(acac)3 91 -

7 Fe(NO3)3.9H2O 99 -

8 Fe(OTf)3 1 -

9 FePO4.2H2O 88 -

10 Fe2(SO4)3.2H2O 97 -

11 Fe(ClO4)3.H2O 88 -

12 Fe2(C2O4)3.6H2O 90 -

13 Fe2O3 96 -

14 K3[Fe(CN)6] 99 -

15 Na2[Fe(CN)5NO] 99 - 16 Sodium Ferric EDTA 97 - Tetraphenylporphyrin 17 98 - Iron(III) chloride 18 Ferric Citrate 99 -

19 Ferrocenium BF4 98 - 20 Ammonium Ferric Chloride 99 - 21 Ammonium Ferric Sulfate 99 - 22 Fe(s) 90 -

23 Cu(OTf)2 95 - a 1 b Using H NMR spectroscopy using MeNO2 standard X = Br

All other Fe(III) salts tested returned solely starting material (Entries 5-22), with the exception of Fe(OTf)3 (Entry 8). Although there was very little starting material left in this reaction, no other products were obtained. Fe(OTf)3 is known to be a strong Lewis acid and so may have promoted side reactions leading to loss of material.123 This may indicate that the poor mass balance observed in previous experiments could be due to a process where FeCl3 is behaving as a Lewis acid. The problem may also have been due to the acidity of the system; Fe(OTf)3 would lead to formation of triflic acid and thus a strongly acidic medium. Interestingly, Cu(OTf)2, which gave some reaction with allyl TMS, failed to give any of the desired product of cross-coupling (Entry 23).

4.2.3 Investigation of Bases and Additives As it was hypothesised that the acidity of the reaction medium may play a role in the amount of degradation observed, the addition of a base to the reaction was investigated (Table 7). The use of KOH appeared to slow the reaction down slightly and gave a lower yield of 99a (Entry 1). K2CO3 and Cs2CO3 did not especially affect the reaction and similar yields as had been seen previously were observed (Entries 2 and 3). These reactions did improve the mass balance however, supporting the concept that the acidity of the reaction was important. It was also thought that addition of base to the reaction mixture may lead to elimination of HCl from 99a to give an alkene in a Heck-like transformation; however no alkene products were observed in these reactions.124 Interestingly, the use of organic bases, such as Et3N and 3,5-di-t-butylpyridine, halted the reaction and led to 99a not being observed (Entries 4 and 5). This is likely due to the bases interacting with iron, resulting in the desired reaction being inhibited. As shown in Section 1, ligands are commonly used in conjunction with iron to tune its reactivity and selectivity.2 The addition of bases seemed to show that the reaction can be affected by the presence of co-ordinating species and so some commonly used additives were also screened (Entries 6-10). These included a range of nitrogen and phosphorus ligands but unfortunately the formation of 99a was not observed.

Table 7 Addition of base to reaction mixture

Entry Additive 91b (%)a 99a (%)a 1 KOH 41 22

2 K2CO3 31 37

3 Cs2CO3 25 33

4 Et3N 82 - 5 DTBPy 83 - 6 TMEDA 93 - 7 1,10-phenanthroline 90 - 8 2,2’-bipyridine 92 -

9 PPh3 92 - 10 S-BINAP 90 - a 1 Determined by H NMR spectroscopy using MeNO2 standard 4.2.4 Further Optimisation Studies The effects of reaction time, atmosphere, stoichiometry and concentration were investigated (Table 8). When the reaction was run under an inert atmosphere, the process appeared to improve slightly after an extended reaction time (Entry 2). Interestingly, the coupling appeared to perform better under an oxygen atmosphere (Entry 3) and was just as successful under air (Entry 4). Future experiments were thus performed open to air to simplify the procedure. The results for entries 3 and 4 were similar to Entry 2, potentially suggesting that running the reaction under air in some way increases the reaction rate (vide infra).

The effects of differing amounts of octene and FeCl3 with respect to 91b were also investigated. Decreasing the equivalents of alkene from 10 to 5 did not affect the reaction greatly (Entry 5) and further decreases gave gradually lower yields (Entries 6-9). Leaving the reaction for longer seemed to give lower yields and mass balance, suggesting in situ degradation may occur (Entry 10). A larger amount of FeCl3 did not appear to increase the yield greatly and merely led to less starting material being recovered (Entry 11). However, decreasing the amount of FeCl3 present in the reaction led to noticeable decreases in yield (Entries 12 and 13). It was previously thought that oxygen may be reoxidising iron,

75 resulting in more Fe(III) being available and thus the higher yields obtained in the presence of O2. However this does not seem to be the case as running the reaction for longer with a small amount of FeCl3 did not lead to a change in yield (Entry 14).

Table 8 Effect of changing various parameters on the reaction

Entry Reaction Atmosphere 98 FeCl3 Conc. T 91b 99a Time (h) (eq.) (eq.) (M) (°C) (%)a (%)a

1 1.5 N2 10 2.2 0.1 rt 9 36

2 16 N2 10 2.2 0.1 rt 10 45

3 1.5 O2 10 2.2 0.1 rt 12 47 4 1.5 Air 10 2.2 0.1 rt 12 49 5 1.5 Air 5 2.2 0.1 rt 15 45 6 1.5 Air 4 2.2 0.1 rt 19 40 7 1.5 Air 3 2.2 0.1 rt 16 39 8 1.5 Air 2 2.2 0.1 rt 19 37 9 1.5 Air 1 2.2 0.1 rt 17 35 10 16 Air 1 2.2 0.1 rt 8 30 11 1.5 Air 10 4.4 0.1 rt 2 51 12 1.5 Air 10 1 0.1 rt 52 25 13 1.5 Air 10 0.1 0.1 rt 91 2 14 16 Air 10 0.1 0.1 rt 89 3 15 1.5 Air 10 2.2 0.01 rt 17 45 16 1.5 Air 10 2.2 1 rt 5 48 17 1.5 Air 10 2.2 0.1 60 11 50 18 1.5 Air 10 2.2 0.1 0 26 43 a 1 b Using H NMR spectroscopy using MeNO2 standard In DCE

It appeared that concentration did not have a dramatic effect on the reaction; increasing the concentration to 1 M gave a similar yield to running the reaction at 0.1 M, however the amount of starting material present following the reaction was lower (Entries 15 and 16). Heating the reaction to 60 °C led to a similar yield as observed at ambient temperature (Entry 17), while performing the reaction at 0 °C gave a slightly lower yield (Entry 18).

4.2.5 Controlled Addition of Reagents

As the reaction was suffering from poor mass recovery, it was hoped that changing the addition rate of oxidant/starting material would rectify this issue (Table 9). It was thought that slow addition of both FeCl3 and 91b to octene may prevent breakdown of the proposed radical cation due to lack of a large excess of oxidant at any one time and the presence of 125 large amounts of alkene. As FeCl3 was not soluble in CH2Cl2, a solution of the oxidant in MeNO2 was required to allow the slow addition to be carried out. As shown previously, the two-solvent system should not greatly affect the potential yield (Section 4.2.1). Pleasingly, this protocol indeed provided much improved mass recoveries (Entries 1 and 2). The use of 5 equivalents of octene, as well as quenching the reaction immediately following addition, led to lower yields (Entries 3 and 4). Increasing the addition time to 1.5 h improved the reaction (Entry 5), yet an addition time of 3 h did not lead to further enhancement (Entry 6).

It was predicted that addition of greater amounts of FeCl3 to the reaction mixture would improve the yield, since a large amount of 91b now remained unreacted. This hypothesis was proven true upon addition of 4 equivalents FeCl3 using the same procedure, which gave an optimal yield of 70% by 1H NMR spectroscopy (Entry 8).

It appeared that addition of FeCl3 to a solution of both 91b and octene gave a slightly decreased yield, but offered a much simpler reaction procedure (Entry 9). Increasing the addition time using this protocol had no effect on the observed yield (Entry 10) and performing the addition at 0 ⁰C did not change the yield to any significant degree (Entry

11). Additionally, slow mixing of two solutions, one containing FeCl3, the other containing 91b and 1-octene, gave a similar yield (Entry 12).

Table 9 Changing the addition rate of reagents

Entry Addition Addition Time 98 91b (%)a 99a (%)a Time Time before (eq.)

FeCl3 (h) 91b (h) quench (h) 1 0.75 0.75 1 10 33 47 2 1 1 1 10 38 54 3 1 1 1 5 39 42 4 1 1 - 10 57 31 5 1.5 1.5 - 10 51 41 6 3 3 - 10 44 38 7 1 - 1 10 34 42 8b 1 1 1 10 6 70 9b 1 - 1 5 5 64 10b 2 - 1 5 2 65 11b, c 1 - 1 5 8 64 12b, d 1 1 1 5 8 61 a 1 b c Determined by H NMR spectroscopy using MeNO2 standard 4 eq. FeCl3 Addition at 0 ⁰C d Octene in solution with 91b

4.3 Substrate Scope

4.3.1 Variation of Alkene Coupling Partners With optimal conditions in hand, the substrate scope was investigated, beginning with the variation of the terminal alkene coupling partner (Scheme 72). The reaction was shown to proceed in the presence of a number of functional groups, such as Br, I, Cl, NO2 and aryl moieties, with all products obtained in good to moderate yields. The reaction also appeared to be largely affected by sterics, as reaction with 4-methyl-1-hexene gave a noticeably reduced yield of 99d compared to the reaction with 1-hexene to give 99b (46% and 65% respectively). Such a reduction in yield was somewhat surprising due to the methyl group being far from the terminal position of the alkene, where coupling took place. Unsurprisingly, this reaction also yielded a 1:1 mixture of diastereomers.

Scheme 72 Variation of the alkene coupling partner Interestingly the reaction of 1,6-heptadiene 145a solely returned the linear product of mono-coupling 99c, which itself contained a terminal alkene moiety. It was thought that this product may further react, however no sign of this was observed. It was also hypothesised that this reaction may give a cyclised product 146 through a 5-exo-trig cyclisation of the proposed radical intermediate II (Scheme 73).126,127 The lack of cyclised product suggested that oxidation of II was faster than 5-exo-trig cyclisation under the reaction conditions (k = 2.3 × 105 s-1).128 Alternatively, the radical may be bound to iron, thereby affecting the proposed cyclisation (vide infra).

Scheme 73 Proposed 5-exo-trig cyclisation of 1,6-heptadiene intermediate In an attempt to make cyclisation in the above system more facile, heptadienes containing a quaternary centre were synthesised and exposed to the reaction conditions (Scheme 74).129

Scheme 74 Reaction of more substituted dienes Surprisingly the use of such alkenes led to neither the cyclised nor the linear, chlorinated products and instead gave allylbenzene compounds 147a and 147b in low yields. Only trace amounts of the expected chlorinated products were observed. It is uncertain how these compounds were formed and whether this was due to elimination of HCl from the chlorinated products 99 or an intermediate in the reaction pathway reacting in a different manner due to the increased steric demand of the alkenes being used. The absence of the conjugated alkene may suggest that elimination from the chlorinated compounds was not occurring as it would need to selectively give the non-conjugated product (see Section 4.6

80 for the expected product distribution of elimination). It is possible that the allyl benzene products 147 arise from a carbocation intermediate by loss of a proton, due to steric blocking of the attack by chloride (vide infra). Interestingly, similar products were reported by Yu et al. when 1-hexene was exposed to the oxidative Heck conditions discussed in Section 3.1 (Scheme 53). This reaction selectively returned the non-conjugated alkene, which was proposed to be due to the intermediate being restricted from undergoing β-H elimination with the benzylic hydrogen atoms due to its conformation.90 It is possible that the bulky substituents in the current iron system enforce a conformation in which this elimination to form the non-conjugated alkene is facile, encouraging formation of these products. A more simple hindered alkene, 4,4-dimethyl-1-pentene 126, was reacted to determine whether a similar product would be formed (Scheme 75). Indeed, the allylbenzene product 147c was isolated in comparable yields to those obtained in the previous reactions. This further demonstrated the strong effect steric hindrance has upon the reaction.

Scheme 75 Reaction of 4,4-dimethyl-1-pentene A number of other unsaturated compounds were tested under the reaction conditions, but failed to undergo the desired coupling reaction (Fig. 3). Reaction of all of the alkenes listed resulted in little sign of the desired products and merely returned varying amounts of unreacted starting material. It was thought that the unprotected alcohol in 148 may be able to co-ordinate to Fe and thus disrupt the reaction; however the TBS-protected alcohol 149 did not fare any better. Moreover, the use of a ketone 150 or an ester 151 also failed to provide the coupled products. Disubstituted alkenes 154 - 156 also did not react successfully, perhaps unsurprising due to the marked steric effect observed in previous studies. Also, the lack of reactivity of styrene

108 may be due to FeCl3 reacting with the alkene partner, possibly leading to polymerisation or other side reactions independent of the sulfide.130 Finally, other unsaturated systems, such as conjugated diene 158, allene 161 and terminal and internal alkynes, 162 and 163 respectively, failed to show signs of cross-coupling.

Figure 3 Unsuccessful coupling partners 4.3.2 Variation of Arene Coupling Partners The scope of the process with regard to the aryl sulfide partner 91 was then investigated (Scheme 76). The reaction proved to be particularly sensitive to substitution in the aryl ring participating in coupling, with successful reaction only being observed when a 3,5-OR substitution was present (vide infra, Fig. 5). Despite this, a large amount of variation is possible in the spectator ring and Me, Br, F, OMe, NO2 and CF3 groups were tolerated in various ring positions (164a-h). It was also shown that variation of the methyl ether groups was compatible with the cross-coupling (164i and 164j). All of these examples gave good to moderate yields.

Scheme 76 Variation of arylsulfide in the cross-coupling

Sulfide 164f, containing 3,5-methoxy substitution in both arenes, showed a notable drop in yield, this may indicate that the product is prone to further decomposition under the reaction conditions. It was thought that this product could further react with an equivalent of alkene as it contains a ring with the requisite substitution pattern; however the product of over-reaction 165 was not observed. 164f was separately subjected to the alkene- coupling conditions, however this only returned 70% unreacted material (by 1H NMR spectroscopy) (Scheme 77). The loss in mass suggests that some reaction with FeCl3 may be occurring, but the desired coupling was not observed.

Scheme 77 Attempted second chloroarylation reaction

Most interesting was the fact that the introduction of the electron-withdrawing groups NO2 and CF3 on the non-reacting ring resulted in higher yields of the desired products (164g and 164h respectively). It was thought that these substrates would be more difficult to oxidise, as the sulfur centre is less electron rich, meaning that the desired reaction may be more difficult to carry out. To probe this, competition experiments were carried out between the standard substrate 91b and the nitro-substituted sulfide 91d in the presence of limiting FeCl3 (Scheme 78).

Scheme 78 Competition experiment between 91b and 91d This competition experiment led to selective formation of 99a, with no 164g being observed. This result illustrated that the rate of reaction of the more electron-deficient sulfides was indeed slower as previously predicted. A competition study was also carried out between 91b and the CF3-substituted sulfide 91e to determine whether an inductively withdrawing group (CF3) performed differently to the mesomerically withdrawing NO2; however the results were similar, suggesting the effect of these two groups on the reaction were comparable (Scheme 79).

Scheme 79 Competition experiment between 91b and 91e The increased yields from reacting these substrates under standard conditions may be rationalised by the slow rate of substrate oxidation preventing the build-up of larger concentrations of radical cation intermediate. This may disfavour destructive side reactions that lead to decomposition of these intermediates and lower mass balances. This is consistent with the previous observation that slow addition of FeCl3 to the aryl sulfide and alkene gave higher yields and mass balances.

4.3.3 Use of Other Aryl Sulfides

A range of other aryl systems was tested under the reaction conditions (Fig. 5). As mentioned previously, the reaction was particularly sensitive to substitution in the reacting aryl ring and the use of sulfides containing a single methoxy group (91c, f and g) resulted in no product formation. It was initially postulated that the absence of the second methoxy group causes the compound to be less electron-rich and thus more difficult to oxidise, however loss of material was still observed and low mass balances were obtained, suggesting oxidation and decomposition were occurring. Switching to a 3,4-methoxy substitution pattern (91h) did not lead to successful reaction, showing that substitution on the meta positions was important, yet using a 3,4,5-trisubstitued system (91i) also failed to give the desired products. This suggested that having a substituent para to sulfur interrupted the standard reaction pathway and led to the formation of undesired products/decomposition of intermediates. This was also demonstrated by introducing a para-electron-donating group (OMe 91j and SMe 91k) on the spectator ring, while still maintaining the 3,5-methoxy pattern on the reacting ring. Note that previously the use of electron-withdrawing substituents in this position increased the yield of the reaction (Section 4.3.2). Intriguingly, the use of these donating groups had the opposite effect and no products were observed. A possible explanation for this effect is that the corresponding radical cation intermediate can be considered a quinone-type species (Fig. 4).131 This

85 species is thus stabilised and likely unable to carry out the anticipated reaction and may decompose in situ or be hydrolysed upon workup. No evidence of by-products from such species was observed in these reactions, with only starting material being observed.

Figure 4 Proposed thioquinone-type radical cation intermediate As it was thought that the electronics of the sulfur centre may be responsible for the lack of reactivity of the mono-methoxy compounds, bis(3-methoxyphenyl)sulfide (91l) was synthesised. Nevertheless, this sulfide also showed no reactivity under our standard Fe(III) conditions. Thus, in keeping the 3,5-substitution pattern, the use of other groups in these positions was investigated, however it appeared that changing even one of the methoxy groups to Me (91o) resulted in an unsuccessful reaction. It is possible that the presence of methyl groups provides new pathways for decomposition of the radical cation intermediate. Notably, a methyl group was present in 164a (Section 4.3.2) and gave the desired cross-coupled product (albeit in slightly lower yield than the compound without Me). Using a naphthyl (91p) or thiophene group (91u) as the reacting ring was also unsuccessful. Introducing other substituents onto the ring whilst maintaining the 3,5-methoxy pattern, such as NO2 (91q-r) and Me (91s), also hindered the reaction; as did the use of other sulfur groups such as t-BuS (91t) or a sulfone (166). Finally, the use of other heteroatoms was investigated to determine whether the presence of SPh is in fact pivotal for the reaction.132 Trimethoxybenzene 167 was subjected to the reaction conditions, but no reaction was observed. The oxygen and nitrogen analogues of the model sulfide 168-170 were also synthesised and exposed to the standard reaction conditions, however they also failed to give the corresponding products. This appears to indicate that sulfur is indeed vital to the cross-coupling reaction. The attempted reactions of all of these compounds (except for 169, which contains a free NH) showed poor mass balances, suggesting that oxidation may be occurring. This may further indicate that sulfur

86 plays an important part in the actual coupling step and may support its role as a directing group for Fe.100

Figure 5 Aromatic substrates that failed to undergo cross-coupling 4.4 Mechanistic Studies

4.4.1 Proposed Mechanism The proposed reaction mechanism is similar to that shown earlier for the allylation reaction using allyl TMS as the nucleophile (Scheme 80). The reaction is initiated by single electron oxidation of the aryl sulfide by Fe(III) to a radical cation species I, which can then be intercepted by the terminal alkene to give another radical cation II. Following rearomatisation, this then provides a radical III that can be further oxidised to a cationic species IV by another equivalent of Fe(III). Quenching of IV with Cl− then leads to the desired product 99. It is possible that conversion of the radical species to the chloride may

87 occur in a concerted manner, through direct quenching with FeCl3, rather than being stepwise.114

Scheme 80 Proposed mechanism for coupling of biaryl sulfides and terminal olefins This mechanism may pose a simplified version of the species present. For example, it is possible that sulfur acts as a chelating group, delivering the observed ortho-selectivity with respect to the sulfur centre (Fig. 6). As hypothesised previously (Section 4.3.1), the lack of radical cyclisation in the reaction of 1,6-heptadiene may be due to metal-bound species, such as 172, rather than discrete free radicals being present.

Figure 6 Alternative intermediate species in chloroarylation reaction Oxidative C–H couplings via an SET process have been reported previously, such as the Cu(II)-catalysed functionalisation of aryl C–H bonds reported by Yu et al. (Scheme 81).133

Scheme 81 Cu(II)-catalysed functionalisation directed by pyridyl group This process is believed to occur by coordination of the pyridyl group to Cu(II), followed by single electron oxidation of the attached aryl ring. The ortho-selectivity is proposed to be due to an intramolecular anion transfer from the resultant cuprate complex II. A second SET followed by rearomatisation then yields the desired product (Scheme 82).133,134

Scheme 82 Proposed mechanism for Cu-catalysed functionalisation of C–H bonds An iron-catalysed oxidative radical cross-coupling/cyclisation between phenols and styrenes was recently reported by Lei et al. (Scheme 83).135 This transformation appears to bear some similarity to the current chloroarylation process and a SET process is also proposed.

Scheme 83 Iron-catalysed oxidative coupling/cyclisation between phenols and styrenes It is proposed that DDQ is the single electron oxidant used to make phenoxy radical II.

Acting as a Lewis acid, FeCl3 is then proposed to form C-centred radical III, which undergoes addition/cyclisation onto the styrene. A second oxidation of the resultant radical species IV followed by rearomatisation then yields the observed product V (Scheme 84). It is important to note that the Lewis acid is believed to be key to this reaction. Electron paramagnetic resonance (EPR) studies could be used to track the formation/reaction of the HDDQ radical VI and found that, whilst it was formed upon reaction of the phenol and DDQ, subsequent reaction only occurred upon addition of a Lewis acid. Catalytic amounts of other Lewis Acids besides FeCl3 also yielded the same product.

Scheme 84 Proposed mechanism of cross-coupling/cyclisation Under similar conditions, a more recent publication by the same group described a related coupling using electron-rich arenes, such as trimethoxybenzene, and diarylethylenes.136

4.4.2 Cyclic Voltammetry Cyclic voltammetry (CV) was used to measure the oxidation potentials of (3,5- dimethoxyphenyl)(phenyl)sulfide 91b and (3-methoxyphenyl)(phenyl)sulfide 91g and so establish the feasibility of their oxidation using FeCl3 (Fig. 7).

Figure 7 Voltammogram for sulfides vs reference electrode These studies determined that the oxidation potential of 91b [+1.71 V (vs SHE) in MeCN] is compatible with the previously proposed mechanism. FeCl3 is a very strong oxidant in non-aqueous media [~+2.00 V (vs SHE) in MeCN]137 and so has the ability to oxidise 91b 137 to the radical cation. This also indicates why FeCl3.6H2O [~+1.50 V (vs SHE) in MeCN] is unable to carry out the reaction (see Table 6). Notably, the oxidation potential of simple terminal alkenes is generally much greater than +2.00 V, meaning oxidation of this partner to the radical cation is unlikely.138 Interestingly, the oxidation potential of 91g [+1.72 (vs SHE) in MeCN] was found to be similar to that of 91b. It was previously thought that the failure of this substrate to undergo the desired reaction may be due to the decreased electron density resulting in a higher oxidation potential, thus making it unreactive (Section 4.3.3). However, the similar oxidation potential does not support this theory. Notably, a low mass balance was obtained upon attempts to react this substrate, suggesting that FeCl3 was indeed oxidising the aryl sulfide, yet the issue may have been the coupling step itself. Therefore, the oxidation potential does not appear to be the key to understanding the scope of this reaction. It is possible that the radical cation formed from 91g is significantly more reactive than that derived from the standard substrate 91b and the rate of decomposition is higher than that of

90 coupling. The 3,5-dimethoxy pattern currently required may be stabilising this intermediate by both steric and electronic effects, thus slowing the rate of decomposition and allowing the coupling step to occur.

4.4.3 Solvent Investigations As the reaction appeared to give higher yields in chlorinated solvents, studies were carried out to determine whether the chlorine in the product came from FeCl3 or the solvent 139 itself. The coupling reaction was carried out in CH2Br2 to determine whether halogen exchange is possible, however this reaction gave a similar yield of chlorinated product 99a compared to standard conditions when using CH2Cl2 solvent (Scheme 85). Also, upon using FeBr3 as the oxidant with CH2Cl2, only the brominated product 144 was observed (Table 6). Thus the ligand on the Fe centre is incorporated into the observed products, suggesting a redox process may be occurring and also possibly indicating a close interaction between iron and the carbon centre that is halogenated.

Scheme 85 Use of brominated solvent to investigate halide incorporation 4.4.4 Use of Other Oxidants The proposed mechanism was also indirectly supported when it was found that the analogous reaction can be carried out using ceric ammonium nitrate (CAN), another commonly used powerful single electron oxidant (Scheme 86). As expected from previous results, this reaction gave the nitrated product 178a in good yield. CAN commonly undergoes SET processes and so formation of a similar product to that observed with FeCl3 suggests a similar process may be in action for the chlorination also.140 Indeed, CAN has also been shown to oxidise biaryl sulfides to their corresponding sulfoxides through the same radical cation intermediate proposed in the current investigation.141

Scheme 86 Reaction of biaryl sulfide and octene with CAN

After the discovery of this CAN-mediated reaction a brief investigation was carried out to determine whether the yield could be improved (Table 10). Interestingly, no product was observed when using CH2Cl2 as a solvent (Entry 1). A reduced yield was observed with 142 MeNO2 (Entry 2) and no product was formed in H2O (Entry 3). Intriguingly, the reaction worked well in EtOH (a commonly used solvent in CAN-mediated reactions)143 to give the nitrated product 178a in good yield (Entry 4). It may be expected that the nucleophilic solvent could intercept some of the proposed intermediates, however no other products were observed.116 This may indicate that the reaction does not proceed through the proposed carbocation. Alternatively, it may suggest that an inner sphere electron transfer is occurring, with the ligand being transferred from the metal during the oxidation step and resulting in the observed products.144,145 Increasing the reaction time in EtOH or MeCN did not improve the reaction greatly (Entries 5 and 7 respectively).

Similar to the FeCl3-mediated reaction, decreasing the amount of oxidant lowers the yield accordingly (Entries 8 and 9). Interestingly, the reaction proceeded to the same degree under an N2 atmosphere as it did in air (Entry 10), in contrast to results observed for the chloroarylation reaction (Section 4.2.4), and decreasing the concentration greatly lowered the observed yield (Entry 11). The mass balance of this reaction was almost quantitative, possibly indicating that the coupling was very favourable, the rate of sulfide oxidation was decreased or that the radical cation was less reactive and the SET reversible under these conditions. The discrepancy in concentration effects may be due to this system being homogeneous, whilst the FeCl3 mixture in CH2Cl2/MeNO2 is heterogeneous. Therefore, the actual concentration of dissolved oxidant may not vary much in the FeCl3 system, leading to the consistent results obtained during those screening studies (Section 4.2.4). Unfortunately, slow addition of CAN over 1 h to the reaction mixture had little effect on the yield (Entry 12).

Other Ce(IV) reagents were tested to determine if the SO4 moiety would be installed at the homobenzylic position to give 178b, however no reaction was observed using

(NH4)4.Ce(SO4)4 or Ce(SO4)2 (Entries 13 and 14). The oxidation potential of ceric ammonium sulfate (CAS) is reported to be lower than CAN [CAS Eo +1.44 V (vs NHE) in o 1 N H2SO4 vs CAN E +1.61 V (vs NHE) in 1 N HNO3] and so appears unable to oxidise the arene partner.146 Of course these potential values are in aqueous systems and so the exact values will be different in MeCN solution. This result further supports the proposal that a SET process is occurring as powerful oxidising agents are required for the reaction to proceed. 92

Table 10 Screen of Ce(IV) reagents/conditions for an analogous cross-coupling

Entry Solvent x Time Atmosphere Conc. Oxidant 91b 178 (eq.) (h) (M) (%)a (%)a

1 CH2Cl2 2.2 2 Air 0.1 CAN 99 -

2 MeNO2 2.2 2 Air 0.1 CAN 6 25

3 H2O 2.2 2 Air 0.1 CAN 99 - 4 EtOH 2.2 2 Air 0.1 CAN 21 50 5 EtOH 2.2 16 Air 0.1 CAN 25 55 6 MeCN 2.2 2 Air 0.1 CAN 10 62 7 MeCN 2.2 5 Air 0.1 CAN 8 64 8 MeCN 1 2 Air 0.1 CAN 61 35 9 MeCN 0.1 2 Air 0.1 CAN 96 -

10 MeCN 2.2 2 N2 0.1 CAN 10 60 11 MeCN 2.2 2 Air 0.01 CAN 70 27 12b MeCN 2.2 2 Air 0.1 CAN 8 66

13 MeCN 2.2 2 Air 0.1 CAS 99 -

14 MeCN 2.2 2 Air 0.1 Ce(SO4)2 99 - a 1 b Yield by H NMR spectroscopy using MeNO2 standard Solution of CAN in MeCN charged over 1 h

4.4.5 Electron Paramagnetic Resonance EPR studies were found to be useful in probing the mechanism of Lei’s reaction (Section 4.4.1).135 It was thus thought that similar studies could be carried out on the current system to determine if the proposed radical species could be observed. When carrying out these studies, a broad signal was observed, however this appeared to originate from Fe(III) and not an organic radical. Therefore, EPR studies were inconclusive, as this signal would block observation of the desired radical. Attempts to reduce the amount of Fe(III) present to minimise this signal would also reduce the amount of radical that may be formed. Further investigations would be required to determine whether any of these limitations can be overcome. Another possibility would be to study the CAN reaction system, as the same mechanism is believed to be occurring. Ce3+ is paramagnetic and so can be observed using EPR;

93 observation of these signals would suggest a redox process is occurring and support the hypothesis of a SET mechanism.147

4.4.6 Alternative Mechanisms

FeCl3 is a commonly used Lewis acid and so an alternate mechanistic proposal may invoke iron adopting this role. The initial reason for the proposal of a radical mechanism came from the observed regioselectivity of the alkene coupling, in that solely the linear (Anti- Markovnikov) product was observed, with no sign of the corresponding branched product.115 The Markovnikov product would be expected if a more standard Lewis acidic mechanism was occurring, as demonstrated by Beller et al. for the Fe-catalysed hydroarylation of styrenes to selectively give the corresponding 1,1-diarylmethanes 180 (Scheme 87).148

Scheme 87 Fe-catalysed hydroarylation of styrenes This reaction was proposed to occur via an electrophilic aromatic substitution pathway, in which FeCl3 is behaving as a Lewis acid to activate the double bond for attack by the aromatic partner. Notably, in this literature example the same product was observed upon use of other Lewis acids, such as Sc(OTf)3. To ensure that this pathway was not playing a role in the current reaction, FeCl3 was replaced by other commonly used Lewis acids

(Table 11). The results from this investigation are consistent with FeCl3 playing a different role in the current reaction as there was no evidence of the desired coupling occurring.

Table 11 Screen of Lewis acids Lewis Acid 91b (%)a 99 (%)a

InCl3 96 -

Sc(OTf)3 98 -

BF3·Et2O 98 -

In(OTf3) 97 -

CeCl3 99 - a 1 Determined by H NMR spectroscopy using MeNO2 standard An alternative approach to viewing the coupling may involve electrophilic metalation of the aryl sulfide, followed by carbometalation of the alkene (Scheme 88).149

Scheme 88 Alternative electrophilic metalation/carbometalation reaction The selectivity of the electrophilic metalation could be explained by Fe-S coordination leading to directed attack ortho to sulfur, which would also justify the requirement of a strongly electron rich compound. The use of a hindered aryl sulfide may account for the regioselectivity of the addition to the double bond, with the hindered aryl adding to the terminal position. Finally, the transfer of the metal-centred ligand into the product would also be explained by the reductive elimination in the final step. It is difficult to account for the poor mass balance obtained in the chloroarylation reactions by invoking this mechanism. Potentially, the aryl sulfide may remain bound to the iron centre and be lost upon workup. However, 2,2’-bipyridine is added as part of the workup procedure, which should displace any Fe-bound product that may be present; performing a

95 workup without 2,2’-bipyridine has little effect on the mass recovery, suggesting this may not be the problem.

If this mechanism were in operation, only 1 equivalent of FeCl3 should be needed; however an excess is currently required. It may also suggest a catalytic reaction would be feasible if the formed Fe(I) can be reoxidised following reaction. It should be noted that this mechanism can be viewed as an extreme of the SET process suggested earlier; rather than the free radical species previously proposed, this mechanism suggests the presence of formal C–M bonds (vide supra).

4.5 Towards a Catalytic Process

4.5.1 Iron Catalysis The adoption of a slow addition process seemed key to the optimisation of the Fe-mediated reaction by reducing the concentration of reactive intermediates. A similar effect may be observed if a catalytic protocol could be developed, as it would also lead to a slow generation of radicals if successful. Thus, preliminary investigations were conducted to determine whether the reaction could be carried out with substoichiometric amounts of iron (Table 12). Standard oxidants utilised in the literature were tested (see Section 1); however it was found that the desired product 99a was not obtained in any notable yield.150 The oxidants of particular interest were DCE and 1,2-dichloroisobutane, as these could play a dual role as oxidant and chlorine source; unfortunately their use does not appear to aid a catalytic process (Entries 1-3). A reduction in the amount of starting material was observed using TBHP (Entry 5). It was thought the small amount of 99a observed may be due to lack of Cl− following the first cycle. However, repeating the reaction with an external chloride source did not increase the amount of product (Entry 6).

It has also been demonstrated that NaNO2 can be used to turnover an Fe-TEMPO species; however no products were observed using catalytic amounts of FeCl3/TEMPO/NaNO2 (Entries 16 and 17).151 As TEMPO can be used as a radical trap, a control was carried out with stoichiometric iron and showed that no reaction occurred with this additive in the reaction system, forgoing the possibility of a catalytic system with these reagents (Entry 18).

Table 12 Attempts to perform the reaction with catalytic amounts of FeCl3

Entry x (mol %) Oxidant 91b (%)a 99a (%)a

1 10 DCE 85 4 b 2 10 DCE 84 3 3 10 1,2-dichloroisobutane 85 4

4 10 O2 87 2 5 10 TBHP 59 2 6c 10 TBHP 42 1 7b 10 TBHP 10 - 8 10 DTBP 94 - 9 - DDQ 90 - 10 10 DDQ 92 - 11b 10 DDQ 85 - 12b, c 10 DDQ 89 -

13 - K2S2O8 93 -

14 10 K2S2O8 85 - b 15 10 K2S2O8 84 -

16 10 NaNO2/TEMPO 95 -

17 10 NaNO2 96 - 18 220 TEMPO 82 - a 1 b c Determined by H NMR spectroscopy using MeNO2 standard Reflux in DCE With 2.2 eq. LiCl

4.5.2 Photoredox Catalysis Photoredox catalysis is a powerful tool that can give access to reactive organic radical species and has garnered much attention recently.152 Accordingly, it was proposed that the desired radical cation species could be accessed using this methodology. Standard oxidative and reductive quenching cycles are shown in Scheme 89. The cycle begins by photoexcitation of the photocatalyst (PC) using visible light to give an excited state (PC*). The excited state is a stronger oxidant and/or reductant than the ground state and so can either lose or accept an electron from another compound present (common quenchers are shown in Scheme 89). The oxidised/reduced forms of the catalyst (PC+ and PC− respectively) are generally powerful reductants/oxidants themselves and so a further

SET returns the ground state catalyst, which can again undergo photoexcitation and repeat the cycle.153

Scheme 89 Standard photoredox catalysis cycle A photocatalytic cycle to perform a similar reaction to that previously investigated would require one of two scenarios:

1. The excited state of the photocatalyst (PC*) is strong enough to oxidise the arene partner to the radical cation species (i.e. the arene is a reductive quencher). This would then require an oxidant to return the reduced form of the catalyst back to the ground state. 2. An oxidative quencher is required to give the oxidised form of the photocatalyst (PC+). This is then strong enough to oxidise the arene partner to give the radical cation and ground state catalyst.

An initial screen of a range of common photoredox catalysts was carried out to probe the feasibility of this process (Table 13). These reactions were carried out in air, with O2 viewed as the oxidant for the photocatalyst; however only unreacted starting material was obtained.154

Table 13 Initial photocatalyst screen

Entry Catalyst 91b (%)a 99 (%)a

1 Ru(bpy)3Cl2 88 -

2 Ru(bpz)3(PF6)2 99 -

3 [Ir(dtbbpy)(py)2]PF6 89 -

4 [Co(bpy)3](PF6)2 94 -

5 Fe(bpy)3Cl2 97 -

6 Ir(ppy)3 91 -

7 [Ir{dF(CF3)ppy}2(dtbbpy)]PF6 94 -

8 Cu(dap)2Cl 91 - 9-mesityl-10- 9 93 - methylacridinium perchlorate 10 Eosin Y 94 - 11 Rose Bengal 89 - 12 Fluorescin 91 - 13 Methylene Blue Hydrate 89 - a 1 Yield by H NMR spectroscopy using MeNO2 standard

Ru(bpy)3Cl2 is the most commonly used photoredox catalyst and so a solvent screen was carried out to see if this allowed for any reactivity to be observed (Table 14).152 Unfortunately, the desired reaction did not occur in any of the solvents tested.

Table 14 Solvent screen with Ru(bpy)3Cl2

Entry Solvent 91b (%)a 99 (%)a

1 CH2Cl2 97 - 2 MeCN 88 - 3 EtOAc 99 - 4 DMF 98 -

5 MeNO2 88 - a 1 Yield by H NMR spectroscopy using MeNO2 standard

As it appeared that no reaction occurred using O2 as oxidant, reactions were carried out with common oxidative quenchers in an attempt to access the oxidised photocatalysts 153 (Table 15). These reactions were carried out under N2 and the solvent sparged to remove

O2 from the system. Fe(III) and Co(III) are common quenchers in oxidative processes but no coupling was observed in these reactions. Viologens are also well-known electron acceptors but did not promote reaction.153 Notably octyl viologen was not soluble in MeCN and so a different solvent was utilised.155 A closer look at electron potentials suggests that many of the photoredox catalysts tested IV III are simply not strong enough oxidants to produce the desired radical cations. E1/2 (Ir /Ir ) for [Ir{dF(CF3)ppy}2(dtbbpy)]PF6 is reported as +1.69 V, which is similar to the biaryl sulfide tested previously (+1.71 V). This may suggest that reaction is possible under the right conditions, however further screening and quenching studies would be required to investigate this.152

Another potential candidate for the photoredox process would be Ru(bpz)3(PF6)2 as this III II 152 also has a high E1/2 (Ru /Ru ) of +1.89 V. This system should therefore be strong enough to carry out the desired oxidation; however attempts to use this catalyst bore no success, which may be due to a failure to access the oxidised form of the catalyst. The II I excited state is also very oxidising (E1/2 (Ru */Ru ) = +1.42 V) and so reduction of the catalyst is a favourable side reaction that may hinder the desired reactivity.152

100

Table 15 Investigation of oxidative quenchers towards a photocatalytic process

Entry Catalyst Solvent Quencher 91b 99 (%)a (%)a

1 Ru(bpy)3Cl2 MeCN - 92 -

2 Ru(bpy)3Cl2 MeCN Fe(acac)3 91 -

3 Ru(bpy)3Cl2 MeCN Co(acac)3 85 -

4 Ru(bpy)3Cl2 MeCN Methyl viologen 93 -

5 Ru(bpy)3Cl2 EtOAc Octyl viologen 89 -

6 Ru(bpy)3Cl2 EtOAc/H2O Octyl viologen 94 - Ru(bpz) (PF ) MeCN - 99 - 7 3 6 2 Ru(bpz) (PF ) MeCN Fe(acac) 98 - 8 3 6 2 3

9 Ru(bpz)3(PF6)2 MeCN Co(acac)3 99 -

10 Ir(ppy)3 MeCN - 95 -

11 Ir(ppy)3 MeCN Fe(acac)3 93 -

12 Ir(ppy)3 MeCN Co(acac)3 86 -

13 [Ir{dF(CF3)ppy}2(dtbbpy)]PF6 MeCN - 97 -

14 [Ir{dF(CF3)ppy}2(dtbpby)]PF6 MeCN Fe(acac)3 98 - a 1 Yield by H NMR spectroscopy using MeNO2 standard

From these initial screens, it appears that a photocatalytic route to the desired cross- coupled products is not feasible, however further investigations may be required before coming to a definitive conclusion.

4.6 Product Manipulation The chlorinated products of the Fe(III)-mediated reaction are of synthetic interest, as there are a range of functionalities present that can be utilised as handles for subsequent manipulation. Further reactions of the products were thus investigated. The organosulfanyl group can be exploited in a variety of reactions via access to different oxidation levels.71 It was demonstrated that the corresponding sulfone 181 could be easily synthesised in excellent yield through meta-chloroperoxybenzoic acid (mCPBA) oxidation of 99a (Scheme 90).156

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Scheme 90 mCPBA oxidation to the sulfone Desulfurisation could also be carried out using excess Raney nickel (Scheme 91).157 Notably this also led to formation of the additionally dechlorinated product 183. This reaction was carried out by Miles Aukland.

Scheme 91 Desulfurisation of products using Raney Ni As the Fe-mediated reaction is currently limited to sulfides with a 3,5-dioxygenation pattern, reactions that could take advantage of such structures were investigated. Pleasingly, ortho-directed metalation was found to be highly efficient and allowed selective functionalisation para to sulfur by varying the electrophilic quench to give 184a-c (Scheme 92).158

Scheme 92 ortho-Directed metalation using various quenches It was thought that the β-chlorine may pose issues in this reaction, as lateral metalation may occur to give the benzylic lithium species, which can eliminate Cl−, giving the corresponding styrene.159 Fortunately no sign of elimination was observed, showing that lateral metalation is not facile. Since the elimination products would formally be the outcome of an oxidative Heck reaction (see section 3.1), they were deemed of interest.

102

Therefore, the use of other bases to promote elimination was investigated; DBU, LDA and KOt-Bu all returned starting material. Pleasingly, it was found that refluxing the compound in EtOH with NaOEt successfully led to elimination to give the corresponding styrene as the major product 185 (Scheme 93).124

Scheme 93 Elimination to give conjugated and non-conjugated alkenes It was thought that elimination from the benzylic position should give the most thermodynamically stable product 185; therefore formation of the non-conjugated isomer 186 was surprising.124 This may be due to the benzylic position being more sterically hindered, which may make deprotonation more difficult. Steric bulk may also mean that styrene 185 is twisted from the plane of the aromatic ring, decreasing conjugation in the molecule as π-π delocalisation between the alkene and arene orbitals is not possible. Further manipulations of the halogen were then investigated (Scheme 94). Displacement of chloride via SN2 reaction was possible using NaN3 to give the corresponding azide 187 in 88% yield based on recovered starting material (brsm) (Scheme 94a).160 Strangely, a Finkelstein reaction to give iodide 188, which should occur via a similar mechanism, was unsuccessful and only returned unreacted starting material. This reaction is usually favourable due to formation of NaCl by-product, which is insoluble in the acetone solvent. A range of standard reaction conditions were attempted but yielded no success (Scheme 94b).161 It was also found that formation and subsequent quenching of a radical using 162 Bu3SnH/AIBN was possible to give the dechlorinated product 189 (Scheme 94c). Potentially, other radical traps may be utilised to install alternate functionalities in this position.116

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Scheme 94 Manipulation of alkyl chloride moiety in cross-coupled products 4.6.1 Formation of Dihydrobenzofuran Motifs It was hypothesised that formation of important dihydrobenzofuran species may be possible by using the oxygen moieties to cyclise and displace chloride (Scheme 95). This work was carried out in collaboration with fellow PhD student Miles Aukland.

Scheme 95 Proposed cyclisation of coupling products to form dihydrobenzofuran

104

The simplest method of carrying out this reaction would be to form a phenol via demethylation and, if cyclisation does not occur in situ, promoting the cyclisation of 190.

However, attempts to demethylate 99a using BBr3 proved unsuccessful and led to decomposition of starting material to give an inseparable mixture of products.163 It was thought that the harsh conditions generally required for demethylation may be the cause and access to the desired compound using a more mild method was investigated.

Scheme 96 Deallylation/cyclisation sequence to form dihydrobenzofuran It was decided that deallylation would be an attractive prospect as a range of procedures are available that utilise fairly mild conditions.164 Pleasingly, exposure of 164j to

Pd(PPh3)4/K2CO3 successfully triggered a deallylation/cyclisation sequence to give a moderate yield of the desired dihydrobenzofuran 191a (Scheme 96).165

Scheme 97 Pd-catalysed deallylation Morpholine is commonly used in deallylation reactions as an efficient allyl scavenger, thus acting as a good nucleophile to turn over the Pd-allyl species IV (Scheme 97).165 After screening a range of conditions it was found that the use of morpholine and either NaH or 166 NaBH4 as additives allowed for high conversion to dihydrobenzofurans (Table 16).

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Table 16 Improved conditions for deallylation/cyclisation cascade

Entry Additive Temperature Time 191b 192 (°C) (h) (%)a (%)a 1 NaH rt 18 - 89 2 NaH 60 18 90 -

3 NaBH4 rt 18 85 -

4 NaBH4 60 5 84 - a Isolated yield

By using NaH at ambient temperature, it was found that selective formation of mono- deprotected 192 occurred (Entry 1). This was somewhat surprising and suggested deallylation of the less hindered O-allyl is not as facile. This could be due to a buttressing effect from the presence of the alkyl chain forcing a conformation leading to an n-π or n-σ* interaction from the lone pair of oxygen with the phenyl ring or C–Cl bond respectively (Fig. 8).167 This may serve to weaken the O-allyl bond and make Pd-insertion easier for this group.

Figure 8 Possible n-σ* interaction It is also possible that deallylation is reversible under these conditions and, as cyclisation is only possible with one oxygen atom, this drives the reaction towards 192. However, if this was the case, it would be expected that a mixture of 191b and 192 would be obtained. Nevertheless, simply heating the reaction mixture to 60 °C for 18 h allows complete deprotection to occur to give 191b (Entry 2).

106

NaBH4 is also a common additive in Pd-catalysed deallylation reactions as it aids reduction of the Pd-allyl intermediate formed in the reaction (Scheme 97).165 Upon using these stronger deallylation conditions at room temperature, it was found that complete deprotection occurred in 18 h to give 191b (Entry 3). The reaction time was reduced to 5 h with a comparable yield of product isolated when the reaction was heated to 60 °C (Entry 4). It was found that these conditions tolerated further functionality on the alkyl chain, with the reaction proceeding in excellent yields with NO2, Br and Ph groups present (Scheme 98).

Scheme 98 Substrate scope for dihydrobenzofuran formation 4.6.1.1 Manipulation of Dihydrobenzofurans Pleasingly, the triflation of 191b was successfully carried out in high yield, opening a path for further functionalisation (Scheme 99a). Pd-catalysed sp2-couplings of the resultant triflate 193 could be carried out using standard Suzuki conditions (Scheme 99b).168 These couplings proceeded in excellent yields to give 194a-c and allowed introduction of both electron-rich and electron-deficient aromatic groups into the molecule. Copper-free Sonogashira conditions with phenylacetylene also allowed for introduction of a sp-C to give 195 in excellent yield (Scheme 99c).168 These reactions demonstrate that through the use of well-known cross-coupling methods, a range of interesting structures can be accessed from the products of Fe-mediated C–H coupling.

107

Scheme 99 Triflation and Pd-catalysed couplings of dihydrobenzofuran Standard desulfurisations of the dihydrobenzofurans using Raney Ni were also carried out to show the ease with which the sulfanyl group can be removed from these compounds (Scheme 100).

Scheme 100 Desulfurisation of dihydrobenzofurans using Raney Ni The organosulfanyl moiety can also be used for Ni-catalysed Kumada-Corriu cross- couplings (Scheme 101).72,64 These coupings all proceeded in good to excellent yields and could be carried out with a range of Grignard reagents. As Ni(0) can insert into either of the two S–Ar bonds present in the molecule, an excess of the Grignard reagent was

108 required to bypass any regioselectivity issues and give high yields of the desired compounds.169

Scheme 101 Ni-catalysed Kumada-Corriu cross-coupling 4.7 Summary A sulfur-directed Fe(III)-mediated ortho C–H coupling of arenes with unactivated terminal alkenes has been developed. The cross-coupling proceeds in moderate to good yield for a range of alkenes and biaryl sulfides, with the latter currently requiring a 3,5-oxygenation pattern with respect to the sulfur. The products of the reaction have shown a range of reactivities and a number of transformations have been carried out to demonstrate various avenues that can further be explored for their exploitation in target synthesis. Most notable was the use of the essential ether groups and the installed chlorine moiety towards an expedient synthesis of decorated dihydrobenzofuran motifs, also utilising classical Pd- and Ni-catalysed cross-coupling chemistry. While so far this reaction has required use of stoichiometric amounts of metal and attempts towards a catalytic system have proven unfruitful, the transformation represents a novel entry in the iron literature and so comparison with the work of others to aid in further optimisation has been difficult. Additional investigations will undoubtedly shine more light on the intricacies of this reaction system and allow for limitations to be addressed.

109

4.8 Future Work

4.8.1 Iron-mediated Chloroarylation of Alkenes Most useful in moving this project forward would be to carry out further mechanistic inquiries to elucidate the role of the metal and the integral part sulfur has to play. A number of techniques have been utilised in probing the mechanism of various Fe-catalysed reactions, such as Mossbauer spectroscopy and magnetic circular dichroism.170 These specialised techniques may provide some insights into the current reactivity. Based on observed results, such as the selectivity for linear products and investigation into relative oxidation potentials, a novel SET activation method has been proposed (see Section 4.4.1). Definitive evidence for this hypothesis has not yet been obtained and other mechanisms are possible. A common experiment in probing whether a radical mechanism is occurring would be to utilise radical clock studies. This was attempted using 1,6-dienes, which may undergo radical 5-exo-trig cyclisations; however no cyclised products were observed, posited to be due to fast radical oxidation/trapping. Another possible trapping experiment would be the use of vinyl cyclopropane 199, with ring-opened products 200 being indicative of a radical process (Scheme 102). The ring-opening reaction (k = 8.0 × 107 s-1)171 should be faster than the 5-exo-trig cyclisation (k = 2.3 × 105 s-1)128 previously investigated.

Scheme 102 Use of vinylcyclopropane in radical clock studies Literature conditions describe the preparation of vinyl cyclopropane 199 via methylenation of cyclopropylcarboxaldehyde 201 (Scheme 103).172 Vinyl cyclopropane was observed in the crude 1H NMR spectrum when this reaction was carried out, however attempts to

110 isolate the product by the described distillation method (with the product boiling at 40 °C) proved unsuccessful and an azeotropic mixture with DMSO was obtained.

Scheme 103 Preparation of vinyl cyclopropane via Wittig reaction A further review of the literature demonstrated that vinyl cyclopropane is notoriously difficult to isolate due to its tendency to azeotrope with most solvents.173 Other methods were followed using toluene and mesitylene, but pure product was not obtained and attempts were eventually ceased. To carry out the radical clock experiment, successful isolation of this compound would be necessary. Alternatively, synthesis of substituted vinyl cyclopropanes that may be easier to isolate could be carried out.174 Despite a number of further manipulations being performed, there exist other possibilities that can be investigated. For example, the dibenzothiepine motif 202 is present in a number of drug molecules and it may be possible to access these structures using the products of the chloroarylation reaction (Scheme 104).175 This reaction would require displacement of chlorine by the second arene ring and so a Friedel-Crafts or radical process may be possible.

Scheme 104 Proposed conversion of chloroarylation products to dibenzothiepines It has also recently been discovered in the Procter group that addition of AgOTf to chloroarylation product 99a leads to formation of sulfonium salt 203 in high yield (Scheme 105). These compounds may show interesting reactivity patterns and so further investigations will be carried out.

111

Scheme 105 Silver-mediated dehalogenation to form sulfonium salts

4.8.2 Manipulation of Allylation Products – The Truce-Smiles Rearrangement Rather than its removal, a repurposing of the sulfanyl group required for the iron-mediated cross-coupling was suggested. It was proposed that ortho-allylphenylsulfides, the products of the Procter group’s sulfoxide-directed C–H alkylation process and also the iron- mediated allylation of sulfides previously discussed, could be used in a Truce-Smiles rearrangement after oxidation to the corresponding sulfones (Scheme 106).176 This reaction would give rise to interesting vinyl-substituted diarylmethane compounds. Diarylmethanes are useful in many industries, such as their presence in a number of dyes.177 Some preliminary work was carried out to investigate the feasibility of this proposal.

Scheme 106 Proposed Truce-Smiles rearrangement of allylphenylsulfones As the iron-mediated allylation of sulfides was not optimised, the most efficient route to the required sulfides was via the C–H allylation of aryl sulfoxides.64 Following this procedure successfully led to formation of 88c in 80% yield (Scheme 107).

Scheme 107 ortho-C–H Allylation of diphenylsulfoxide

112

Oxidation to the corresponding sulfone 204 was attempted using mCPBA, which had proven successful in earlier manipulations of the chloroarylation products (Section 4.6). However, the presence of the allyl group led to a complex mixture of products which proved difficult to purify. Thus, a method for the selective oxidation of sulfur that would tolerate the presence of a terminal olefin was sought. A procedure utilising

(NH4)2MoO4/H2O2 in MeOH was assessed, yet this gave a low yield of the desired product 204.178 After a short optimisation, it was found that carrying out this protocol in MeCN successfully gave 204 in 58% yield (Scheme 108). This step will likely require further optimisation in the future.

Scheme 108 Selective oxidation to the allylated sulfone With 204 in hand, the Truce-Smiles rearrangement was attempted using n-BuLi as base (Scheme 109).179 The sought-after rearrangement appeared to be successful, though the corresponding sulfinic acid proved difficult to isolate and was prone to decomposition; as such, only 23% of 205 was obtained.

Scheme 109 Preliminary studies on the Truce-Smiles rearrangement It was found that the intermediate metal sulfinates 206 formed following rearrangement can be easily intercepted using a range of electrophiles to give the corresponding sulfones.180 The use of MeI was examined and, following a short investigation of conditions, methyl sulfone 207 could be obtained in 70% after the two steps (Scheme 110).

113

Scheme 110 Use of MeI as quench for intermediary metal sulfinate A number of other bases were inspected, such as LDA and KOt-Bu, however these failed to give the rearranged product.181 The triad of n-BuLi/KOt-Bu/TMP is reported to efficiently carry out benzylic metalation, but these conditions proved incompatible with this system and decomposition of the starting material was observed without any 159 concomitant rearrangement occurring. Interestingly, the use of NaNH2 led to isomerisation of the allyl unit to the internal alkene 208 in high yield (Scheme 111).182 This may be due to reversible deprotonation, which leads to formation of the thermodynamic alkene and the observed lack of rearrangement.

Scheme 111 Isomerisation of the allyl unit using NaNH2 Additional work is required to further optimise the Truce-Smiles reaction system and to determine its scope. A number of possibilities can be explored in the future, as the metal sulfinate intermediates are versatile reagents that can be used to access a variety of compounds.183 Some interesting examples are demonstrated in Scheme 112.

114

Scheme 112 Potential further manipulations of metal sulfinate intermediates The use of diphenyl iodonium salts to synthesise arylsulfones from sulfinates has previously been reported (Pathway A).184 The products 209 may undergo another Truce- Smiles rearrangement to form vinyl triarylmethanes 210. The formation of arylsulfoxides from sulfinates is also known (Pathway B); these arylsulfoxides 211 can then carry out another ortho-allylation/oxidation/Truce-Smiles procedure to give structures such as 212.185 This protocol can be repeated using the new metal sulfinate species as an iterative approach towards extended or polymeric structures. A number of other prospects, such as an asymmetric variant of the Truce-Smiles rearrangement,186 metathesis reactions involving the vinyl moieties187 or the use of sulfinate intermediates in Pd-catalysed reactions,188 can be further explored using this chemistry and there are clearly many avenues to investigate.

115

5. Experimental

5.1 General Experimental

All experiments were performed under an atmosphere of nitrogen unless stated otherwise.

THF was distilled from sodium/benzophenone and CH2Cl2 was distilled from CaH2. All other solvents and reagents were purchased from commercial sources and used as supplied. Following reaction workup, the crude reaction mixtures were dissolved in a solution of 1 MeNO2 in CDCl3 of known concentration and crude yields were determined by H NMR spectroscopy. 1H NMR spectra were obtained at room temperature on a 300, 400 or 500 MHz Bruker spectrometer, 13C NMR spectra were recorded on a 75, 100 or 125 MHz Bruker spectrometer. All chemical shift values are reported in parts per million (ppm) relative to the solvent signal and were determined in CDCl3, with coupling constant (J) values reported in Hz. The notation of signals is: Proton: δ chemical shift in ppm (number of protons, multiplicity, J value(s), proton assignment). Carbon: δ chemical shift in ppm (carbon assignment). If assignment is ambiguous, for example in the case of overlapping signal, a range of shifts is reported. Column chromatography was carried out using 35 – 70 μm, 60 Å silica gel. Routine TLC analysis was carried out on silica gel 60 Å F254 coated aluminium sheets of 0.2 mm thickness. Plates were viewed using a 254 nm ultraviolet lamp and dipped in aqueous potassium permanganate, p-anisaldehyde or phosphomolybdic acid solutions. Low resolution and high resolution mass spectra were obtained using either positive and/or negative electrospray ionisation (ES), electron impact ionisation (EI), chemical ionisation (CI) and photoionisation (PI) techniques.

IR spectra were recorded on a FTIR spectrometer as evaporated films (from CHCl3) using sodium chloride windows or using neat samples.

5.2 Cyclic Voltammetry All voltammetry was performed in a 5 mL water jacketed glass cell at 25 °C under Ar, following purging with Ar (MeCN saturated with Ar for MeCN solutions), using CH Instruments CHI600B Electrochemical Analyser with 3 mm diameter glassy carbon working electrode and platinum wire counter electrode . Reference electrodes used were Ag/AgCl 3 M KCl(aq) and a pseudo-reference electrode consisting of Ag wire coated in AgCl (Ag wire dipped in concentrated HCl for a few minutes) in 0.1 M

116 tetrabutylammonium hexafluorophosphate (TBAHFP) separated from the analyte solution via a glass frit. The condition of the Ag/AgCl 3 M KCl(aq) reference electrode was tested by measuring the formal potential of 1 mM K4Fe(CN)6.3H2O in 0.1 M KCl at pH 7. The pseudo- reference electrode was calibrated by measuring the formal potential of 1 mM ferrocene in 0.1 M TBAHFP MeCN vs. Ag/AgCl 3 M KCl(aq) then measuring the formal potential of 1 mM ferrocene in 0.1 M TBAHFP in MeCN vs. the pseudo-reference electrode. The stability of the pseudo-reference electrode was checked by repeating the ferrocene formal potential measurement after measurement of analyte solutions had been completed. Potassium ferrocyanide and ferrocene formal potentials were calculated by taking the value at the mid-point between reduction and oxidation peaks. The formal potentials of (3,5- dimethoxyphenyl)(phenyl)sulfide and (3-methoxyphenyl)(phenyl)sulfide were calculated by fitting an EC mechanism model to the experimental data and finding the best fit over all scan rates investigated (using 'sensible' values for the EC model parameters).

5.3 Sulfide Synthesis General Procedure A: Pd-catalysed sulfide formation 74

Tetrakis(triphenylphosphine)palladium(0) (58.0 mg, 0.05 mol), (S)-BINAP (62 mg, 0.10 mmol), potassium hydroxide (1.12 g, 20.0 mmol), the corresponding arylbromide (10.0 mmol), 2-propanol (10.3 mL) and the corresponding thiol (10.0 mmol) were charged to a metal-capped, oven-dried test tube with Teflon-lined septum, pre-flushed with N2 at room temperature. The mixture was heated to 80 ⁰C and stirred for 24 h. The reaction mixture was then allowed to cool to room temperature before the addition of H2O (5 mL) and dilution with EtOAc (5 mL). The organic layer was separated and washed twice more with

H2O (2 × 5 mL). The combined aqueous extracts were then further extracted with EtOAc (2 × 10 mL) and the combined organic layers washed with brine (5 mL), dried over

Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel.

General Procedure B: Cu-catalysed sulfide formation 75

Cu(I) iodide (19.0 mg, 0.10 mmol), potassium carbonate (553 mg, 4.00 mmol) and the corresponding aryl iodide (2.00 mmol) were charged to a metal-capped, oven-dried test tube with Teflon-lined septum. The tube was then evacuated and backfilled with argon three times. 2-Propanol (2 mL), ethylene glycol (220 μL, 4.00 mmol) and the

117 corresponding thiol (1.00 mmol) were added and the mixture heated to 80 °C for 24 h with stirring. The mixture was then cooled, passed through a plug of Celite® 545 with EtOAc eluent and concentrated in vacuo. The crude product was purified by column chromatography.

(2,5-Dimethoxyphenyl)(phenyl)sulfide 68 91a

Thiophenol (2.16 mL, 20.0 mmol) was charged to a stirred solution of p-benzoquinone (2.16 g, 20.0 mmol) in MeOH (50 mL). The mixture was stirred for 10 min., followed by removal of solvent in vacuo to give a yellow solid; δH (400 MHz, CDCl3) 6.12 (1 H, br. S, OH), 6.85 - 7.04 (3 H, m, aryl H), 7.09 - 7.21 (3 H, m, aryl H), 7.22 - 7.30 (2 H, m, aryl H).189 The solid was dissolved in THF (50 mL) and added dropwise to a stirred mixture of NaH (60% in oil, 2.40 g, 60 mmol) in 150 mL THF. MeI (4.98 mL, 80.0 mmol) was added dropwise to this mixture and left to stir at room temperature for 24 h. The mixture was then quenched with H2O (100 mL) and extracted with EtOH (3 × 100 mL).

The combined organic residues were washed with brine (50 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude product was purified using column chromatography (50:1 petroleum ether:EtOAc) to give 91a (4.63 g, 18.8 mmol,

94% yield) as a colourless oil; δH (400 MHz, CDCl3) 3.58 (3 H, s, OCH3), 3.76 (3 H, s,

OCH3), 6.52 (1 H, d, J 3.0 Hz, aryl H), 6.66 (1 H, dd, J 8.8, 3.0 Hz, aryl H), 6.75 (1 H, d, J 8.8 Hz, aryl H), 7.16 - 7.28 (3 H, m, aryl H), 7.29 - 7.34 (2 H, m, aryl H).

(3,5-Dimethoxyphenyl)(phenyl)sulfide 190 91b

As described in general procedure A, 1-bromo-3,5-dimethoxybenzene (2.19 g, 10.0 mmol) and thiophenol (1.08 mL, 10.0 mmol), after purification by column chromatography (50:1 hexanes:EtOAc) gave 91b (2.21 g, 8.97 mmol, 90% yield) as a colourless oil; δH (400

MHz, CDCl3) 3.74 (6 H, s, OCH3), 6.34 (1 H, t, J 2.3 Hz, aryl H), 6.47 (2 H, d, J 2.3 Hz,

118 aryl H), 7.25 - 7.36 (3 H, m, aryl H), 7.38 - 7.43 (2 H, m, aryl H); δC (100 MHz, CDCl3)

55.8 (OCH3), 99.6 (aryl C-H), 108.4 (aryl C-H), 127.6 (aryl C-H), 129.4 (aryl C-H), 122.1

(aryl C-H), 135.3 (aryl Cq), 138.3 (aryl Cq), 161.4 (aryl Cq).

(4-Methoxyphenyl)(phenyl)sulfide 191 91c

As described in general procedure A, 4-bromoanisole (1.25 mL, 10.0 mmol) and thiophenol (1.08 mL, 10.0 mmol), after purification by column chromatography (50:1 hexanes:EtOAc) gave 91c (1.87 g, 8.65 mmol, 87% yield) as a colourless oil; δH (400

MHz, CDCl3) 3.65 (3 H, s, OCH3), 6.73 (2 H, d, J 9.1 Hz, aryl H), 6.93 - 7.10 (5 H, m, aryl

H), 7.24 (2 H, d, J 9.1 Hz, aryl H); δC (100 MHz, CDCl3) 55.6 (OCH3), 115.1 (aryl C-H),

124.7 (aryl Cq), 126.2 (aryl C-H), 128.3 (aryl C-H), 129.4 (aryl C-H), 135.7 (aryl C-H),

140.0 (aryl Cq), 160.3 (aryl Cq).

(3,5-Dimethoxyphenyl)(4-nitrophenyl)sulfide192 91d

As described in general procedure B, 1-iodo-4-nitrobenzene (498 mg, 2.00 mmol) and 3,5- dimethoxybenzenethiol (340 mg, 2.00 mmol), after purification by column chromatography (10% EtOAc in hexanes) gave 91d (542 mg, 1.86 mmol, 93%) as a yellow solid; δH (400 MHz, CDCl3) 3.80 (6 H, s, OCH3), 6.53 (1 H, t, J 2.3 Hz, aryl H), 6.68 (2 H, d, J 2.3 Hz, aryl H), 7.24 (2 H, d, J 8.8 Hz, aryl H), 8.09 (2 H, d, J 8.8 Hz, aryl

H); δC (100 MHz, CDCl3) 55.6 (OCH3), 101.9 (aryl C-H), 112.0 (aryl C-H), 124.0 (aryl C-

H), 127.0 (aryl C-H), 132.0 (aryl Cq), 145.4 (aryl Cq), 148.0 (aryl Cq), 161.6 (aryl Cq).

119

(3,5-Dimethoxyphenyl)(4-(trifluoromethyl)phenyl)sulfide 91e

As described in general procedure B, 4-iodobenzotrifluoride (295 μL, 2.00 mmol) and 3,5- dimethoxybenzenethiol (340 mg, 2.00 mmol), after purification by column chromatography (50:1 hexanes:EtOAc) gave 91e (465 mg, 1.48 mmol, 68%) as a colourless oil; δH (500 MHz, CDCl3) 3.78 (6 H, m, OCH3), 6.47 (1 H, t, J 2.4 Hz, aryl H), 6.62 (2 H, d, J 2.4 Hz, aryl H), 7.34 (2 H, d, J 8.2 Hz, aryl H), 7.51 (2 H, d, J 8.2 Hz, aryl

H); δC (125 MHz, CDCl3) 55.5 (OCH3), 100.9 (aryl C-H), 110.7 (aryl C-H), 124.1 (q, J

271.6 Hz, CF3), 125.8 (q, J 4.5 Hz, aryl C-H), 128.5 (q, J 32.7 Hz, aryl Cq), 128.8 (aryl C- -1 H), 134.4 (aryl Cq), 142.2 (aryl Cq), 161.3 (aryl Cq); νmax (thin film/cm ) 1013 (s), 1043 (s), 1061 (s), 1061 (s), 1088 (s), 1119 (s), 1154 (s), 1205 (m), 1321 (s), 1419 (w), 1581 (s), + + + 2940 (w); MS (ES ) m/z 315 [(M+H) ]; HRMS C15H14F3O2S [(M+H) ] Expected 315.0667, Found 315.0671.

(2-Methoxy)(phenyl)sulfide 190 91f

As described in general procedure A, 2-bromoanisole (1.25 mL, 10.0 mmol) and thiophenol (1.08 mL, 10.0 mmol) after purification by column chromatography (50:1 hexanes:EtOAc) gave 91f (1.29 g, 5.96 mmol, 60% yield) as a colourless oil;  (400

MHz, CDCl3) 3.89 (3 H, s, OCH3), 6.86 - 6.94 (2 H, m, aryl H), 7.09 (1 H, dd, J 7.7, 1.6

Hz, aryl H), 7.22 - 7.39 (6 H, m, aryl H); δC (100 MHz, CDCl3) 55.9 (OCH3), 110.9 (aryl

C-H), 121.2 (aryl C-H), 124.1 (aryl Cq), 127.1 (aryl C-H), 128.3 (aryl C-H), 129.2 (aryl C-

H), 131.5 (aryl C-H), 131.6 (aryl C-H), 134.5 (aryl Cq), 157.3 (aryl Cq).

120

(3-Methoxy)(phenyl)sulfide 193 91g

As described in general procedure A, 3-bromoanisole (1.27 mL, 10.0 mmol) and thiophenol (1.08 mL, 10.0 mmol), after purification by column chromatography (50:1 hexanes:EtOAc) gave 91g (1.98 g, 9.15 mmol, 92% yield) as a colourless oil;  (400

MHz, CDCl3) 3.77 (3 H, s, OCH3), 6.79 (1 H, ddd, J 8.3, 2.5, 0.9 Hz, aryl H), 6.87 - 6.89 (1 H, m, aryl H), 6.90 – 6.94 (1 H, m, aryl H), 7.19 - 7.35 (4 H, m, aryl H), 7.36 – 7.41 (2

H, m, aryl H); δC (100 MHz, CDCl3) 55.3 (OCH3), 112.8 (aryl C-H), 115.9 (aryl C-H), 123.0 (aryl C-H), 127.3 (aryl C-H), 129.2 (aryl C-H), 130.0 (aryl C-H), 131.4 (aryl C-H),

135.3 (aryl Cq), 137.2 (aryl Cq), 160.0 (aryl Cq).

(3,4-Dimethoxyphenyl)(phenyl)sulfide 91h

As described in general procedure A, 4-bromoveratrole (1.44 mL, 10.0 mmol) and thiophenol (1.08 mL, 10.0 mmol), after column chromatography (50:1 hexanes:EtOAc) gave 91h (2.05 g, 8.32 mmol, 83%) as a white solid; m.p. 41.4-42.8 °C;  (400 MHz,

CDCl3) 3.85 (3 H, s, OCH3), 3.91 (3 H, s, OCH3), 6.87 (1 H, d, J 8.3 Hz, aryl H), 7.00 (1 H, d, J 2.1 Hz, aryl H), 7.09 (1 H, dd, J 8.3, 2.1 Hz, aryl H), 7.13 - 7.22 (3 H, m, aryl H),

7.23 - 7.29 (2 H, m, aryl H); δC (100 MHz, CDCl3) 55.9 (OCH3), 56.0 (OCH3), 111.8 (aryl

C-H), 116.6 (aryl C-H), 124.6 (aryl Cq), 125.9 (aryl C-H), 126.7 (aryl C-H), 128.2 (aryl C- -1 H), 129.0 (aryl C-H), 138.4 (aryl Cq), 149.4 (aryl Cq), 149.5 (aryl Cq); νmax (thin film/cm ); 1024 (s), 1136 (m), 1230 (s), 1253 (vs), 1439 (m), 1503 (vs), 1583 (m), 2836 (w), 2905 + (w), 2952 (w), 3000 (w), 3056 (w); MS (GCMS) m/z 246 (M ); HRMS (PI) C14H15O2S [(M+H)+] Expected 247.0787, Found 247.0786.

121

(3,4,5-Trimethoxyphenyl)(phenyl)sulfide 91i

As described in general procedure A, 5-bromo-1,2,3-trimethoxybenzene (2.47 g, 10.0 mmol) and thiophenol (1.08 mL, 10.0 mmol), after purification by column chromatography (10% EtOAc in hexanes) gave 91i (1.80 g, 6.51 mmol, 65%) as a white solid; m.p 51.0-

53.1 °C;  (400 MHz, CDCl3) 3.80 (6 H, s, OCH3), 3.86 (3 H, s, OCH3), 6.66 (2 H, s, aryl

H), 7.19 - 7.26 (1 H, m, aryl H), 7.28 – 7.32 (4 H, m, aryl H); δC (100 MHz, CDCl3) 56.1

(OCH3), 60.9 (OCH3), 109.4 (aryl C-H), 126.6 (aryl C-H), 129.1 (aryl C-H), 129.3 (aryl -1 Cq), 129.6 (aryl C-H), 136.7 (aryl Cq), 137.8 (aryl Cq), 153.6 (aryl Cq); νmax (thin film/cm ) 1005 (m), 1125 (vs), 1231 (s), 1307 (m), 1403 (s), 1578 (s), 2829 (w), 2935 (w), 2999 (w), + + + 3056 (w); MS (ES ) m/z 277 [(M+H) ]; HRMS C15H17O3S [(M+H) ] Expected 277.0893, Found 277.0891.

(3,5-Dimethoxyphenyl)(4-methoxyphenyl)sulfide 91j

As described in general procedure A, 1-bromo-3,5-dimethoxybenzene (2.19 g, 10.0 mmol) and 4-methoxythiophenol (1.23 mL, 10.0 mmol), after purification by column chromatography (50:1 hexanes:EtOAc) gave 91j (1.77 g, 6.40 mmol, 64% yield) as a white solid; m.p. 61.2-63.8 °C;  (400 MHz, CDCl3) 3.72 (6 H, s, OCH3), 3.84 (3 H, s, OCH3), 6.25 (1 H, t, J 2.3 Hz, aryl H), 6.30 (2 H, d, J 2.3 Hz, aryl H), 6.89 - 6.95 (2 H, m, aryl H),

7.43 - 7.48 (2 H, m, aryl H); δC (100 MHz, CDCl3) 55.3 (OCH3), 55.4 (OCH3), 98.0 (aryl

C-H), 105.6 (aryl C-H), 115.0 (aryl C-H), 123.3 (aryl Cq), 135.9 (aryl C-H), 141.1 (aryl -1 Cq), 160.1 (aryl Cq), 161.0 (aryl Cq); νmax (thin film/cm ) 1030 (m), 1043 (m), 1153 (vs), 1203 (s), 1244 (s), 1282 (m), 1418 (m), 1453 (m), 1492 (s), 1582 (vs), 2834 (w), 2937 (w), + + + 2958 (w), 3000 (w); MS (ES ) m/z 277 [(M+H) ]; HRMS C15H17O3S [(M+H) ] Expected 277.0893, Found 277.0884.

122

(3,5-Dimethoxyphenyl)[4-(methylsulfanyl)phenyl]sulfide 91k

As described in general procedure A, 1-bromo-3,5-dimethoxybenzene (2.19 g, 10.0 mmol) and 4-(methylsulfanyl)-thiophenol (1.56 g, 10.0 mmol), after purification by column chromatography (50:1 hexanes:EtOAc) gave 91k (2.61 g, 8.93 mmol, 89% yield) as a colourless oil;  (400 MHz, CDCl3) 2.49 (3 H, s, SCH3), 3.74 (6 H, s, OCH3), 6.31 (1 H, t, J 2.3 Hz, aryl H), 6.41 (2 H, d, J 2.3 Hz, aryl H), 7.19 - 7.24 (2 H, m, aryl H), 7.33 - 7.37

(2 H, m, aryl H); δC (100 MHz, CDCl3) 15.6 (SCH3), 55.4 (OCH3), 98.9 (aryl C-H), 107.4

(aryl C-H), 127.1 (aryl C-H), 130.3 (aryl Cq), 133.0 (aryl C-H), 138.7 (aryl Cq), 138.9 (aryl -1 Cq), 161.0 (aryl Cq); νmax (thin film/cm ) 1044 (m), 1063 (m), 1154 (vs), 1204 (s), 1419 (m), 1453 (m), 1476 (m), 1583 (vs), 2832 (w), 2936 (w), 2958 (w), 3000 (w); MS (ES+) + + m/z 293 [(M+H) ]; HRMS C15H17O2S2 [(M+H) ] Expected 293.0664, Found 293.0655. bis(3-Methoxyphenyl)sulfide194 91l

As described in general procedure A, 3-bromoanisole (1.27 mL, 10.0 mmol) and 3- methoxythiophenol (1.24 mL, 10.0 mmol), after purification by column chromatography

(50:1 hexanes:EtOAc) gave 91l (2.05 g, 8.32 mmol, 83%) as a colourless oil;  (400

MHz, CDCl3) 3.78 (6 H, s, OCH3), 6.80 (2 H, ddd, J 8.3, 2.5, 0.9 Hz, aryl H), 6.89 - 6.92

(2 H, m, aryl H), 6.93 - 6.97 (2 H, m, aryl H), 7.23 (2 H, t, J 8.0 Hz, aryl H); δC (100 MHz,

CDCl3) 55.3 (OCH3), 113.0 (aryl C-H), 116.3 (aryl C-H), 123.4 (aryl C-H), 130.0 (aryl C-

H), 136.7 (aryl Cq), 160.1 (aryl Cq). bis(4-Methoxyphenyl)sulfide191 91m

As described in general procedure A, 4-bromoanisole (1.25 mL, 10.0 mmol) and 4- methoxythiophenol (1.23 mL, 10.0 mmol), after purification by column chromatography

(50:1 hexanes:EtOAc) gave 91m (2.04 g, 83% yield) as a white solid;  (400 MHz,

123

CDCl3) 3.80 (6 H, s, OCH3), 6.82 – 6.88 (4 H, m, aryl H), 7.26 – 7.31 (4 H, m, aryl H); δC

(100 MHz, CDCl3) 55.3 (OCH3), 114.7 (aryl C-H), 127.4 (aryl Cq), 132.7 (aryl C-H), 158.9

(aryl Cq).

(3,5-Dimethylphenyl)(phenyl)sulfide 195 91n

As described in general procedure A, 1-bromo-3,5-dimethylbenzene (1.85 g, 10.0 mmol) and thiophenol (1.08 mL, 10.0 mmol), after purification by column chromatography (50:1 hexanes:EtOAc) gave 91n (1.96 g, 9.14 mmol, 91%) as a colourless oil;  (400 MHz,

CDCl3) 2.29 (6 H, s, ArCH3), 6.89 - 6.92 (1 H, m, aryl H), 7.00 - 7.03 (2 H, m, aryl H),

7.20 - 7.26 (1 H, m, aryl H), 7.27 - 7.35 (4 H, m, aryl H); δC (100 MHz, CDCl3) 21.2

(ArCH3), 126.7 (aryl C-H), 129.0 (aryl C-H), 129.1 (aryl C-H), 130.5 (aryl C-H), 134.7

(aryl Cq), 136.3 (aryl Cq), 138.9 (aryl Cq).

(3-Methoxy-5-methylphenyl)(phenyl)sulfide 91o

As described in general procedure A, 3-bromo-5-methoxytoluene (2.01 g, 10.0 mmol) and thiophenol (1.08 mL, 10.0 mmol), after purification by column chromatography (50:1 hexanes:EtOAc) gave 91o (1.61 g, 6.99 mmol, 70%) as a colourless oil; ;  (400 MHz,

CDCl3) 2.29 (3 H, s, CH3), 3.75 (3 H, s, OCH3), 6.60 – 6.63 (1 H, m, aryl H), 6.69 (1 H, t, J 1.5 Hz, aryl H), 6.78 (1 H, td, J 1.5, 0.8 Hz, aryl H), 7.22 - 7.29 (1 H, m, aryl H), 7.29 -

7.35 (2 H, m, aryl H), 7.35 - 7.39 (2 H, m, aryl H); δC (100 MHz, CDCl3) 21.4 (ArCH3),

55.2 (OCH3), 113.2 (aryl C-H), 113.9 (aryl C-H), 123.9 (aryl C-H), 127.1 (aryl C-H),

129.2 (aryl C-H), 131.1 (aryl C-H), 135.6 (aryl Cq), 136.5 (aryl Cq), 140.2 (aryl Cq), 160.0 -1 (aryl Cq); νmax (thin film/cm ) 1058 (s), 1152 (s), 1165 (m), 1274 (s), 1415 (m), 1438 (m), 1463 (m), 1575 (s), 2833 (w), 2937 (w), 3001 (w), 3058 (w); MS (ES+) m/z 231 [(M+H)+]; + HRMS C14H15OS [(M+H) ] Expected 231.0838, Found 231.0838.

124

Naphthalen-2-yl(phenyl)sulfide196 91p

As described in general procedure A, 2-bromonaphthalene (2.07 g, 10.0 mmol) and thiophenol (1.08 mL, 10.0 mmol), after purification by column chromatography (50:1 hexanes:EtOAc) gave 91p (1.90 g, 8.04 mmol, 80%) as a white solid;  (400 MHz,

CDCl3) 7.19 - 7.30 (3 H, m, aryl H), 7.31 - 7.39 (3 H, m, aryl H), 7.39 - 7.47 (2 H, m, aryl

H), 7.67 - 7.82 (4 H, m, aryl H); δC (100 MHz, CDCl3) 126.2 (aryl C-H), 126.6 (aryl C-H), 127.1 (aryl C-H), 127.4 (aryl C-H), 127.7 (aryl C-H), 128.7 (aryl C-H), 128.8 (aryl C-H),

129.2 (aryl C-H), 129.9 (aryl C-H), 130.9 (aryl C-H), 132.3 (aryl Cq), 133.0 (aryl Cq),

133.8 (aryl Cq), 135.8 (aryl Cq).

(3,5-Dimethoxy-2-nitrophenyl)(phenyl)sulfide 91q and (3,5-dimethoxy-4- nitrophenyl)(phenyl)sulfide 91r

Fe(NO3)3.9H2O (1.21 g, 3.00 mmol) was charged to a solution of 91b (500 mg, 2.03 mmol) in MeCN (30 mL). The mixture was heated to reflux and stirred for 2 h, before cooling to room temperature. The solvent was then removed in vacuo and the crude dissolved in EtOAc (20 mL). The mixture was extracted with H2O (3 × 20 mL) and the aqueous extracts washed with EtOAc (3 × 20 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (50% CHCl3 in hexanes) to give 91q (273 mg, 0.937 mmol, 47%) as a yellow solid and 91r (128 mg, 0.439 mmol, 22%) as an orange solid; For 91q, m.p

75.5-76.2 °C; δH (400 MHz, CDCl3) 3.65 (3 H, s, OCH3), 3.89 (3 H, s, OCH3), 6.12 (1 H, d, J 2.5 Hz, aryl H), 6.35 (1 H, d, J 2.5 Hz, aryl H), 7.35 - 7.43 (3 H, m, aryl H), 7.45 - 7.53

(2 H, m, aryl H); δC (100 MHz, CDCl3) 55.6 (OCH3), 56.6 (OCH3), 97.6 (aryl C-H), 106.4

(aryl C-H), 129.0 (aryl C-H), 129.6 (aryl C-H), 132.3 (aryl Cq), 133.9 (aryl C-H), 135.3 -1 (aryl Cq), 153.8 (aryl Cq), 161.4 (aryl Cq); νmax (thin film/cm ) 1039 (s), 1166 (m), 1222 (m), 1292 (s, N-O sym), 1319 (m), 1520 (s), 1579 (vs, N-O asym), 2841 (vw), 2942 (vw), + + + 2973 (vw), 3010 (vw); MS (ES ) m/z 292 [(M+H) ]; HRMS C14H14NO4S [(M+H) ]

125

Expected 292.0638, Found 292.0628; For 91r, m.p 71.4-72.2 °C; δH (400 MHz, CDCl3)

3.76 (6 H, s, OCH3), 6.44 (2 H, s, aryl H), 7.36 - 7.45 (3 H, m, aryl H), 7.45 - 7.52 (2 H, m, aryl H); δC (100 MHz, CDCl3) 56.4 (OCH3), 104.5 (aryl C-H), 128.8 (aryl C-H), 129.7

(aryl C-H), 132.3 (aryl Cq), 133.4 (aryl C-H), 142.5 (aryl Cq), 152.0 (aryl Cq); νmax (thin film/cm-1) 880 (s, para aryl), 1131 (vs), 1234 (s), 1373 (s, N-O sym), 1404 (m), 1526 (vs, N-O asym), 1577 (s), 2839 (vw), 2943 (vw), 3013 (vw); MS (ES+) m/z 292 [(M+H)+]; + HRMS C14H14NO4S [(M+H) ] Expected 292.0638, Found 292.0626.

(3,5-Dimethoxy-4-methylphenyl)(phenyl)sulfide 91s

91b (400 mg, 1.60 mmol) was dissolved in THF (16 mL) and cooled to −78 °C. A solution of n-butyllithium (1.60 M in hexanes, 1.22 mL, 1.95 mmol) was then added and the mixture was warmed to room temperature and MeI (896 µL, 14.4 mmol) added dropwise.

The solution was left to stir for 10 min. and sat. aq. NH4Cl (2 mL) and EtOAc (2 mL) were then added. The organic layer was then washed twice more with sat. aq. NH4Cl (2 ml). The aqueous layer was extracted with EtOAc (2 × 2 mL) and the combined organic extracts were dried with Na2SO4, filtered and solvent removed in vacuo. The crude product was purified by column chromatography (30% CHCl3 in hexanes) to give 91s (352 mg, 1.35 mmol, 84%) as a colourless oil; δH (400 MHz, CDCl3) 2.09 (3 H, s, ArCH3), 3.77 (6 H, s,

OCH3), 6.62 (2 H, s, aryl H), 7.18 - 7.24 (1 H, m, aryl H), 7.27 - 7.32 (4 H, m, aryl H); δC

(100 MHz, CDCl3) 8.2 (ArCH3), 55.8 (OCH3), 107.8 (aryl C-H), 114.5 (aryl Cq), 126.4

(aryl C-H), 129.0 (aryl C-H), 129.5 (aryl C-H), 131.8 (aryl Cq), 137.0 (aryl Cq), 158.6 (aryl -1 Cq); νmax (thin film/cm ) 1136 (vs), 1231 (m), 1288 (w), 1398 (s), 1439 (m), 1449 (m), 1477 (m), 1578 (s), 2831 (w), 2937 (w), 3000 (w); MS (ES+) m/z 261 [(M+H)+]; HRMS + C15H17O2S [(M+H) ] Expected 261.0944, Found 261.0936.

126 t-Butyl(3,5-dimethoxyphenyl)sulfide 197 91t

1-Bromo-3,5-dimethoxybenzene (450 mg, 2.00 mmol), Pd(PPh3)4 (23.1 mg, 20.0 µmol), NaOt-Bu (392 mg, 4.00 mmol), n-BuOH (20 mL) and t-BuSH (225 µL, 2.00 mmol) were added to a metal-capped, oven-dried test tube with Teflon-lined septum, pre-flushed with

N2 at room temperature. The mixture was heated to 120 °C and stirred for 18 h. The reaction mixture was then allowed to cool to room temperature before the addition of H2O (20 mL) and dilution with EtOAc (20 mL). The organic layer was separated and washed twice more with H2O (2 × 20 mL). The combined aqueous extracts were then further extracted with EtOAc (2 × 20 mL) and the combined organic layers washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (5% EtOAc in hexanes) to give 91t (427 mg, 1.89 mmol, 94%) as a colourless oil; δH (400 MHz, CDCl3) 1.33 (9 H, s, C(CH3)3),

3.80 (6 H, s, OCH3), 6.48 (1 H, t, J 2.5 Hz, aryl H), 6.71 (2 H, d, J 2.5 Hz, aryl H); δC (100

MHz, CDCl3) 31.1 (C(CH3)3), 46.1 (C(CH3)3), 55.4 (OCH3), 101.3 (aryl C-H), 115.0 (aryl -1 C-H), 134.3 (aryl Cq), 160.2 (aryl Cq); νmax (thin film/cm ) 1046 (m), 1062 (m), 1152 (vs), 1204 (s), 1276 (m), 1363 (w), 1416 (m), 1455 (m), 1582 (vs), 2833 (w), 2861 (w), 2939 + + (w), 2959 (w), 3000 (w); MS (APCI) m/z 227 [(M+H) ]; HRMS C12H19O2S [(M+H) ] Expected 227.1100, Found 227.1095.

(3,5-Dimethoxyphenyl)(p-tolyl)sulfide 91v

As described in general procedure A, 1-bromo-3,5-dimethoxybenzene (2.19 g, 10.0 mmol) and p-thiocresol (1.24 g, 10.0 mmol), after purification by column chromatography (50:1 hexanes:EtOAc) gave 91v (2.37 g, 9.10 mmol, 91%) as a white solid; m.p. 64.7-67.4 ⁰C;

δH (400 MHz, CDCl3) 2.37 (3 H, s, ArCH3), 3.74 (6 H, s, OCH3), 6.30 (1 H, t, J 2.3 Hz,

127 aryl H), 6.40 (2 H, d, J 2.3 Hz, aryl H), 7.17 (2 H, d, J 7.8 Hz, aryl H), 7.36 (2 H, d, J 7.8

Hz, aryl H); δC (100 MHz, CDCl3) 21.1 (ArCH3), 55.3 (OCH3), 98.6 (aryl C-H), 107.0

(aryl C-H), 130.0 (aryl C-H), 130.2 (aryl Cq), 132.9 (aryl C-H), 138.0 (aryl Cq), 139.5 (aryl -1 Cq), 161.0 (aryl Cq); νmax (thin film/cm ) 1044 (s), 1103 (s), 1203 (s), 1280.2 (w), 1418 + + (m), 1581 (s), 2833 (w), 2936 (s); MS (ES ) m/z 261 [(M+H) ]; HRMS C15H17O2S [(M+H)+] Expected 261.0949, Found 261.0945.

3,5-Dimethoxybenzenethiol163 94a

Dimethylthiocarbamoyl chloride (7.90 g, 64.0 mmol) in DMF (10 mL) was added slowly to a mixture of 3,5-dimethoxyphenol (5.00 g, 32.0 mmol) and 1,4- diazabicylclo[2.2.2]octane (7.18 g, 64.0 mmol) in DMF (30 mL). The mixture was stirred at room temperature overnight and 10% aq. LiCl (40 mL) and ether (150 mL) were added. The organic layer was separated and washed with 10% aq. LiCl (3 × 40 mL) and brine (20 mL). The combined organic layers were dried with Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (4:1 hexanes:EtOAc) to give O-3,5-dimethoxyphenyl dimethylthiocarbamate (7.54 g, 31.2 mmol, 98%) as a white solid; δH (500 MHz, CDCl3) 3.33 (3 H, s, C(O)N(CH3)2), 3.46 (3 H, s, C(O)N(CH3)2), 3.79 (6 H, s, OCH3), 6.26 (2 H, d, J 2.5 Hz, aryl H), 6.37 (1 H, t, J 2.2 Hz, aryl H). The solid was heated to 260 °C for 3 h under nitrogen to give a brown oil after cooling, which was dissolved in MeOH (100 mL). KOH (11.60 g, 200 mmol) was added and the mixture was refluxed for 2 h with stirring. After cooling, the mixture was concentrated and EtOAc (150 mL) and 1N HCl (30 mL) were added. The organic layer was washed with brine (3 × 40 mL), dried with Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (10% EtOAc in hexanes) to give 94a (3.48 g, 20.4 mmol, 64% (3 steps)) as a colourless oil; δH (400 MHz,

CDCl3) 3.47 (1 H, s, SH), 3.77 (6 H, s, OCH3), 6.27 (1 H, t, J 2.3 Hz, aryl H), 6.43 (2 H, d, J 2.3 Hz, aryl H).

128

(4-Bromophenyl)(3,5-dimethoxyphenyl)sulfide 91w

As described in general procedure B, 1-bromo-4-iodobenzene (566 mg, 2.00 mmol) and 94a (340 mg, 2.00 mmol), after purification by column chromatography (50:1 hexanes:EtOAc) gave 91w (534 mg, 1.64 mmol, 80%) as a white solid; m.p. 54.2-56.2 ⁰C;

δH (400 MHz, CDCl3) 3.76 (6 H, s, OCH3), 6.37 (1 H, t, J 2.1 Hz, aryl H), 6.48 (2 H, d, J

2.1 Hz, aryl H), 7.23 (2 H, d, J 8.5 Hz, aryl H), 7.43 (2 H, d, J 8.5 Hz, aryl H); δC (100

MHz, CDCl3) 55.4 (OCH3), 99.7 (aryl C-H), 108.7 (aryl C-H), 121.3 (aryl Cq), 132.3 (aryl - C-H), 132.7 (aryl C-H), 134.5 (aryl Cq), 137.0 (aryl Cq), 161.1 (aryl Cq); νmax (thin film/cm 1) 1044 (m), 1154 (s), 1204 (m), 1281 (w), 1418 (m), 1581 (s), 2833 (w), 2936 (w), 3001 + 79 81 + + (w); MS (ES ) m/z 326 Br, 328 Br [(M+H) ]; HRMS C14H14BrO2S [(M+H) ] Expected 325.9878, Found 325.9886.

(3,5-Dimethoxyphenyl)(4-fluorophenyl)sulfide 91x

As described in general procedure B, 1-bromo-3,5-dimethoxybenzene (2.19 g, 10.0 mmol) and 4-fluorobenzenethiol (1.10 mL, 10.0 mmol), after purification by column chromatography (50:1 hexanes:EtOAc) gave 91x(1.40 g, 5.30 mmol, 53%) as a colourless oil; δH (400 MHz, CDCl3) 3.74 (6 H, s, OCH3), 6.31 (1 H, t, J 2.3 Hz, aryl H), 6.38 (2 H, d,

J 2.3 Hz, aryl H), 7.06 (2 H, t, J 8.8 Hz, aryl H), 7.44 (2 H, dd, J 8.8, 5.3 Hz, aryl H); δC

(100 MHz, CDCl3) 55.3 (OCH3), 98.8 (aryl C-H), 107.1 (aryl C-H), 116.4 (d, J 22.1 Hz, aryl C-H), 129.2 (d, J 3.7 Hz, aryl Cq), 134.8 (d, J 8.1 Hz, aryl C-H), 139.0 (aryl Cq), 161.1 -1 (aryl Cq), 163.0 (d, J 248.4 Hz, aryl C-F); νmax (thin film/cm ) 1043 (m), 1152 (s), 1203

129

(s), 1281 (w), 1418 (m), 1453 (m), 1488 (s), 1581 (s), 2834 (w), 2938 (w); MS (ES+) m/z + + 265 [(M+H) ]; HRMS C14H14FO2S [(M+H) ] Expected 265.0699, Found 265.0711.

(3,5-Dimethoxyphenyl)(2-fluorophenyl)sulfide 91y

As described in general procedure A, 1-bromo-3,5-dimethoxybenzene (2.19 g, 10.0 mmol) and 2-fluorothiophenol (1.49 mL, 10.0 mmol), after purification by column chromatography (50:1 hexanes:EtOAc) gave 91y (1.53 g, 5.79 mmol, 58% yield) as a colourless oil; δH (500 MHz, CDCl3) 3.78 (6 H, s, OCH3), 6.40 (1 H, t, J 2.2 Hz, aryl H),

6.51 (2 H, d, J 2.2 Hz, aryl H), 7.10 - 7.19 (2 H, m, aryl H), 7.28 - 7.42 (2 H, m, aryl H); δC

(125 MHz, CDCl3) 55.3 (OCH3), 99.4 (aryl C-H), 108.0 (aryl C-H), 115.9 (d, J 22.7 Hz, aryl C-H), 121.7 (d, J 18.2 Hz, aryl Cq), 124.7 (d, J 3.6 Hz, aryl C-H), 129.7 (d, J 8.2 Hz, aryl C-H), 134.0 (aryl C-H), 136.3 (aryl Cq), 161.0 (aryl Cq), 161.2 (d, J 247 Hz, aryl C-F); -1 νmax (thin film/cm ) 1042 (m), 1153 (s), 1203 (s), 1281 (w), 1418 (m), 1454 (m), 1471 (s), + + + 1581 (s), 2834 (w), 2938 (w); MS (ES ) m/z 265 [(M+H) ]; HRMS C14H14FO2S [(M+H) ] Expected 265.0699, Found 265.0705.

(3,5-Dimethoxyphenyl)(3-methoxyphenyl)sulfide 91z

As described in general procedure A, 1-bromo-3,5-dimethoxybenzene (2.19 g, 10.0 mmol) and 3-methoxythiophenol (1.20 mL, 10.0 mmol), after purification by column chromatography (50:1 hexanes:EtOAc) gave 91z (2.39 g, 8.64 mmol, 86% yield) as a colourless oil; δH (500 MHz, CDCl3) 3.75 (6 H, s, OCH3), 3.78 (3 H, s, OCH3), 6.35 (1 H, t, J 2.2 Hz, aryl H), 6.50 (2 H, d, J 2.2 Hz, aryl H), 6.81 (1 H, dt, J 7.9, 1.9 Hz, aryl H), 6.94 (1 H, t, J 1.9 Hz, aryl H), 6.98 (1 H, dt, J 7.9, 1.9 Hz, aryl H), 7.24 (1 H, t, J 7.9 Hz,

130 aryl H); δC (125 MHz, CDCl3) 55.3 (OCH3), 55.4 (OCH3), 99.6 (aryl C-H), 108.5 (aryl C-H), 113.2 (aryl C-H), 116.6 (aryl C-H), 123.7 (aryl C-H), 130.0 (aryl C-H), 136.2 (aryl -1 Cq), 138.7 (aryl Cq), 160.0 (aryl Cq), 161.1 (aryl Cq); νmax (thin film/cm ) 1039 (s), 1152 (s), 1203 (m), 1281 (m), 1417 (m), 1574 (s), 2832 (w), 2936 (w), 3000 (w); MS (ES+) m/z + + 277 [(M+H) ]; HRMS C15H17O3S [(M+H) ] Expected 277.0898, Found 277.0903. bis(3,5-Dimethoxyphenyl)sulfide192 91aa

As described in general procedure A, 1-bromo-3,5-dimethoxybenzene (2.19 g, 10.0 mmol) and 94a (1.70 g, 10.0 mmol), after purification by column chromatography (50:1 hexanes:EtOAc) gave 91aa (2.25 g, 7.34 mmol, 73%) as a white solid; δH (400 MHz,

CDCl3) 3.76 (12 H, s, OCH3), 6.36 (2 H, t, J 2.3 Hz, aryl H), 6.53 (4 H, d, J 2.3 Hz, aryl

H); δC (100 MHz, CDCl3) 55.4 (OCH3), 99.7 (aryl C-H), 108.8 (aryl C-H), 137.0 (aryl Cq),

161.0 (aryl Cq).

1-Bromo-3,5-diisopropoxybenzene163 93a

A solution of 1-bromo-3,5-dimethoxybenzene (2.50 g, 12.0 mmol) in CH2Cl2 (7 ml) was cooled to 0 ⁰C and a 1 M BBr3 solution in CH2Cl2 (25 mL) was added dropwise. The ice bath was removed and the reaction was stirred at room temperature for 18 h. The reaction was quenched with MeOH and concentrated in vacuo. The residue was dissolved in EtOAc

(100 mL) and washed with H2O (50 mL). The organic layer was separated, dried over

Na2SO4 and concentrated to give 5-bromobenzene-1,3-diol as an orange oil; δH (400 MHz,

CDCl3) 5.10 (2 H, br s, OH), 6.30 (1 H, t, J 2.1 Hz, aryl H), 6.60 (2 H, d, J 2.3 Hz, aryl H).

5-bromobenzene-1,3-diol (2.09 g) was dissolved in DMF (40 mL) and K2CO3 (6.08 g, 44.0 mmol) was added at room temperature, followed by 2-bromopropane (4.13 mL, 44.0 mol).

131

The mixture was heated to 60 ⁰C and stirred for 18 h. The reaction was cooled to room temperature, quenched with water (120 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was separated, dried with Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (10:1 hexanes:EtOAc) to give 93a (2.48 g, 9.08 mmol, 76%) as a colourless oil; δH (500 MHz, CDCl3) 1.25 (12 H, d, J 6.0 Hz), 4.40 (2 H, sept, J 6.0 Hz), 6.27 (1 H, t, J 2.2 Hz), 6.54 (2 H, d, J 2.2 Hz).

(3,5-Diisopropoxyphenyl)(phenyl)sulfide 91ab

As described in general procedure A, 93a (2.19 g, 8.00 mmol) and thiophenol (0.80 mL, 8.00 mmol), after purification by column chromatography (50:1 hexanes:EtOAc) gave

91ab (1.84 g, 6.08 mmol, 76% yield), as a colourless oil; δH (500 MHz, CDCl3) 1.31 (12

H, d, J 6.0 Hz, (OCH(CH3)2), 4.46 (2 H, sept, J 6.0 Hz, OCH(CH3)2)), 6.33 (1 H, t, J 2.2 Hz, aryl H), 6.46 (2 H, d, J 2.2 Hz, aryl H), 7.25 - 7.29 (1 H, m, aryl H), 7.31 - 7.36 (2 H, m, aryl H), 7.39 - 7.43 (2 H, m, aryl H); δC (125 MHz, CDCl3) 22.0 (OCH(CH3)2), 70.0

(OCH(CH3)2), 102.8 (aryl C-H), 109.9 (aryl C-H), 127.2 (aryl C-H), 129.1 (aryl C-H), -1 131.5 (aryl C-H), 135.2 (aryl Cq), 137.6 (aryl Cq), 159.3 (aryl Cq); νmax (thin film/cm ) 1033 (m), 1112 (s), 1151 (s), 1182 (m), 1277 (w), 1428 (w), 1575 (s), 2931 (w), 2975 (w); + + + MS (ES ) m/z 303 [(M+H) ]; HRMS C18H23O2S [(M+H) ] Expected 303.1419, Found 303.1425.

5-(Phenylsulfanyl)benzene-1,3-diol 91ac

A 1 M BBr3 solution in CH2Cl2 (10 mL, 10.0 mmol) was added dropwise to a solution of

91b (0.62 g, 2.50 mmol) in CH2Cl2 (6 mL) at 0 °C under N2. When addition was complete, the mixture was warmed to room temperature and stirred for 2 h. The reaction was then quenched with MeOH (4 mL) and concentrated in vacuo. The residue was dissolved in

EtOAc (5 mL) and extracted with H2O (2 × 5 mL). The combined organic layers were then

132 washed with brine (5 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (30% EtOAc in hexanes) to give 91ac (0.45 g, 2.06 mmol, 82%) as an off-white crystalline solid; m.p. 136.0 – 140.0

°C (from CHCl3); δH (400 MHz, CDCl3) 4.68 (2 H, s, OH), 6.20 (1 H, t, J 2.2 Hz, aryl H),

6.32 (2 H, d, J 2.2 Hz, aryl H), 7.29 - 7.38 (3 H, m, aryl H), 7.42 - 7.46 (2 H, m, aryl H); δC

(100 MHz, CDCl3) 101.2 (aryl C-H), 108.9 (aryl C-H), 127.9 (aryl C-H), 129.4 (aryl C-H), -1 132.7 (aryl C-H), 133.9 (aryl Cq), 139.3 (aryl Cq), 156.9 (aryl Cq); νmax (thin film/cm ) 996 (s), 1066 (w), 1155 (s), 1200 (w), 1265 (w), 1300 (w), 1328 (w), 1344 (w), 1439 (w), 1471 (s), 1587 (s), 1620 (s), 2853 (w), 2923 (w), 2956 (w), 3055 (w), 3233 (w, br); MS (ES-) m/z − − 217 [(M−H) ]; HRMS C12H9O2S [(M−H )] Expected 217.0323, Found 217.0324.

[3,5-bis(Allyloxy)phenyl](phenyl)sulfide 91ad

Allyl bromide (0.700 mL, 8.00 mmol) was added to a solution of 91ac (426 mg, 2.00 mmol) and K2CO3 (0.832 g, 6.0 mmol) in acetone (2 mL) at room temperature under N2.

The resulting mixture was stirred for 48 h, before adding H2O until the disappearance of the precipitate. The crude product was then extracted with Et2O (3 × 5 mL). The combined organic extracts were washed with H2O (2 × 5 mL) and brine (5 mL), dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (25% CH2Cl2 in hexanes) to give 91ad (0.32 g, 1.07 mmol, 54%) as a colourless oil; δH (500 MHz, CDCl3) 4.45 (4 H, dt, J 5.4, 1.5 Hz, OCH2), 5.27 (2 H, dq, J 10.5, 1.5

Hz, CH=CH2), 5.37 (2 H, dq, J 17.3, 1.5 Hz, CH=CH2), 6.00 (2 H, ddt, J 17.3, 10.5, 5.4

Hz, CH=CH2), 6.37 (1 H, t, J 2.2 Hz, aryl H), 6.47 (2 H, d, J 2.2 Hz, aryl H), 7.28 - 7.36 (3

H, m, aryl H), 7.38 - 7.42 (2 H, m, aryl H); δC (100 MHz, CDCl3) 68.9 (CH2), 100.7

(CH=CH2), 108.9 (aryl C-H), 118.1 (C=CH2), 127.5 (aryl C-H), 129.3 (aryl C-H), 131.9

(aryl C-H), 132.9 (aryl C-H), 134.6 (aryl Cq), 138.1 (aryl Cq), 159.9 (aryl Cq); νmax (thin film/cm-1) 924 (w), 997 (w), 1023 (w), 1084 (w), 1149 (s), 1278 (w), 1419 (w), 1439 (s), 1578 (s), 2862 (w), 2918 (w), 2983 (w), 3019 (w), 3076 (w); MS (ES+) m/z 299 [(M+H)+]; + HRMS C18H18O2SNa [(M+Na) ] Expected 321.0925, Found 321.0921.

133

5.4 Synthesis of Other Arenes 1,3-Dimethoxy-5-(phenylsulfonyl)benzene 166

m-CPBA (≤77%, 0.672 g, 3.00 mmol) was added to a solution of 91b (246 mg, 1 mmol) in

CH2Cl2 (10 mL). The mixture was stirred at ambient temperature for 18 h and then quenched with aq. NaHCO3 (2 mL). The aqueous layer was washed with CH2Cl2 (3 × 2 mL) and the combined organic extracts were dried with MgSO4, filtered and the solvent removed in vacuo. The crude product was purified by column chromatography (20% EtOAc in hexanes) to give 166 (233 mg, 0.837 mmol, 84%) as a white solid; m.p. 81.7-

82.8 °C; δH (400 MHz, CDCl3) 3.82 (6 H, s, OCH3), 6.60 (1 H, t, J 2.5 Hz, aryl H), 7.07 (2 H, d, J 2.5 Hz, aryl H), 7.47 - 7.54 (2 H, m, aryl H), 7.55 - 7.61 (1 H, m, aryl H), 7.91 -

7.98 (2 H, m, aryl H); δC (100 MHz, CDCl3) 55.8 (OCH3), 105.4 (aryl C-H), 105.5 (aryl C-

H), 127.6 (aryl C-H), 129.2 (aryl C-H), 133.2 (aryl C-H), 141.4 (aryl Cq), 143.3 (aryl Cq), -1 161.2 (aryl Cq); νmax (thin film/cm ) 1040 (m), 1067 (m), 1099 (m), 1151 (vs, S=O sym), 1206 (s), 1289 (s), 1306 (s, S=O asym), 1426 (m), 1460 (m), 1600 (s), 2837 (w), 2942 (m), + + + 3006 (m), 3088 (m); MS (ES ) m/z 279 [(M+H) ]; HRMS C14H14O4NaS [(M+Na) ] Expected 301.0505, Found 301.0495.

1,3-Dimethoxy-5-phenoxybenzene198 168

Bromobenzene (0.52 mL, 4.90 mmol), 3,5-dimethoxyphenol (500 mg, 3.20 mmol), CuI

(6.10 mg, 32.0 µmol), Fe(acac)3 (22.6 mg, 64.0 µmol), K2CO3 (885 mg, 6.40 mmol) and DMF (5 mL) were added to a metal-capped, oven-dried test tube with Teflon-lined septum, pre-flushed with N2 at room temperature. The mixture was heated to 135 °C and stirred for 18 h. The mixture was then cooled to room temperature, filtered on Celite® 545 using

Et2O and the filtrate washed with 10% aq. LiCl (2 × 10 mL). The organic layer was dried over MgSO4, filtered and solvent removed in vacuo. The crude reaction mixture was then purified by column chromatography on silica gel (5% EtOAc in hexanes) to give 168 (94.4

134 mg, 0.410 mmol, 13%) as a colourless oil; δH (400 MHz, CDCl3) 3.76 (6 H, s, OCH3), 6.18 (2 H, d, J 2.3 Hz, aryl H), 6.23 (1 H, t, J 2.3 Hz, aryl H), 7.02 - 7.07 (2 H, m, aryl H), 7.09

- 7.15 (1 H, m, aryl H), 7.31 - 7.38 (2 H, m, aryl H); δC (100 MHz, CDCl3) 55.4 (OCH3), 95.4 (aryl C-H), 97.2 (aryl C-H), 119.2 (aryl C-H), 123.5 (aryl C-H), 129.7 (aryl C-H), -1 156.7 (aryl Cq), 159.2 (aryl Cq), 161.6 (aryl Cq); νmax (thin film/cm ) 1053 (m), 1063 (m), 1130 (s), 1204 (s), 1427 (m), 1472 (m), 1489 (m), 1584 (s), 2837 (w), 2941 (w), 2959 (w), + + + 3002 (w); MS (ES ) m/z 231 [(M+H) ]; HRMS C14H15O3 [(M+H) ] Expected 231.1016, Found 231.1007.

3,5-Dimethoxy-N-phenylaniline199 169

Bromobenzene (290 µL, 2.70 mmol), 3,5-dimethoxyaniline (500 mg, 3.30 mmol),

Pd2(dba)3 (7.50 mg, 8.00 µmol), BINAP (13.4 mg, 2.20 µmol), NaOt-Bu (366 mg, 3.80 mmol) and toluene (5 mL) were added to a metal-capped, oven-dried test tube with Teflon- lined septum, pre-flushed with N2 at room temperature. The mixture was heated to 100 °C and stirred for 24 h, before being cooled to room temperature. Sat. aq. NH4Cl (10 mL) was added and the aqueous layer extracted with CH2Cl2 (3 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO4, filtered and solvent removed in vacuo. The crude product was purified by column chromatography on silica gel (15% EtOAc in hexanes) and recrystallised from hexane to give 169 (562 mg, 2.45 mmol, 90%) as white crystals; δH (400 MHz, CDCl3) 3.77 (6 H, s, OCH3), 5.70 (1 H, br s, NH), 6.08 (1 H, t, J 2.1 Hz, aryl H), 6.25 (2 H, d, J 2.1 Hz, aryl H), 6.96 (1 H, tt, J 7.3, 1.2 Hz, aryl H),

7.09 – 7.14 (2 H, m, aryl H), 7.25 - 7.32 (2 H, m, aryl H); δC (100 MHz, CDCl3) 55.3

(OCH3), 93.0 (aryl C-H), 95.8 (aryl C-H), 118.8 (aryl C-H), 121.5 (aryl C-H), 129.3 (aryl

C-H), 142.6 (aryl Cq), 145.3 (aryl Cq), 161.6 (aryl Cq).

135

3,5-Dimethoxy-N,N-diphenylaniline200 170

Bromobenzene (1.05 mL, 9.80 mmol), 3,5-dimethoxyaniline (500 mg, 3.30 mmol),

Pd2(dba)3 (59.7 mg, 70.0 µmol), JohnPhos (77.8 mg, 260 µmol), NaOt-Bu (783 mg, 8.20 mmol) and toluene (15 mL) were charged to a metal-capped, oven-dried test tube with

Teflon-lined septum, pre-flushed with N2 at room temperature. The mixture was heated to 100 °C and stirred for 24 h, before being cooled to room temperature. The mixture was filtered on Celite® 545 using CH2Cl2 and then dried over MgSO4, filtered and solvent removed in vacuo. The crude product was purified by column chromatography on silica gel

(5% EtOAc in hexanes) and recrystallised from Et2O to give 170 (787 mg, 2.58 mmol,

79%) as a white solid; δH (400 MHz, CDCl3) 3.73 (6 H, s, OCH3), 6.19 (1 H, t, J 2.3 Hz, aryl H), 6.26 (2 H, d, J 2.3 Hz, aryl H), 7.06 (2 H, tt, J 7.3, 1.0 Hz, aryl H), 7.12 - 7.17 (4

H, m, aryl H), 7.26 - 7.32 (4 H, m, aryl H); δC (100 MHz, CDCl3) 55.3 (OCH3), 94.7 (aryl C-H), 102.2 (aryl C-H), 123.0 (aryl C-H), 124.6 (aryl C-H), 129.2 (aryl C-H), 147.6 (aryl

Cq), 149.7 (aryl Cq), 161.2 (aryl Cq).

5.5 Synthesis of Alkenes 5-Nitro-1-pentene201 213a

5-Bromo-1-pentene (2.53 g, 17.0 mmol) was added to a solution of NaNO2 (1.29 g, 18.7 mmol) in DMF (35 mL) and stirred at room temperature for 2 h. The reaction was quenched with H2O (30 mL) and extracted with Et2O (3 × 30 mL). The combined organic extracts were washed with 10% aq. LiCl (2 × 30 mL), dried with MgSO4, filtered and solvent removed in vacuo. The crude product was purified by column chromatography on silica gel (10% CHCl3 in hexanes) to give 213a (510 mg, 4.43 mmol, 26%) as a yellow oil;

δH (400 MHz, CDCl3) 2.07 - 2.22 (4 H, m, CH2), 4.40 (2 H, t, J 6.5 Hz, CH2NO2), 5.04 -

5.13 (2 H, m, CH=CH2), 5.77 (1 H, ddt, J 17.0, 10.4, 6.5 Hz, CH=CH2); δC (125 MHz,

CDCl3) 26.3 (CH2), 30.1 (CH2CH=CH2), 74.7 (CH2NO2), 116.8 (CH=CH2), 135.7

(CH=CH2).

136

8-Nitro-1-octene202 213b

8-Bromo-1-octene (1.68 mL, 10.0 mmol) was added dropwise to a solution of NaNO2 (759 mg, 11.0 mmol) in DMF (20 mL). The mixture was stirred at room temperature for 4 h and then quenched with 10% aq. LiCl (30 mL) and diluted with Et2O (30 mL). The organic layer was washed with H2O (2 × 20 mL), dried over MgSO4, filtered and solvent removed in vacuo. The crude product was purified by column chromatography on silica gel (5%

Et2O in hexanes) to give 213b (738 mg, 4.69 mmol, 47%) as a yellow oil; δH (500 MHz,

CDCl3) 1.33 - 1.48 (6 H, m, CH2), 1.97 - 2.12 (4 H, m, CH2), 4.40 (2 H, t, J 6.6 Hz,

CH2NO2), 4.97 (1 H, ddt, J 10.2, 1.8, 1.1 Hz, CH=CH2), 5.03 (1 H, dq, J 17.0, 1.8 Hz,

CH=CH2), 5.82 (1 H, ddt, J 17.0, 10.2, 6.6 Hz, CH=CH2); δC (125 MHz, CDCl3) 26.3

(CH2), 26.8 (CH2), 28.7 (CH2), 29.2 (CH2), 30.1 (CH2CH=CH2), 74.7 (CH2NO2), 116.8

(CH=CH2), 135.7 (CH=CH2).

9-Phenyl-1-nonene203 214

Benzylmagnesium bromide (5.00 mL, 2.00 M in THF, 10.0 mmol) was added to a suspension of CuCl2 (33.6 mg, 250 µmol) in Et2O (5 mL) at −78 °C. 8-Bromo-1-octene (956 mg, 5.00 mmol) was then added and the mixture warmed to room temperature and stirred for 4 h. The mixture was then cooled to 0 °C and quenched with 1 M HCl (30 mL) and the aqueous layer extracted with EtOAc (3 × 30 mL). The organic layer was dried with

MgSO4, filtered and solvent removed in vacuo. The crude product was purified by column chromatography on silica gel (hexanes) to give 214 (637 mg, 3.15 mmol, 68%) as a colourless oil; δH (500 MHz, CDCl3) 1.23 - 1.43 (8 H, m, CH2), 1.62 (2 H, quin, J 7.4 Hz,

ArCH2CH2), 2.05 (2 H, q, J 7.0 Hz, CH2CH=CH2), 2.61 (2 H, t, J 7.4 Hz, ArCH2), 4.94 (1

H, d, J 10.2 Hz, CH=CH2), 5.00 (1 H, d, J 17.0 Hz, CH=CH2), 5.82 (1 H, ddt, J 17.0, 10.2,

7.0 Hz, CH=CH2), 7.15 - 7.21 (3 H, m, aryl H), 7.25 - 7.31 (2 H, m, aryl H); δC (125 MHz,

CDCl3) 28.9 (CH2), 29.1 (CH2), 29.3 (CH2), 29.4 (CH2), 31.5 (CH2CH=CH2), 33.8

(ArCH2CH2), 36.0 (ArCH2), 114.1 (CH=CH2), 125.5 (aryl C-H), 128.2 (aryl C-H), 128.4

(aryl C-H), 139.2 (CH=CH2), 142.9 (ArCH2).

137

4,4-Dimethylhepta-1,6-diene204 145b

In a dried, nitrogen-filled flask fitted with stirrer and addition funnel, a solution of allyl bromide (12.1 g, 100 mmol) in anhydrous THF (50 mL), was added dropwise to zinc (6.54 g, 100 mmol) at 20 °C. The resulting solution was stirred at room temperature for 1 h. Propynylmagnesium bromide (75.0 mL, 0.5 M in THF, 37.5 mmol) was then added dropwise to the mixture and the solution was stirred at 60 °C for 2 h. The mixture was then cooled to 0 °C and quenched with 1 M HCl (20 mL). The mixture was diluted with Et2O and the aqueous layer further extracted with Et2O (3 × 20 mL). The combined organic phases were washed with brine (3 × 10 mL), dried over MgSO4, filtered and solvent removed in vacuo. The crude product was distilled to give 145b (1.86 g, 15.0 mmol, 40%) as a colourless oil; δH (400 MHz, CDCl3) 0.87 (6 H, s, (CH3)2), 1.96 (4 H, d, J 7.5 Hz,

CH2CH=CH2), 4.96 - 5.07 (4 H, m, CH=CH2), 5.83 (2 H, ddt, J 16.9, 10.3, 7.5 Hz,

CH=CH2); δC (100 MHz, CDCl3) 26.7 (CH3), 33.4 (CH2CH=CH2), 46.3 alkyl Cq), 116.8

(CH=CH2), 135.6 (CH=CH2).

1,1-Diallylcyclohexane205 145c

A mixture of catechol (4.40 g, 40.0 mmol), cyclohexanone (1.96 g, 20.0 mmol) and p- toluenesulfonic acid (462 mg, 2.00 mmol) in toluene was heated under reflux for 24 h. Water was removed by azeotropic distillation using a Dean-Stark trap. The reaction mixture was allowed to cool and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether 60-80) to give spiro[benzo(d)(1,3)dioxole-2,1'-cyclohexane] (3.24 g, 16.8 mmol, 84%) as a colourless oil;

δH (400 MHz, CDCl3) 1.46 - 1.57 (2 H, m), 1.70- 1.79 (4 H, m), 1.87 - 1.97 (4 H, m), 6.72 - 6.80 (4 H, m).206 A flask equipped with a thermometer, a magnetic stirring bar and argon outlet was charged with anhydrous CH2Cl2 (70 mL) and anhydrous MeNO2 (4.33 mL, 80 mmol). The solution was cooled to −78 °C and TiCl4 was added (4.39 mL, 40.0 mmol), followed by the dioxole (16.8 mmol) in CH2Cl2 (10 mL) and then allyl TMS (6.85 g, 60.0 mmol) in CH2Cl2 (20 mL). The reaction was followed by TLC and, upon completion, the solution was warmed to room temperature and poured into sat. aq. NH4Cl solution (50

138 mL). The aqueous layer was extracted with CH2Cl2 (2 × 30 mL) and the combined extracts washed until neutrality. The solution was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (5% Et2O in pentane) to give 145c (1.18 g, 7.18 mmol, 42%) as a colourless oil; δH (400 MHz, CDCl3) 1.21 - 1.52

(10 H, m, CH2), 2.03 (4 H, dt, J 7.5, 1.0 Hz, CH2CH=CH2), 4.99 - 5.07 (4 H, m, CH=CH2),

5.82 (2 H, ddt, J 16.7, 10.4, 7.5 Hz, CH=CH2); δC (100 MHz, CDCl3) 21.8 (CH2), 26.4

(CH2), 35.4 (CH2CH=CH2), 35.9 (CH2), 42.0 (alkyl Cq), 117.1 (CH=CH2), 135.2

(CH=CH2).

5.6 Iron-mediated Allylation of Arylsulfides

General Procedure C

FeCl3 (0.1-2.2 eq.) was added to a solution of the corresponding sulfide (0.20 mmol,

0.1 M) and allyl TMS (1-10 eq.) and the mixture was stirred for 1.5 h under N2. The solution was then quenched with H2O (2 ml), diluted with EtOAc (2 mL) and the organic layer washed with H2O (2 × 2 ml). The aqueous layer was extracted with EtOAc (3 × 2 mL) and the combined organic extracts were dried with Na2SO4, filtered and solvent removed in vacuo.

(2-Allyl-3,5-dimethoxyphenyl)(phenyl)sulfide 88a and (2,6-Diallyl-3,5- dimethoxyphenyl)(phenyl)sulfide 97

As described in general procedure C, 91b (50.0 mg, 0.203 mmol), allyl TMS (320 μl, 2.00 mmol) and FeCl3 (72.4 mg, 0.450 mmol) with MeNO2 solvent, after purification by column chromatography (20% CHCl3 in hexanes) gave 88a (20.2 mg, 70.5 µmol, 35%) and 97 (7.31 mg, 22.4 µmol, 11%) as colourless oils; For 88a, δH (500 MHz, CDCl3) 3.56

(2 H, dt, J 6.1, 1.5 Hz, ArCH2CH=CH2), 3.68 (3 H, s, OCH3), 3.82 (3 H, s, OCH3), 4.92 -

4.98 (2 H, m, CH2CH=CH2), 5.91 (1 H, ddt, J 17.7, 9.5, 6.1 Hz, CH2CH=CH2), 6.42 (1 H, d, J 2.5 Hz, aryl H), 6.43 (1 H, d, J 2.5 Hz, aryl H), 7.19 - 7.25 (1 H, m, aryl H), 7.25 - 7.31

139

(4 H, m, aryl H); δC (125 MHz, CDCl3) 31.2 (ArCH2), 55.3 (OCH3), 55.8 (OCH3), 98.4

(aryl C-H), 108.6 (aryl C-H), 114.6 (CH=CH2), 122.6 (aryl Cq), 126.6 (aryl C-H), 129.0

(aryl C-H), 130.3 (aryl C-H), 135.8 (aryl Cq), 136.3 (CH=CH2), 136.4 (aryl Cq), 158.8 (aryl -1 Cq), 158.9 (aryl Cq); νmax (thin film/cm ): 1047 (s), 1146 (s), 1247 (s), 1296 (s), 1437 (s), 1140 (s), 1477 (s), 1572 (s), 1596 (s), 2956 (w), 3002 (w), 3074 (w); MS (ES+) m/z 287 + + [(M+H) ]; HRMS C17H19O2S [(M+H) ] Expected 287.1100, Found 287.1108; For 97, δH

(400 MHz, CDCl3) 3.58 (4 H, dt, J 6.1, 1.5 Hz, ArCH2CH=CH2), 3.88 (6 H, s, OCH3), 4.81

- 4.88 (4 H, m, CH2CH=CH2), 5.84 (2 H, ddt, J 18.2, 9.1, 6.1 Hz, CH2CH=CH2), 6.62 (1 H, s, aryl H), 6.90 - 6.95 (2 H, m, aryl H), 7.04 (1 H, tt, J 7.3, 1.3 Hz, aryl H), 7.13 - 7.19

(2 H, m, aryl H); δC (100 MHz, CDCl3) 32.6 (ArCH2), 55.9 (OCH3), 97.5 (aryl C-H), 114.4

(CH=CH2), 124.5 (aryl C-H), 125.7 (aryl C-H), 125.8 (aryl Cq), 128.7 (aryl C-H), 132.1 -1 (aryl Cq), 137.1 (CH=CH2), 139.0 (aryl Cq), 157.3 (aryl Cq); νmax (thin film/cm ) 734, 910 (w), 1047 (w), 1125 (s), 1196 (s), 1297 (s), 1436 (s), 1458 (s), 1478 (s), 1583 (s), 1636 (w), + + + 2936 (w), 3002 (w), 3074 (w); MS (ES ) 327 [(M+H) ]; HRMS C20H23O2S [(M+H) ] Expected 327.1413, Found 327.1403.

(4-Allyl-3,5-dimethoxyphenyl)(phenyl)sulfide 96

As described in general procedure C, 91b (50.0 mg, 0.203 mmol), allyl TMS (320 μl, 2.00 mmol) and FeCl3 (72.4 mg, 0.450 mmol) with CH2Cl2 solvent, after purification by column chromatography (20% CHCl3 in hexanes) gave 96 (4.6 mg, 16.1 µmol, 8%) as a colourless oil; δH (500 MHz, CDCl3) 3.39 (2 H, dt, J 6.2, 1.5 Hz, ArCH2CH=CH2), 3.76 (6 H, s,

OCH3), 4.95 (1 H, dd, J 10.1, 1.5 Hz, CH2CH=CH2), 4.99 (1 H, dd, J 17.0, 1.5 Hz,

CH2CH=CH2), 5.94 (1 H, ddt, J 17.0, 10.1, 6.2 Hz, CH2CH=CH2), 6.61 (2 H, s, aryl H),

7.20 - 7.25 (1 H, m, aryl H), 7.28 - 7.35 (4 H, m, aryl H); δC (125 MHz, CDCl3) 27.1

(ArCH2), 55.9 (OCH3), 107.6 (aryl C-H), 114.2 (CH=CH2), 116.2 (aryl Cq), 126.6 (aryl C-

H), 129.1 (aryl C-H), 130.0 (aryl C-H), 133.3 (aryl Cq), 136.4 (CH=CH2), 136.5 (aryl Cq), -1 158.5 (aryl Cq); νmax (thin film/cm ) 1121 (s), 1136 (s), 1237 (w), 1292 (w), 1400 (s), 1439 (w), 1478 (w), 1578 (s), 1577 (s), 2832 (w), 2937 (w), 3074 (w); MS (ES+) 287 [(M+H)+]; + HRMS C17H19O2S [(M+H) ] Expected 287.1100, Found 287.1105.

140

[2,2',5,5'-Tetramethoxy-(1,1'-biphenyl)-4,4'-diyl]bis(phenylsulfide)68 92

As described in general procedure C, 91a (50.0 mg, 0.203 mmol), allyl TMS (320 μl, 2.00 mmol) and FeCl3 (72.4 mg, 0.450 mmol) with MeNO2 solvent, after purification by column chromatography (50:1 hexanes:EtOAc) gave 92 (64.8 mg, 0.132 mmol, 65%) as a yellow solid; δH (400 MHz, CDCl3) 3.50 (6 H, s, OCH3), 3.76 (6 H, s, OCH3), 6.65 (2 H, s, aryl H), 6.78 (2 H, s, aryl H), 7.21 (2 H, dt, J 7.3, 1.5 Hz, aryl H), 7.27 (4 H, t, J 7.3 Hz, aryl H), 7.31 – 7.38 (4 H, m, aryl H); δC (100 MHz, CDCl3) 56.4 (OCH3), 56.6 (OCH3),

114.6 (aryl C-H), 115.1 (aryl C-H), 123.9 (aryl Cq), 126.7 (aryl Cq), 127.3 (aryl C-H),

129.2 (aryl C-H), 131.6 (aryl C-H), 134.4 (aryl Cq), 151.1 (aryl Cq), 151.2 (aryl Cq).

5.7 Iron-mediated C-H Coupling of Arylsulfides and Terminal Alkenes General Procedure D

A solution of FeCl3 (0.800 mmol) in MeNO2 (1 mL) was added dropwise over 1 h to a stirred solution of the corresponding sulfide (0.200 mmol) and alkene (1.00 mmol) in

CH2Cl2 (1 mL). The mixture was then left to stir for 1 h. The reaction mixture was then quenched with H2O (2 ml), diluted with CH2Cl2 (2 mL), 2,2’-bipyridine (127 mg, 0.800 mmol) added and stirred for 15 min. at room temperature. The organic layer was then washed with H2O (2 × 2 ml) and the combined aqueous layers were extracted with CH2Cl2

(3 × 2 mL). The combined organic extracts were dried with MgSO4, filtered and solvent removed in vacuo. The crude mixture was then passed through a silica plug with CHCl3 eluent.

141

[2-(2-Chlorooctyl)-3,5-dimethoxyphenyl](phenyl)sulfide 99a

As described in general procedure D, 91b (50.0 mg, 0.203 mmol), 1-octene (160 μl, 1 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography

(30% CHCl3 in hexanes) gave 99a (51.2 mg, 0.130 mmol, 64%) as a colourless oil; δH

(500 MHz, CDCl3) 0.79 (3 H, t, J 6.9, CH2CH3), 1.11 - 1.34 (7 H, m, CH2), 1.44 - 1.56 (1

H, m, CH2), 1.60 - 1.68 (2 H, m, CH2), 3.14 (1 H, dd, J 13.6, 6.9 Hz, ArCH2CHCl), 3.24 (1

H, dd, J 13.6, 7.6 Hz, ArCH2CHCl), 3.59 (3 H, s, OCH3), 3.74 (3 H, s, OCH3), 4.18 (1 H, dt, J 12.9, 7.3 Hz, CHCl), 6.32 (1 H, d, J 2.5 Hz, aryl H), 6.35 (1 H, d, J 2.5 Hz, aryl H),

7.09 - 7.22 (5 H, m, aryl H); δC (125 MHz, CDCl3) 14.1 (CH3), 22.6 (CH2), 26.7 (CH2),

28.8 (CH2), 31.7 (CH2), 36.3 (ArCH2CHCl), 37.7 (CH2), 55.3 (OCH3), 55.6 (OCH3), 63.4

(CHCl), 98.3 (aryl C-H), 108.8 (aryl C-H), 121.3 (aryl Cq), 126.6 (aryl C-H), 129.1 (aryl

C-H), 130.0 (aryl C-H), 136.4 (aryl Cq), 136.6 (aryl Cq), 159.1 (aryl Cq), 159.3 (aryl Cq); -1 νmax (thin film/cm ) 1046 (s), 1163 (s), 1198, 1459 (w), 1570 (s), 1596 (s), 2856 (w), 2929 + 35 37 + + (w), 2954 (w); MS (ES ) m/z 393 Cl, 395 Cl [(M+H) ]; HRMS C22H30O2ClS [(M+H) ] Expected 393.1650, Found 393.1651.

[2-(2-Chlorohexyl)-3,5-dimethoxyphenyl](phenyl)sulfide 99b

As described in general procedure D, 91b (50.0 mg, 0.203 mmol), 1-hexene (127 μl, 1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography

(30% CHCl3 in hexanes) gave 99b (46.0 mg, 0.126 mmol, 62%) as a colourless oil; δH

(500 MHz, CDCl3) 0.90 (3 H, t, J 7.3 Hz, CH2CH3), 1.23 - 1.43 (3 H, m, CH2), 1.54 - 1.65

(1 H, m, CH2), 1.71 - 1.78 (2 H, m, CH2), 3.24 (1 H, dd, J 13.6, 7.3 Hz, ArCH2CHCl), 3.34

(1 H, dd, J 13.6, 7.6 Hz, ArCH2CHCl), 3.69 (3 H, s, OCH3), 3.84 (3 H, m, OCH3), 4.28 (1

142

H, m, CHCl), 6.42 (1 H, d, J 2.2 Hz, aryl H), 6.45 (1 H, d, J 2.2 Hz, aryl H), 7.20 - 7.32 (5

H, m, aryl H); δC (125 MHz, CDCl3) 14.0 (CH3), 22.2 (CH2), 28.9 (CH2), 36.3

(ArCH2CHCl), 37.5 (CH2), 55.3 (OCH3), 55.6 (OCH3), 63.3 (CHCl), 98.3 (aryl C-H),

108.9 (aryl C-H), 121.3 (aryl Cq), 126.6 (aryl C-H), 129.1 (aryl C-H), 130.1 (aryl C-H), -1 136.4 (aryl Cq), 136.7 (aryl Cq), 159.2 (aryl Cq), 159.3 (aryl Cq); νmax (thin film/cm ) 1048 (s), 1156 (s), 1198, 1459 (w), 1581 (s), 1598 (s), 2856 (w), 2935 (w); MS (ES+) m/z 365 35 37 + + Cl, 367 Cl [(M+H) ]; HRMS C20H26O2ClS [(M+H) ] Expected 365.1337, Found 365.1334.

[2-(2-Chlorohept-6-en-1-yl)-3,5-dimethoxyphenyl](phenyl)sulfide 99c

As described in general procedure D, 91b (50.0 mg, 0.203 mmol), 1,6-heptadiene (138 μl,

1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography (30% CHCl3 in hexanes) gave 99c (42.2 mg, 0.112 mmol, 55%) as a colourless oil; δH (500 MHz, CDCl3) 1.43 - 1.54 (1 H, m, CH2), 1.67 - 1.80 (3 H, m, CH2),

1.96 - 2.12 (2 H, m. CH2CH2CH=CH2), 3.24 (1 H, dd, J 13.6, 7.3 Hz, ArCH2CHCl), 3.34

(1 H, dd, J 13.6, 7.6 Hz, ArCH2CHCl), 3.69 (3 H, s, OCH3), 3.84 (3 H, s, OCH3), 4.29 (1

H, m, CHCl), 4.95 (1 H, dq, J 10.1, 1.3 Hz, CH=CH2), 5.00 (1 H, dq, J 17.1, 1.8 Hz,

CH=CH2), 5.79 (1 H, ddt, J 17.1, 10.1, 6.6 Hz, CH2CH=CH2), 6.42 (1 H, d, J 2.2 Hz, aryl

H), 6.44 (1 H, d, J 2.2 Hz, aryl H), 7.21 - 7.32 (5 H, m, aryl H); δC (125 MHz, CDCl3) 25.9

(CH2), 33.2 (CH2CH2CH=CH2), 36.3 (ArCH2CHCl), 37.1 (CH2), 55.3 (OCH3), 55.6

(OCH3), 63.0 (CHCl), 98.3 (aryl C-H), 108.9 (aryl C-H), 114.7 (CH=CH2), 121.2 (aryl Cq),

126.6 (aryl C-H), 129.1 (aryl C-H), 130.1 (aryl C-H), 136.3 (aryl Cq), 136.7 (aryl Cq), -1 138.5 (CH=CH2), 159.1 (aryl Cq), 159.3 (aryl Cq); νmax (thin film/cm ) 1047 (s), 1144 (s), 1198 (s), 1295 (w), 1460 (m), 1571 (s), 1597 (s), 2835 (w), 2936 (w); MS (ES+) m/z 377 35 37 + + Cl, 379 Cl [(M+H) ]; HRMS C21H26O2ClS [(M+H) ] Expected 377.1337, Found 377.1339.

143

[2-(2-Chloro-4-methylpentyl)-3,5-dimethoxyphenyl](phenyl)sulfide 99d

As described in general procedure D, 91b (50.0 mg, 0.203 mmol), 4-methyl-1-hexene

(142 μL, 1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography (30% CHCl3 in hexanes) gave 99d (35.7 mg, 94.2 µmol, 46% as a 1:1 mixture of diastereoisomers) as a colourless oil; δH (400 MHz, CDCl3) 0.75 - 0.93 (6 H, m,

CH3), 0.98 - 1.58 (3 H, m, CH2), 1.60 - 1.88 (2 H, m, CH2), 3.17 - 3.40 (2 H, m,

ArCH2CHCl), 3.69 (3 H, s, OCH3), 3.83 (3 H, s, OCH3), 4.31 - 4.44 (1 H, m, CHCl), 6.42

(1 H, app. s, aryl H), 6.45 (1 H, app. s, aryl H), 7.17 - 7.32 (5 H, m, aryl H); δC (100 MHz,

CDCl3) 10.7 + 11.4 (CH3), 18.0 + 19.4 (CH3), 27.9, 30.0, 31.5, 31.7, 36.3 + 36.8

(ArCH2CHCl), 44.7 + 45.2 (alkyl H), 55.3 (OCH3), 55.6 (OCH3), 61.3 + 61.4 (CHCl), 98.4

(aryl C-H), 109.0 (aryl C-H), 121.4 + 121.5 (aryl Cq), 126.5 (aryl C-H), 129.1 (aryl C-H),

129.8 (aryl C-H), 136.4 (aryl Cq), 136.5 + 136.6 (aryl Cq), 159.1 (aryl Cq), 159.2 (aryl Cq); -1 νmax (thin film/cm ) 1047 (s), 1146 (s), 1199 (s), 1296 (w), 1461 (m), 1477 (m), 1571 (s), 1597 (s), 2931 (m), 2959 (m); MS (ES+) m/z 379 35Cl, 381 37Cl [(M+H)+]; HRMS + C21H27O2S [(M−Cl) ] Expected 343.1732, Found 343.1729.

[2-(8-Bromo-2-chlorooctyl)-3,5-dimethoxyphenyl](phenyl)sulfide 99e

As described in General Procedure D, 91b (50.0 mg, 0.203 mmol), 8-bromo-1-octene (171

μL, 1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography (30% CHCl3 in hexanes) gave 99e (53.8 mg, 0.114 mmol, 56%) as a colourless oil; δH (400 MHz, CDCl3) 1.19 - 1.47 (5 H, m, CH2), 1.58 - 1.67 (1 H, m, CH2),

1.68 - 1.76 (2 H, m, CH2), 1.84 (2 H, quin, J 7.1 Hz, CH2CH2CH2Br), 3.23 (1 H, dd, J

13.6, 7.3 Hz, ArCH2CHCl), 3.33 (1 H, dd, J 13.6, 7.3 Hz ArCH2CHCl), 3.40 (2 H, t, J 7.1

144

Hz, CH2CH2Br), 3.68 (3 H, s, OCH3), 3.83 (3 H, s, OCH3), 4.20 - 4.31 (1 H, m, CHCl), 6.41 (1 H, d, J 2.3 Hz, aryl H), 6.43 (1 H, d, J 2.3 Hz, aryl H), 7.18 - 7.32 (5 H, m, aryl H);

δC (100 MHz, CDCl3) 26.5 (CH2), 28.0 (CH2), 28.2 (CH2), 32.7 (CH2CH2Br), 34.0

(CH2Br), 36.2 (ArCH2CHCl), 37.4 (CH2), 55.3 (OCH3), 55.6 (OCH3), 63.1 (CHCl), 98.3

(aryl C-H), 108.8 (aryl C-H), 121.1 (aryl Cq), 126.6 (aryl C-H), 129.1 (aryl C-H), 130.0

(aryl C-H), 136.3 (aryl Cq), 136.5 (aryl Cq), 159.1 (aryl Cq), 159.3 (aryl Cq); νmax (thin film/cm-1) 1046 (s), 1146 (s), 1198 (s), 1296 (w), 1461 (m), 1571 (s), 1596 (s), 2856 (w), 2933.67 (w); MS (ES+) m/z 471 35Cl79Br, 473 37Cl79Br and 35Cl81Br, 475 37Cl81Br + + [(M+H) ]; HRMS C22H28BrO2S [(M−Cl) ] Expected 435.0993, Found 435.1008.

[2-(6-Bromo-2-chlorohexyl)-3,5-dimethoxyphenyl](phenyl)sulfide 99f

As described in General Procedure D, 91b (50.0 mg, 0.203 mmol), 6-bromo-1-octene

(136 μL, 1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography (30% CHCl3 in hexanes), gave 99f (47.9 mg, 0.108 mmol, 53%) as a colourless oil; δH (500 MHz, CDCl3) 1.46 - 1.56 (1 H, m, CH2), 1.69 - 1.91 (5 H, m, CH2),

3.24 (1 H, dd, J 13.6, 7.6 Hz, ArCH2CHCl), 3.33 (1 H, dd, J 13.6, 7.3 Hz, ArCH2CHCl),

3.38 (2 H, t, J 6.8 Hz, CH2CH2Br), 3.69 (3 H, s, OCH3), 3.83 (3 H, s, OCH3), 4.22 - 4.30 (1 H, m, CHCl), 6.41 (1 H, d, J 2.2 Hz, aryl H), 6.44 (1 H, d, J 2.2 Hz, aryl H), 7.20 - 7.32 (5

H, m, aryl H); δC (125 MHz, CDCl3) 25.5 (CH2), 32.3 (CH2), 33.5 (CH2CH2Br), 36.2

(ArCH2CHCl), 36.6 (CH2), 55.3 (OCH3), 55.6 (OCH3), 62.6 (CHCl), 98.3 (aryl C-H),

108.9 (aryl C-H), 120.9 (aryl Cq), 126.7 (aryl C-H), 129.2 (aryl C-H), 130.0 (aryl C-H), -1 136.2 (aryl Cq), 136.6 (aryl Cq), 159.1 (aryl Cq), 159.4 (aryl Cq); νmax (thin film/cm ) 1046 (s), 1146 (s), 1197 (s), 1295 (w), 1459 (m), 1571 (s), 1596 (s), 2835 (w), 2937 (w), 3001 (w); MS (ES+) m/z 443 35Cl79Br, 445 37Cl79Br and 35Cl81Br, 447 37Cl81Br [(M+H)+]; + HRMS C20H24O2BrS [(M−Cl) ] Expected 407.0680, Found 407.0663.

145

[2-(2,6-Dichlorohexyl)-3,5-dimethoxyphenyl](phenyl)sulfide 99g

As described in general procedure D, 91b (50.0 mg, 0.203 mmol), 6-chloro-1-hexene

(135 μl, 1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography (30% CHCl3 in hexanes) gave 99g (36.8 mg, 92.1 µmol, 45%) as a colourless oil; δH (500 MHz, CDCl3) 1.39 - 1.46 (1 H, m, CH2) 1.61 - 1.73 (5 H, m, CH2),

3.16 (1 H, dd, J 13.9, 7.6 Hz, ArCH2CHCl), 3.25 (1 H, dd, J 13.9, 7.3 Hz, ArCH2CHCl),

3.42 (2 H, t, J 6.6 Hz, CH2CH2Cl), 3.60 (3 H, s, OCH3), 3.75 (3 H, m, OCH3), 4.18 (1 H, m, CHCl), 6.33 (1 H, d, J 2.5 Hz, aryl H), 6.35 (1 H, d, J 2.5 Hz, aryl H), 7.11 - 7.23 (5 H, m, aryl H); δC (125 MHz, CDCl3) 24.2 (CH2), 32.2 (CH2), 36.2 (ArCH2CHCl), 36.8 (CH2),

44.8 (CH2Cl), 55.3 (OCH3), 55.7 (OCH3), 62.6 (CHCl), 98.4 (aryl C-H), 109.0 (aryl C-H),

121.0 (aryl Cq), 126.7 (aryl C-H), 129.2 (aryl C-H), 130.0 (aryl C-H), 136.3 (aryl Cq), -1 136.6 (aryl Cq), 159.1 (aryl Cq), 159.4 (aryl Cq); νmax (thin film/cm ) 1046 (s), 1148 (s), 1198 (s), 1295 (w), 1460 (m), 1477 (m), 1571 (s), 1596 (s), 2835 (w), 2938 (w); MS (ES+) 35 35 37 35 37 37 + + m/z 399 Cl Cl, 401 Cl Cl, 403 Cl Cl [(M+H) ]; HRMS C20H24O2ClS [(M−Cl) ] Expected 363.1186, Found 363.1201.

[2-(2-Chloro-6-iodohexyl)-3,5-dimethoxyphenyl](phenyl)sulfide 99h

As described in general procedure D, 91b (50.0 mg, 0.203 mmol), 6-iodo-1-hexene (135

μl, 1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography (30% CHCl3 in hexanes) gave 99h (49.1 mg, 0.100 mmol, 49%) as a yellow oil; δH (500 MHz, CDCl3) 1.49 (1 H, m, CH2), 1.66 - 1.89 (5 H, m, CH2), 3.15 (2 H, m, CH2CH2I), 3.24 (1 H, dd, J 13.6, 7.3 Hz, ArCH2CHCl), 3.33 (1 H, dd, J 13.6, 7.3 Hz,

ArCH2CHCl), 3.69 (3 H, s, OCH3), 3.84 (3 H, m, OCH3), 4.22 - 4.29 (1 H, m, CHCl), 6.42

146

(1 H, d, J 2.5 Hz, aryl H), 6.44 (1 H, d, J 2.5 Hz, aryl H), 7.20 - 7.32 (5 H, m, aryl H); δC

(125 MHz, CDCl3) 6.4 (CH2I), 27.8 (CH2), 33.1 (CH2), 36.3 (ArCH2CHCl), 36.4 (CH2),

55.3 (OCH3), 55.7 (OCH3), 62.3 (CHCl), 98.4 (aryl C-H), 109.0 (aryl C-H), 121.0 (aryl

Cq), 126.7 (aryl C-H), 129.2 (aryl C-H), 130.0 (aryl C-H), 136.3 (aryl Cq), 136.6 (aryl Cq), -1 159.1 (aryl Cq), 159.4 (aryl Cq); νmax (thin film/cm ) 1045 (s), 1147 (s), 1198 (s), 1295 (w), 1437 (m), 1458 (m), 1478 (m), 1571 (s), 1595 (s), 2834 (w), 2936 (w), 3000 (w); MS (ES+) 35 37 + + m/z 491 Cl, 493 Cl [(M+H) ]; HRMS C20H25IO2ClS [(M+H) ] Expected 491.0303, Found 491.0298.

[2-(2-Chloro-8-nitrooctyl)-3,5-dimethoxyphenyl](phenyl)sulfide 99i

As described in general procedure D, 91b (50.0 mg, 0.203 mmol), 6-nitro-1-octene (160.4 mg, 1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography (10% EtOAc in hexanes) gave 99i (42.1 mg, 96.1 µmol, 47%) as a yellow oil; δH (500 MHz, CDCl3) 1.23 - 1.44 (5 H, m, CH2), 1.56 - 1.66 (1 H, m, CH2), 1.67 - 1.77

(2 H, m, CH2), 1.99 (2 H, quin, J 7.2 Hz, CH2CH2CH2NO2), 3.23 (1 H, dd, J 13.6, 7.3 Hz,

ArCH2CHCl), 3.33 (1 H, dd, J 13.6, 7.3 Hz, ArCH2CHCl), 3.69 (3 H, s, OCH3), 3.83 (3 H, s, OCH3), 4.26 (1 H, m, CHCl), 4.36 (2 H, t, J 7.2 Hz, CH2CH2NO2), 6.41 (1 H, d, J 2.2

Hz, aryl H), 6.44 (1 H, d, J 2.2 Hz, aryl H), 7.19 - 7.32 (5 H, m, aryl H); δC (125 MHz,

CDCl3) 26.1 (CH2), 26.3 (CH2), 27.3 (CH2CH2NO2), 28.3 (CH2), 36.3 (ArCH2CHCl), 37.3

(CH2), 55.3 (OCH3), 55.7 (OCH3), 62.9 (CHCl), 75.6 (CH2NO2), 98.4 (aryl C-H), 108.9

(aryl C-H), 121.1 (aryl Cq), 126.7 (aryl C-H), 129.2 (aryl C-H), 130.0 (aryl C-H), 136.3 -1 (aryl Cq), 136.6 (aryl Cq), 159.1 (aryl Cq), 159.4 (aryl Cq); νmax (thin film/cm ) 1046 (s), 1144 (s), 1198 (s), 1295 (w), 1390 (m), 1458 (m), 1560 (s), 2844 (w), 2926 (m); MS (ES+) 35 37 + + m/z 438 Cl, 440 Cl [(M+H) ]; HRMS C22H28NO4S [(M−Cl) ] Expected 402.1739, Found 402.1741.

147

[2-(2-Chloro-9-phenylnonyl)-3,5-dimethoxyphenyl](phenyl)sulfide 99j

As described in general procedure D, 91b (50.0 mg, 0.203 mmol), 9-phenyl-1-nonene (206 mg, 1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography (30% CHCl3 in hexanes) gave 99j (61.9 mg, 0.128 mmol, 63%) as a colourless oil; δH (400 MHz, CDCl3) 1.18 - 1.44 (7 H, m, CH2), 1.59 - 1.67 (3 H, m, CH2),

1.69 - 1.78 (2 H, m, CH2), 2.61 (2 H, t, J 7.5 Hz, CH2CH2Ph), 3.24 (1 H, dd, J 13.6, 7.0

Hz, ArCH2CHCl), 3.34 (1 H, dd, J 13.6, 7.5 Hz, ArCH2CHCl), 3.69 (3 H, s, OCH3), 3.83

(3 H, s, OCH3), 4.28 (1 H, m, CHCl), 6.42 (1 H, d, J 2.3 Hz, aryl H), 6.45 (1 H, d, J 2.3

Hz, aryl H), 7.16 - 7.33 (10 H, m, aryl H); δC (100 MHz, CDCl3) 26.8 (CH2), 29.1 (CH2),

29.3 (CH2), 29.4 (CH2), 31.6 (CH2), 36.0 (CH2CH2Ph), 36.3 (ArCH2CHCl), 37.7 (CH2),

55.4 (OCH3), 55.7 (OCH3), 63.4 (CHCl), 98.3 (aryl C-H), 108.8 (aryl C-H), 121.3 (aryl

Cq), 125.6 (aryl C-H), 126.6 (aryl C-H), 128.3 (aryl C-H), 128.5 (aryl C-H), 129.2 (aryl C-

H), 130.0 (aryl C-H), 136.4 (aryl Cq), 136.6 (aryl Cq), 142.9 (aryl Cq), 159.1 (aryl Cq), -1 159.3 (aryl Cq); νmax (thin film/cm ) 1047 (s), 1146 (s), 1198 (s), 1296 (w), 1454 (m), 1495 (m), 1571 (s), 1596 (s), 2854 (m), 2928 (s); MS (ES+) m/z 483 35Cl, 485 37Cl [(M+H)+]; + HRMS C29H35O2S [(M−Cl) ] Expected 447.2358, Found 447.2323.

[2-(2-Chloro-3-phenylpropyl)-3,5-dimethoxyphenyl](phenyl)sulfide 99k

As described in general procedure D, 91b (50.0 mg, 0.203 mmol), allylbenzene (135 μL,

1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography (30% CHCl3 in hexanes) gave 99k (30.1 mg, 75.4 µmol, 37%) as a colourless oil; δH (500 MHz, CDCl3) 3.02 (1 H, dd, J 14.5, 8.8 Hz, ArCH2CHCl), 3.08 (1

H, dd, J 14.5, 4.7 Hz, ArCH2CHCl), 3.29 (1 H, dd, J 13.6, 6.6 Hz, ArCH2CHCl), 3.39 (1

148

H, dd, J 13.6, 7.6 Hz, ArCH2CHCl), 3.69 (3 H, s, OCH3), 3.81 (3 H, s, OCH3), 4.45 - 4.52 (1 H, m, CHCl), 6.41 (1 H, d, J 2.5 Hz, aryl H), 6.45 (1 H, d, J 2.5 Hz, aryl H), 7.15 - 7.31

(10 H, m); δC (125 MHz, CDCl3) 36.1 (ArCH2CHCl), 44.3 (ArCH2CHCl), 55.3 (OCH3),

55.6 (OCH3), 63.1 (CHCl), 98.4 (aryl C-H), 109.0 (aryl C-H), 121.0 (aryl Cq), 126.5 (aryl C-H), 126.6 (aryl C-H), 128.2 (aryl C-H), 129.1 (aryl C-H), 129.2 (aryl C-H), 130.0 (aryl

C-H), 136.3 (aryl Cq), 136.6 (aryl Cq), 138.7 (aryl Cq), 159.1 (aryl Cq), 159.4 (aryl Cq); νmax (thin film/cm-1) 1046 (vs), 1154 (s), 1198 (s), 1296 (m), 1437 (m), 1454 (s), 1477 (s), 1571 (vs), 1596 (vs), 2835 (w), 2935 (w), 2957 (w), 3000 (w), 3025 (w); MS (APCI) m/z 399 35 37 + + Cl, 401 Cl [(M+H) ]; HRMS C23H24O2ClS [(M+H) ] Expected 399.1180, Found 399.1169.

(E)-[2-(4,4-Dimethylhepta-2,6-dien-1-yl)-3,5- dimethoxyphenyl](phenyl)sulfide 147a

As described in general procedure D, 91b (50.0 mg, 0.203 mmol), 4,4-dimethylhepta-1,6- diene (127 mg, 1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography (30% CHCl3 in hexanes) gave 147a (15.3 mg, 41.5 µmol, 21%) as a colourless oil; δH (400 MHz, CDCl3) 0.89 (6 H, s, C(CH3)2), 1.95 (2 H, d, J 7.3 Hz,

CH2CH=CH2), 3.50 (2 H, dd, J 6.1, 1.0 Hz, ArCH2CH=CH), 3.69 (3 H, s, OCH3), 3.81 (3

H, s, OCH3), 4.90 - 4.97 (2 H, m, CH=CH2), 5.29 (1 H, dt, J 15.6, 6.1 Hz, ArCH2CH=CH),

5.40 (1 H, dt, J 15.6, 1.0 Hz, ArCH2CH=CH), 5.72 (1 H, ddt, J 16.6, 10.6, 7.3 Hz,

CH=CH2), 6.41 (1 H, d, J 2.5 Hz, aryl H), 6.43 (1 H, d, J 2.5 Hz, aryl H), 7.16 - 7.30 (5 H, m, aryl H); δC (100 MHz, CDCl3) 26.9 (C(CH3)2), 30.5 (ArCH2CH=CH), 35.6 (alkyl Cq),

47.5 (CH2CH=CH2), 55.3 (OCH3), 55.7 (OCH3), 98.5 (aryl C-H), 108.7 (aryl C-H), 116.2

(CH=CH2), 123.4 (ArCH2CH=CH), 124.1 (aryl Cq), 126.4 (aryl C-H), 129.0 (aryl C-H),

130.0 (aryl C-H), 135.5 (aryl Cq), 136.1 (CH=CH2), 136.8 (aryl Cq), 140.4 -1 (ArCH2CH=CH), 158.7 (aryl Cq), 158.8 (aryl Cq); νmax (thin film/cm ) 1050 (s), 1150 (m), 1274 (w), 1295 (w), 1409 (m), 1436 (m), 1477 (m), 1571 (s), 1596 (s), 2834 (w), 2935 (m), + + + 2957 (m), 3000 (w), 3072 (w); MS (ES ) m/z 369 [(M+H) ]; HRMS C23H29O2S [(M+H) ] Expected 369.1883, Found 369.1881.

149

(E)-[2-(3-(1-Allylcyclohexyl)allyl)-3,5-dimethoxyphenyl](phenyl)sulfide 147b

As described in general procedure D, 91b (50.0 mg, 0.203 mmol), 1,1-diallylcyclohexane

(168 mg, 1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography (30% CHCl3 in hexanes) gave 147b (19.1 mg, 46.7 µmol, 23%) as a colourless oil; δH (400 MHz, CDCl3) 1.15 - 1.31 (4 H, m, CH2), 1.33 - 1.48 (6 H, m, CH2),

1.97 (2 H, d, J 7.3 Hz, CH2CH=CH2), 3.53 (2 H, d, J 5.3 Hz, ArCH2CH=CH), 3.69 (3 H, s,

OCH3), 3.81 (3 H, s, OCH3), 4.89 - 4.96 (2 H, m, CH=CH2), 5.22 (1 H, d, J 15.9 Hz,

ArCH2CH=CH), 5.29 (1 H, dt, J 15.9, 5.3 Hz, ArCH2CH=CH), 5.63 – 5.76 (1 H, m,

CH=CH2), 6.41 (1 H, d, J 2.5, Hz aryl H), 6.42 (1 H, d, J 2.5 Hz, aryl H), 7.16 - 7.22 (1 H, m, aryl H), 7.24 - 7.29 (4 H, m); δC (100 MHz, CDCl3) 22.1 (CH2), 26.5 (CH2), 30.7

(ArCH2CH=CH), 35.8 (CH2), 38.7 (alkyl Cq), 46.5 (CH2CH=CH2), 55.3 (OCH3), 55.6

(OCH3), 98.4 (aryl C-H), 108.5 (aryl C-H), 116.0 (CH=CH2), 123.9 (aryl Cq), 125.7

(ArCH2CH=CH), 126.4 (aryl C-H), 129.0 (aryl C-H), 130.1 (aryl C-H), 135.5 (aryl Cq),

135.8 (CH=CH2), 136.7 (aryl Cq), 138.4 (ArCH2CH=CH), 158.7 (aryl Cq), 158.8 (aryl Cq); -1 νmax (thin film/cm ) 1050 (s), 1144 (m), 1204 (s), 1275 (w), 1295 (w), 1460 (m), 1572 (s), 1597 (s), 2852 (m), 2925 (vs), 3000 (w), 3071 (w); MS (ES+) m/z 409 [(M+H)+]; HRMS + C26H33O2S [(M+H) ] Expected 409.2196, Found 409.2196.

(E)-[2-(4,4-Dimethylpent-2-en-1-yl)-3,5-dimethoxyphenyl](phenyl)sulfide 147c

As described in general procedure D, 91b (50.0 mg, 0.203 mmol), 4,4-dimethyl-1-pentene

(147 µL, 1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column

150 chromatography (30% CHCl3 in hexanes) gave 147c (13.9 mg, 40.6 µmol, 20%) as a colourless oil; δH (400 MHz, CDCl3) 0.92 (9 H, s, (CH3)3), 3.49 (2 H, dd, J 6.4, 1.1 Hz,

ArCH2CH=CH), 3.69 (3 H, s, OCH3), 3.82 (3 H, s, OCH3), 5.30 (1 H, dt, J 15.6, 6.4 Hz,

ArCH2CH=CH), 5.45 (1 H, dt, J 15.6, 1.1 Hz, ArCH2CH=CH), 6.42 (1 H, d, J 2.5 Hz, aryl H), 6.45 (1 H, d, J 2.5 Hz, aryl H), 7.15 - 7.22 (1 H, m, aryl H), 7.22 - 7.30 (4 H, m, aryl

H); δC (100 MHz, CDCl3) 29.6 ((CH3)3), 30.5 (ArCH2CH=CH), 51.4 (alkyl Cq), 55.3

(OCH3), 55.8 (OCH3), 98.6 (aryl C-H), 108.9 (aryl C-H), 121.9 (ArCH2CH=CH), 124.3

(aryl Cq), 126.3 (aryl C-H), 129.0 (aryl C-H), 129.9 (aryl C-H), 135.4 (aryl Cq), 136.9 (aryl -1 Cq), 142.1 (ArCH2CH=CH), 158.7 (aryl Cq), 158.8 (aryl Cq); νmax (thin film/cm ) 1049 (s), 1136 (m), 1157 (m), 1194 (m), 1207 (m), 1460 (m), 1476 (m), 1570 (s), 1596 (s), 2834 + + (w), 2864 (w), 2955 (m), 3000 (w); MS (ES ) m/z 343 [(M+H) ]; HRMS C21H27O2S [(M+H)+] Expected 343.1726, Found 343.1727.

[2-(2-Chlorooctyl)-3,5-dimethoxyphenyl](p-tolyl)sulfide 164a

As described in general procedure D, 91v (52.9 mg, 0.203 mmol), 1-octene (160 μL, 1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography

(30% CHCl3 in hexanes) gave 164a (43.6 mg, 0.107 mmol, 53%) as a colourless oil; δH

(500 MHz, CDCl3) 0.89 (3 H, t, J 6.9 Hz, CH2CH3), 1.20 - 1.43 (7 H, m, CH2), 1.60 (1 H, m, CH2), 1.70 - 1.77 (2 H, m, CH2), 2.34 (3 H, s, ArCH3), 3.24 (1 H, dd, J 13.6, 7.3 Hz,

ArCH2CHCl), 3.32 (1 H, dd, J 13.6, 7.6 Hz, ArCH2CHCl), 3.66 (3 H, s, OCH3), 3.82 (3 H, m, OCH3), 4.29 (1 H, m, CHCl), 6.34 (1 H, d, J 2.5 Hz, aryl H), 6.36 (1 H, d, J 2.5 Hz, aryl

H), 7.12 (2 H, d, J 7.9 Hz, aryl H), 7.21 (2 H, d, J 7.9 Hz, aryl H); δC (125 MHz, CDCl3)

14.1 (CH3), 21.1 (ArCH3), 22.6 (CH2), 26.7 (CH2), 28.8 (CH2), 31.7 (CH2), 36.2

(ArCH2CHCl), 37.7 (CH2), 55.3 (OCH3), 55.6 (OCH3), 63.3 (CHCl), 97.6 (aryl C-H),

107.9 (aryl C-H), 120.3 (aryl Cq), 130.0 (aryl C-H), 131.3 (aryl C-H), 131.9 (aryl Cq), -1 137.1 (aryl Cq), 138.0 (aryl Cq), 159.0 (aryl Cq), 159.2 (aryl Cq); νmax (thin film/cm ) 1048 (s), 1145 (s), 1199 (s), 1295 (w), 1460 (m), 1572 (s), 1596 (s), 2867 (w), 2929 (m); MS

151

+ 35 37 + + (ES ) m/z 407 Cl, 409 Cl [(M+H) ]; HRMS C23H32O2ClS [(M+H) ] Expected 407.1808, Found 407.1806.

(4-Bromophenyl)[2-(2-chlorooctyl)-3,5-dimethoxyphenyl]sulfide 164b

As described in general procedure D, 91w (66.0 mg, 0.203 mmol), 1-octene (160 μL, 1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography

(30% CHCl3 in hexanes) gave 164b (62.7 mg, 0.133 mmol, 65%) as a colourless oil; δH

(400 MHz, CDCl3) 0.88 (3 H, t, J 6.8 Hz, CH2CH3) 1.17 - 1.43 (7 H, m, CH2), 1.51 - 1.64

(1 H, m, CH2), 1.65 - 1.77 (2 H, m, CH2), 3.20 (1 H, dd, J 13.7, 6.7 Hz, ArCH2CHCl), 3.30

(1 H, dd, J 13.7, 7.7 Hz, ArCH2CHCl), 3.71 (3 H, s, OCH3), 3.83 (3 H, s, OCH3), 4.24 (1 H, m, CHCl), 6.44 (1 H, d, J 2.3 Hz, aryl H), 6.45 (1 H, d, J 2.3 Hz, aryl H), 7.08 (2 H, d, J

8.4 Hz, aryl H), 7.39 (2 H, d, J 8.4 Hz, aryl H); δC (100 MHz, CDCl3) 14.1 (CH3), 22.6

(CH2), 26.7 (CH2), 28.8 (CH2), 31.8 (CH2), 36.3 (ArCH2CHCl), 37.8 (CH2), 55.4 (OCH3),

55.7 (OCH3), 63.3 (CHCl), 98.8 (aryl C-H), 109.3 (aryl C-H), 120.2 (aryl Cq), 121.9 (aryl

Cq), 130.9 (aryl C-H), 132.1 (aryl C-H), 135.6 (aryl Cq), 136.2 (aryl Cq), 159.2 (aryl Cq), -1 159.4 (aryl Cq); νmax (thin film/cm ) 1007 (s), 1047 (s), 1144 (s), 1198 (s), 1295 (m), 1434 (m), 1471 (s), 1570 (s), 1596 (s), 2856 (w), 2929 (m); MS (ES+) m/z 471 35Cl79Br, 473 37 79 35 81 37 81 + + Cl Br and Cl Br, 475 Cl Br [(M+H) ]; HRMS C22H29BrO2ClS [(M+H) ] Expected 471.0755, Found 471.0751.

152

[2-(2-Chlorooctyl)-3,5-dimethoxyphenyl](4-fluorophenyl)sulfide 164c

As described in general procedure D, 91x (53.7 mg, 0.203 mmol), 1-octene (160 μL, 1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography

(30% CHCl3 in hexanes) gave 164c (55.9 mg, 0.136 mmol, 66%) as a colourless oil; δH

(400 MHz, CDCl3) 0.89 (3 H, t, J 6.8 Hz, CH2CH3), 1.20 - 1.45 (7 H, m, CH2), 1.54 - 1.67

(1 H, m, CH2), 1.68 - 1.78 (2 H, m, CH2), 3.22 (1 H, dd, J 13.8, 6.8 Hz, ArCH2CHCl), 3.31

(1 H, dd, J 13.8, 7.5 Hz, ArCH2CHCl), 3.67 (3 H, s, OCH3), 3.83 (3 H, s, OCH3), 4.28 (1 H, m, CHCl), 6.30 (1 H, d, J 2.3 Hz, aryl H), 6.38 (1 H, d, J 2.3 Hz, aryl H), 7.02 (2 H, t, J

8.7 Hz, aryl H), 7.25 - 7.33 (2 H, dd, J 8.7, 5.3 Hz, aryl H); δC (100 MHz, CDCl3) 14.1

(CH3), 22.6 (CH2), 26.7 (CH2), 28.8 (CH2), 31.7 (CH2), 36.2 (ArCH2CHCl), 37.8 (CH2),

55.3 (OCH3), 55.6 (OCH3), 63.3 (CHCl), 97.7 (aryl C-H), 107.8 (aryl C-H), 116.4 (d, J

22.0 Hz, aryl C-H), 120.3 (aryl Cq), 130.8 (d, J 2.9 Hz, aryl Cq), 133.2 (d, J 8.1 Hz, aryl C-

H), 137.7 (aryl Cq), 159.1 (aryl Cq), 159.3 (aryl Cq), 162.2 (d, J 247.2 Hz, aryl C-F); νmax (thin film/cm-1) 1047 (s), 1145 (s), 1198 (m), 1226 (m), 1295 (w), 1460 (w), 1488 (s), 1571 (m), 1590 (m), 2856 (w), 2929 (w); MS (ES+) m/z 411 35Cl, 413 37Cl [(M+H)+]; HRMS + C22H29O2ClFS [(M+H) ] Expected 411.1555, Found 411.1556.

[2-(2-Chlorooctyl)-3,5-dimethoxyphenyl](2-fluorophenyl)sulfide 164d

As described in general procedure D, 91y (53.7 mg, 0.203 mmol), 1-octene (160 μL, 1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography

(30% CHCl3 in hexanes) gave 164d (53.5 mg, 0.130 mmol, 64%) as a colourless oil; δH

(500 MHz, CDCl3) 0.89 (3 H, t, J 6.9 Hz, CH3), 1.19 - 1.44 (7 H, m, CH2), 1.55-1.64 (1 H,

153 m, CH2), 1.68 - 1.80 (2 H, m, CH2), 3.25 (1 H, dd, J 13.9, 6.9 Hz, ArCH2CHCl), 3.35 (1 H, dd, J 13.9, 7.6 Hz, ArCH2CHCl), 3.69 (3 H, s, OCH3), 3.83 (3 H, s, OCH3), 4.29 (1 H, m, CHCl), 6.39 (1 H, d, J 2.5 Hz, aryl H), 6.42 (1 H, d, J 2.5 Hz, aryl H), 7.03 - 7.15 (3 H, m, aryl H), 7.21 - 7.26 (1 H, m, aryl H); δC (125 MHz, CDCl3) 14.1 (CH3), 22.6 (CH2), 26.7

(CH2), 28.9 (CH2), 31.7 (CH2), 36.3 (ArCH2CHCl), 37.7 (CH2), 55.3 (OCH3), 55.6

(OCH3), 63.2 (CHCl), 98.4 (aryl C-H), 108.6 (aryl C-H), 115.8 (d, J 21.8 Hz, aryl C-H),

121.4 (aryl Cq), 123.4 (d, J 17.3 Hz, aryl Cq), 124.7 (d, J 3.6 Hz, aryl C-H), 128.8 (d, J 7.3

Hz, aryl C-H), 132.4 (aryl C-H), 135.2 (aryl Cq), 159.2 (aryl Cq), 159.4 (aryl Cq), 160.7 (d, -1 J 246.1 Hz, aryl C-F); νmax (thin film/cm ) 1047 (s), 1145 (s), 1221 (m), 1297 (w), 1472 (s), 1572 (s), 1597 (s), 2857 (w), 2930 (m); MS (ES+) m/z 411 35Cl, 413 37Cl [(M+H)+]; + HRMS C22H29O2ClFS [(M+H) ] Expected 411.1555, Found 411.1557.

[2-(2-Chlorooctyl)-3,5-dimethoxyphenyl](3-methoxyphenyl)sulfide 164e

As described in general procedure D, 91z (56.1 mg, 0.203 mmol), 1-octene (160 μL, 1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography

(30% CHCl3 in hexanes) gave 164e (52.7 mg, 0.125 mmol, 60%) as a colourless oil; δH

(500 MHz, CDCl3) 0.90 (3 H, t, J 7.1 Hz, CH3), 1.20 - 1.44 (7 H, m, CH2), 1.56-1.66 (1 H, m, CH2), 1.70 - 1.78 (2 H, m, CH2), 3.26 (1 H, dd, J 13.6, 6.9 Hz, ArCH2CHCl), 3.35 (1 H, dd, J 13.6, 7.3 Hz, ArCH2CHCl), 3.71 (3 H, s, OCH3), 3.77 (3 H, s, OCH3), 3.84 (3 H, s,

OCH3), 4.30 (1 H, m, CHCl), 6.44 (1 H, d, J 2.5 Hz, aryl H), 6.52 (1 H, d, J 2.5 Hz, aryl H), 6.76 (1 H, ddd, J 8.0, 2.5, 0.9 Hz, aryl H), 6.80 (1 H, dd, J 3.5, 2.5 Hz, aryl H), 6.82 -

6.85 (1 H, m, aryl H), 7.20 (1 H, t, J 8.0 Hz, aryl H); δC (125 MHz, CDCl3) 14.1 (CH3),

22.6 (CH2), 26.7 (CH2), 28.8 (CH2), 31.8 (CH2), 36.3 (ArCH2CHCl), 37.8 (CH2), 55.26

(OCH3), 55.4 (OCH3), 55.6 (OCH3), 63.4 (CHCl), 98.6 (aryl C-H), 109.4 (aryl C-H), 112.2

(aryl C-H), 115.0 (aryl C-H), 121.7 (aryl Cq), 122.0 (aryl C-H), 129.9 (aryl C-H), 136.0

(aryl Cq), 138.0 (aryl Cq), 159.2 (aryl Cq), 159.4 (aryl Cq), 160.1 (aryl Cq); νmax (thin film/cm-1) 1045 (s), 1144 (m), 1199 (m), 1247 (m), 1462 (m), 1476 (m), 1572 (s), 1585 (s),

154

2856 (w), 2930 (m), 3000 (w); MS (ES+) m/z 423 35Cl, 425 37Cl [(M+H)+]; HRMS + C23H31O3S [(M−Cl) ] Expected 387.1994, Found 387.1992.

[2-(2-Chlorooctyl)-3,5-dimethoxyphenyl](3,5-dimethoxyphenyl)sulfide 164f

As described in general procedure D, 91aa (62.2 mg, 0.203 mmol), 1-octene (160 μL, 1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography

(50% CHCl3 in hexanes) gave 164f (43.0 mg, 94.9 µmol, 47%) as a white solid; m.p 62.1-

64.3 ⁰C; δH (400 MHz, CDCl3) 0.88 (3 H, t, J 6.9 Hz, CH2CH3), 1.16 - 1.41 (7 H, m, CH2),

1.51-1.64 (1 H, m, CH2), 1.65 - 1.76 (2 H, m, CH2), 3.21 (1 H, dd, J 13.8, 7.0 Hz,

ArCH2CHCl), 3.31 (1 H, dd, J 13.8, 7.5 Hz, ArCH2CHCl), 3.72 (3 H, s, OCH3), 3.74 (6 H, s, OCH3), 3.83 (3 H, s, OCH3), 4.25 (1 H, m, CHCl), 6.29 (1 H, t, J 2.0 Hz, aryl H), 6.35 (2

H, d, J 2.0 Hz, aryl H), 6.43 (1 H, d, J 2.3 Hz, aryl H), 6.55 (1 H, d, J 2.3 Hz, aryl H); δC

(100 MHz, CDCl3) 14.2 (CH3), 22.7 (CH2), 26.7 (CH2), 28.8 (CH2), 31.2 (CH2), 36.3

(ArCH2CHCl), 37.8 (CH2), 55.4 (OCH3), 55.4 (OCH3), 55.6 (OCH3), 63.5 (CHCl), 98.6

(aryl C-H), 98.9 (aryl C-H), 107.0 (aryl C-H), 109.7 (aryl C-H), 122.0 (aryl Cq), 135.3

(aryl Cq), 139.0 (aryl Cq), 159.1 (aryl Cq), 159.3 (aryl Cq), 161.0 (aryl Cq); νmax (thin film/cm-1) 1044 (s), 1154 (s), 1202 (s), 1279 (m), 1417 (m), 1454 (m), 1570 (s), 1585 (s), + 35 37 + 2856 (w), 2930 (m); MS (ES ) m/z 453 Cl, 455 Cl [(M+H) ]; HRMS C24H34O4ClS [(M+H)+] Expected 453.1866, Found 453.1873.

[2-(2-Chlorooctyl)-3,5-dimethoxyphenyl](4-nitrophenyl)sulfide 164g

As described in general procedure D, 91d (59.1 mg, 0.203 mmol), 1-octene (160 μL, 1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography

155

(30% CHCl3 in hexanes) gave 164g (66.9 mg, 0.153 mmol, 75%) as a yellow solid; m.p

50.2-52.6 ⁰C; δH (400 MHz, CDCl3) 0.87 (3 H, t, J 6.8 Hz, CH2CH3), 1.14 - 1.42 (7 H, m,

CH2), 1.47 - 1.62 (1 H, m, CH2), 1.65 - 1.75 (2 H, m, CH2), 3.17 (1 H, dd, J 13.7, 6.1 Hz,

ArCH2CHCl), 3.26 (1 H, dd, J 13.7, 8.2 Hz, ArCH2CHCl), 3.78 (3 H, s, OCH3), 3.87 (3 H, s, OCH3), 4.21 (1 H, m, CHCl), 6.57 (1 H, d, J 2.2 Hz, aryl H), 6.66 (1 H, d, J 2.2 Hz, aryl

H), 7.13 (2 H, d, J 8.9 Hz, aryl H), 8.06 (2 H, d, J 8.9 Hz, aryl H); δC (100 MHz, CDCl3)

14.0 (CH3), 22.6 (CH2), 26.6 (CH2), 28.7 (CH2), 31.6 (CH2), 36.5 (ArCH2CHCl), 38.0

(CH2), 55.5 (OCH3), 55.7 (OCH3), 63.1 (CHCl), 100.6 (aryl C-H), 111.3 (aryl C-H), 123.9

(aryl Cq), 124.0 (aryl C-H), 126.2 (aryl C-H), 131.6 (aryl Cq), 145.1 (aryl Cq), 148.6 (aryl -1 Cq), 159.5 (aryl Cq), 159.8 (aryl Cq); νmax (thin film/cm ) 1044 (m), 1086 (m), 1144 (m), 1198 (m), 1298 (w), 1334 (s), 1460 (w), 1513 (m), 1595 (m), 2855 (w), 2929 (w); MS + 35 37 + + (ES ) m/z 438 Cl, 440 Cl [(M+H) ]; HRMS C22H29NO4ClS [(M+H) ] Expected 438.1506, Found 438.1500.

[(2-(2-Chlorooctyl)-3,5-dimethoxyphenyl](4-trifluoromethylphenyl)sulfide 164h

As described in general procedure D, 91e (63.8 mg, 0.203 mmol), 1-octene (160 μL, 1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography

(30% CHCl3 in hexanes) gave 164h (69.8 mg, 0.151 mmol, 75%) as a colourless oil; δH

(400 MHz, CDCl3) 0.88 (3 H, t, J 6.9 Hz, CH2CH3), 1.16 - 1.42 (7 H, m, CH2), 1.50 - 1.63

(1 H, m, CH2), 1.63 - 1.78 (2 H, m, CH2), 3.20 (1 H, dd, J 13.6, 6.5 Hz, ArCH2CHCl), 3.30

(1 H, dd, J 13.6, 8.0 Hz, ArCH2CHCl), 3.75 (3 H, s, OCH3), 3.86 (3 H, s, OCH3), 4.23 (1 H, m, CHCl), 6.52 (1 H, d, J 2.5 Hz, aryl H), 6.61 (1 H, d, J 2.5 Hz, aryl H), 7.18 (2 H, d, J

8.3 Hz, aryl H), 7.47 (2 H, d, J 8.3 Hz, aryl H); δC (100 MHz, CDCl3) 14.1 (CH3), 22.6

(CH2), 26.7 (CH2), 28.8 (CH2), 31.7 (CH2), 36.4 (ArCH2CHCl), 37.9 (CH2), 55.5 (OCH3),

55.7 (OCH3), 63.3 (CHCl), 99.9 (aryl C-H), 110.8 (aryl C-H), 123.3 (aryl Cq), 124.3 (q, J

271.4 Hz, CF3), 125.7 (q, J 3.7 Hz, aryl C-H), 127.3 (aryl C-H), 128.3 (q, J 32.3 Hz, aryl -1 Cq), 133.3 (aryl Cq), 143.3 (aryl Cq), 159.4 (aryl Cq), 159.6 (aryl Cq); νmax (thin film/cm )

156

1013 (m), 1047 (m), 1063 (m), 1123 (m), 1163 (m), 1324 (s), 1461 (w), 1570 (m), 1598 + 35 37 + (m), 2857 (w), 2931 (w); MS (ES ) m/z 461 Cl, 463 Cl [(M+H) ]; HRMS C23H28O2F3S [(M−Cl)+] Expected 425.1757, Found 425.1755.

[2-(2-Chlorooctyl)-3,5-diisopropoxyphenyl](phenyl)sulfide 164i

As described in general procedure D, 91ab (61.4 mg, 0.203 mmol), 1-octene (160 μL, 1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography

(30% CHCl3 in hexanes) gave 164i (59.5 mg, 0.132 mmol, 65%) as a colourless oil; δH

(400 MHz, CDCl3) 0.89 (3 H, t, J 6.8 Hz, CH3), 1.20 - 1.33 (12 H, m, OCH(CH3)2), 1.33 -

1.41 (7 H, m, CH2), 1.50 - 1.65 (1 H, m, CH2), 1.68-1.77 (2 H, q, J 7.4 Hz, CH2), 3.23 (1

H, dd, J 13.6, 7.3 Hz, ArCH2CHCl), 3.30 (1 H, dd, J 13.6, 7.0 Hz, ArCH2CHCl), 4.23 -

4.40 (2 H, m, CHCl and OCH(CH3)2), 4.53 (1 H, sept, J 6.0 Hz, OCH(CH3)2), 6.36 (2 H, app. s, aryl H), 7.17 - 7.32 (5 H, m, aryl H); δC (100 MHz, CDCl3) 14.2 (CH3), 21.9

(OCH(CH3)2), 22.0 (OCH(CH3)2), 22.1 (OCH(CH3)2), 22.7 (CH2), 26.8 (CH2), 28.8 (CH2),

31.8 (CH2), 36.6 (ArCH2CHCl), 37.8 (CH2), 63.6 (CHCl), 69.8 (OCH(CH3)2), 69.9

(OCH(CH3)2), 101.3 (aryl C-H), 110.1 (aryl C-H), 121.6 (aryl Cq), 126.5 (aryl C-H), 129.1

(aryl C-H), 130.1 (aryl C-H), 136.6 (aryl Cq), 136.7 (aryl Cq), 157.3 (aryl Cq), 157.4 (aryl -1 Cq); νmax (thin film/cm ) 1037 (m), 1113 (s), 1135 (s), 1179 (m), 1273 (w), 1373 (w), 1384 (w), 1464 (m), 1566 (s), 1593 (w), 2857 (w), 2929 (m), 2975 (m); MS (ES+) m/z 449 35Cl, 37 + + 451 Cl [(M+H) ]; HRMS C26H38O2ClS [(M+H) ] Expected 449.2281, Found 449.2293.

157

[3,5-bis(Allyloxy)-2-(2-chlorooctyl)phenyl](phenyl)sulfide 164j

As described in general procedure D, 91ad (59.6 mg, 0.203 mmol), 1-octene (160 μL, 1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography

(30% CHCl3 in hexanes) gave 164j (46.7 mg, 0.105 mmol, 50%) as a colourless oil; δH

(400 MHz, CDCl3) 0.88 (3 H, t, J 6.8 Hz, CH3), 1.20 - 1.42 (7 H, m, CH2), 1.53 - 1.65 (1

H, m, CH2), 1.70 - 1.78 (2 H, m, CH2), 3.26 (1 H, dd, J 13.6, 7.2 Hz, ArCH2CHCl), 3.36 (1

H, dd, J 13.6, 7.2 Hz, ArCH2CHCl), 4.30 (1 H, m, CHCl), 4.37 (2 H, dt, J 5.4, 1.3 Hz,

OCH2), 4.53 (2 H, dt, J 5.0, 1.5 Hz, OCH2), 5.23 (1 H, dq, J 10.4, 1.3 Hz, CH=CH2), 5.29

(1 H, dq, J 10.7, 1.5 Hz, CH=CH2), 5.32 (1 H, dq, J 17.2, 1.3 Hz, CH=CH2), 5.45 (1 H, dq,

J 17.2, 1.5 Hz, CH=CH2), 5.95 (1 H, ddt, J 17.2, 10.4, 5.4 Hz, CH=CH2), 6.06 (1 H, ddt, J

17.2, 10.7, 5.0 Hz, CH=CH2), 6.42 (1 H, d, J 2.4 Hz, aryl H), 6.43 (1 H, d, J 2.4 Hz, aryl

H), 7.19 - 7.33 (5 H, m, aryl H); δC (125 MHz, CDCl3) 14.1 (CH3), 22.6 (CH2), 26.7 (CH2),

28.7 (CH2), 31.7 (CH2), 36.4 (ArCH2CHCl), 37.8 (CH2), 63.3 (CHCl), 68.9 (OCH2), 69.0

(OCH2), 99.9 (CH=CH2), 109.7 (CH=CH2), 117.3 (CH=CH2), 118.0 (CH=CH2), 121.4

(aryl Cq), 126.7 (aryl C-H), 129.1 (aryl C-H), 130.3 (aryl C-H), 132.8 (aryl C-H), 132.9

(aryl C-H), 136.2 (aryl Cq), 136.8 (aryl Cq), 158.0 (aryl Cq), 158.1 (aryl Cq); νmax (thin film/cm-1); 924 (s), 1023 (s), 1044 (s), 1140 (w), 1172 (s), 1274 (w), 1416 (w), 1455 (w), 1569 (s), 1595 (s), 2856 (w), 2926 (w), 2953 (w), 3060 (w), 3074 (w); MS (ES+) m/z 455 35 37 + + Cl, 457 Cl [(M+H) ]; HRMS C26H33O2S [(M−Cl) ] Expected 409.2201, Found 409.2193.

158

[3,5-bis(Allyloxy)-2-(2-chlorohexyl)phenyl](phenyl)sulfide 164k

As described in general procedure D, 91ad (1.00 g, 3.35 mmol), 1-hexene (2.10 mL, 16.8 mmol) and FeCl3 (2.16 g, 13.4 mmol), after purification by column chromatography (30%

CHCl3 in hexanes) gave 164k (700 mg, 1.68 mmol 50%) as a colourless oil; δH (400 MHz,

CDCl3) 0.88 (3 H, t, J 7.2 Hz, CH3), 1.20 - 1.42 (3 H, m, CH2), 1.51 - 1.64 (1 H, m, CH2),

1.70 - 1.78 (2 H, m, CH2), 3.26 (1 H, dd, J 13.7, 7.0 Hz, ArCH2CHCl), 3.36 (1 H, dd, J

13.7, 7.6 Hz, ArCH2CHCl), 4.24 - 4.34 (1 H, m, CHCl), 4.37 (2 H, dt, J 5.4, 1.3 Hz,

OCH2), 4.53 (2 H, dt, J 5.1, 1.6 Hz, OCH2), 5.23 (1 H, dq, J 10.4, 1.3 Hz, CH=CH2), 5.27-

5.34 (2 H, m, CH=CH2), 5.45 (1 H, dq, J 17.2, 1.6 Hz, CH=CH2), 5.95 (1 H, ddt, J 17.2,

10.4, 5.4 Hz, CH=CH2), 6.06 (1 H, ddt, J 17.2, 10.6, 5.1 Hz, CH=CH2), 6.39 - 6.44 (2 H, m, aryl H), 7.19 - 7.32 (5 H, m, aryl H); δC (100 MHz, CDCl3) 14.0 (CH3), 22.2 (CH2),

28.9 (CH2), 36.4 (ArCH2CHCl), 37.5 (CH2), 63.3 (CHCl), 68.8 (OCH2), 68.9 (OCH2), 99.8

(aryl C-H), 109.6 (aryl C-H), 117.3 (CH=CH2), 118.1 (CH=CH2), 121.4 (aryl Cq), 126.7

(aryl C-H), 129.1 (aryl C-H), 130.3 (aryl C-H), 132.8 (CH=CH2 x 2), 136.2 (aryl Cq), 136.8 -1 (aryl Cq), 157.9 (aryl Cq), 158.1 (aryl Cq); νmax (thin film/cm ) 928 (m), 1024 (s), 1045 (s), 1142 (s), 1176 (s), 1276 (w), 1412 (m), 1456 (m), 1477 (m), 1570 (s), 1595 (s), 2860 (w), 2929 (w), 2956 (w), 3080 (w); MS (ES+) m/z 417 35Cl, 419 37Cl [(M+H)+]; HRMS + C24H30ClO2S [(M+H) ] Expected 417.1650, Found 417.1649.

[3,5-bis(Allyloxy)-2-(2-chloro-5-nitropentyl)phenyl](phenyl)sulfide 164l

As described in general procedure D, 91ad (95.5 mg, 0.320 mmol), 5-nitro-1-pentene (193 mg, 1.70 mmol) and FeCl3 (217 mg, 1.35 mmol), after purification by column chromatography (50% CHCl3 in hexanes) gave 164l (42.3 mg, 94.4 µmol, 30%) as a

159 yellow oil; δH (400 MHz, CDCl3) 1.72 - 1.87 (2 H, m, CH2), 2.01 - 2.15 (1 H, m, CH2),

2.27 - 2.41 (1 H, m, CH2), 3.28 (1 H, dd, J 13.6, 7.8 Hz, ArCH2CHCl), 3.38 (1 H, dd, J

13.6, 6.6 Hz, ArCH2CHCl), 4.25 - 4.40 (5 H, m, CH2NO2 + CHCl + OCH2), 4.54 (2 H, dt,

J 5.1, 1.6 Hz, OCH2), 5.24 (1 H, dq, J 10.5, 1.3 Hz, CH=CH2), 5.27 - 5.36 (2 H, m,

CH=CH2), 5.44 (1 H, dq, J 17.2, 1.6 Hz, CH=CH2), 5.95 (1 H, ddt, J 17.2, 10.5, 5.4 Hz,

CH=CH2), 6.06 (1 H, ddt, J 17.2, 10.5, 5.1 Hz, CH=CH2), 6.42 (2 H, s, aryl H), 7.21 - 7.34

(5 H, m, aryl H); δC (100 MHz, CDCl3) 24.6 (CH2), 33.7 (CH2), 36.2 (ArCH2CHCl), 61.3

(CHCl), 68.9 (OCH2), 69.0 (OCH2), 75.0 (CH2NO2), 99.9 (aryl C-H), 109.8 (aryl C-H),

117.6 (CH=CH2), 118.1 (CH=CH2), 120.3 (aryl Cq), 126.9 (aryl C-H), 129.2 (aryl C-H),

130.3 (aryl C-H), 132.7 (CH=CH2), 132.8 (CH=CH2), 135.7 (aryl Cq), 136.8 (aryl Cq), -1 157.9 (aryl Cq), 158.4 (aryl Cq); νmax (thin film/cm ) 1138 (s), 1169 (s), 1417 (m), 1551 (vs), 1569 (s), 1595 (s), 2864 (w), 2920 (w), 3075 (w); MS (APCI) m/z 448 35Cl, 450 37Cl + + [(M+H) ]; HRMS C23H27NO4ClS [(M+H) ] Expected 448.1344, Found 448.1339.

[3,5-bis(Allyloxy)-2-(5-bromo-2-chloropentyl)phenyl](phenyl)sulfide 164m

As described in general procedure D, 91ad (95.5 mg, 0.320 mmol), 5-bromo-1-pentene

(250 mg, 1.70 mmol) and FeCl3 (217 mg, 1.35 mmol), after purification by column chromatography (30% CHCl3 in hexanes) gave 164m (59.6 mg, 0.124 mmol, 39%) as a colourless oil; δH (400 MHz, CDCl3) 1.70 - 1.93 (3 H, m, CH2), 2.03 - 2.17 (1 H, m, CH2),

3.20 (1 H, dd, J 13.9, 7.6 Hz, ArCH2CHCl), 3.25 - 3.36 (3 H, m, ArCH2CHCl + CH2Br),

4.17 - 4.26 (1 H, m, CHCl), 4.29 (2 H, dt, J 5.4, 1.3 Hz, OCH2), 4.46 (2 H, dt, J 5.0, 1.5

Hz, OCH2), 5.15 (1 H, dq, J 10.6, 1.3 Hz, CH=CH2), 5.18 - 5.27 (2 H, m, CH=CH2), 5.36

(1 H, dq, J 17.2, 1.5 Hz, CH=CH2), 5.81 - 5.92 (1 H, m, CH=CH2) 5.93 - 6.04 (1 H, m,

CH=CH2), 6.32 - 6.35 (2 H, m, aryl H), 7.12 - 7.25 (5 H, m, aryl H); δC (100 MHz, CDCl3)

29.8 (CH2), 33.2 (CH2Br), 35.9 (CH2), 36.2 (ArCH2CHCl), 61.8 (CHCl), 68.9 (OCH2),

69.0 (OCH2), 99.9 (aryl C-H), 109.8 (aryl C-H), 117.8 (CH=CH2), 118.0 (CH=CH2), 120.8

(aryl Cq), 126.8 (aryl C-H), 129.2 (aryl C-H), 130.3 (aryl C-H), 132.7 (CH=CH2), 132.8

(CH=CH2), 135.9 (aryl Cq), 136.8 (aryl Cq), 157.9 (aryl Cq), 158.2 (aryl Cq); νmax (thin film/cm-1) 927.0 (m), 1023 (s), 1044 (s), 1275 (m), 1417 (m), 1439 (m), 1455 (m), 1476 160

(m), 1569 (s), 1595 9s), 2863 (w), 2916 (w), 2959 (w), 3075 (w); MS (APCI) m/z 481 35 79 37 79 35 81 37 81 + Cl Br, 483 Cl Br and Cl Br, 485 Cl Br [(M+H) ]; HRMS C23H27ClBrO2S [(M+H)+] Expected 481.0598, Found 481.0612.

[3,5-bis(Allyloxy)-2-(2-chloro-9-phenylnonyl)phenyl](phenyl)sulfide 164n

As described in general procedure D, 91ad (103 mg, 0.345 mmol), 9-phenyl-1-nonene

(346 mg, 1.70 mmol) and FeCl3 (217 mg, 1.35 mmol), after purification by column chromatography (30% CHCl3 in hexanes) gave 164n (78.1 mg, 0.146 mmol, 42%) as a colourless oil; δH (500 MHz, CDCl3) 1.23 - 1.41 (7 H, m, CH2), 1.57 - 1.65 (3 H, m, CH2),

1.71 - 1.78 (2 H, m, CH2), 2.59 - 2.64 (2 H, m, ArCH2CH2), 3.28 (1 H, dd, J 13.7, 6.9 Hz,

ArCH2CHCl), 3.37 (1 H, dd, J 13.7, 7.6 Hz, ArCH2CHCl), 4.26 - 4.34 (1 H, m, CHCl),

4.39 (2 H, dt, J 5.4, 1.4 Hz, OCH2), 4.54 (2 H, dt, J 5.1, 1.5 Hz, OCH2), 5.24 (1 H, dq, J

10.4, 1.5 Hz, CH=CH2), 5.26 – 5.33 (2 H, m, CH=CH2), 5.45 (1 H, dq, J 17.3, 1.4 Hz,

CH=CH2), 5.96 (1 H, ddt, J 17.3, 10.6, 5.4 Hz, CH=CH2), 6.06 (1 H, ddt, J 17.2, 10.4, 5.1

Hz, CH=CH2), 6.42 - 6.45 (2 H, m, aryl H), 7.16 - 7.27 (5 H, m, aryl H), 7.27 - 7.32 (5 H, m, aryl H); δC (125 MHz, CDCl3) 26.7 (CH2), 29.0 (CH2), 29.2 (CH2), 29.3 (CH2), 31.5

(CH2), 36.0 (ArCH2CH2), 36.4 (ArCH2CHCl), 37.8 (CH2), 63.2 (CHCl), 68.9 (OCH2), 69.0

(OCH2), 100.0 (aryl C-H), 109.8 (aryl C-H), 117.3 (CH=CH2), 118.0 (CH=CH2), 121.4

(aryl Cq), 125.6 (aryl C-H), 126.7 (aryl C-H), 128.2 (aryl C-H), 128.4 (aryl C-H), 129.1

(aryl C-H), 130.3 (aryl C-H), 132.9 (CH=CH2), 132.9 (CH=CH2), 136.2 (aryl Cq), 136.9 -1 (aryl Cq), 142.9 (aryl Cq), 158.0 (aryl Cq), 158.2 (aryl Cq); νmax (thin film/cm ) 925 (m), 1024 (s), 1045 (s), 1106 (w), 1145 (s), 1175 (s), 1215 (s), 1275 (w), 1380 (vw), 1416 (m), 1476 (s), 1495 (m), 1569 (vs), 1648 (vw), 2854 (m), 2926 (m), 3024 (w), 3082 (w); MS 35 37 + + (APCI) m/z 535 Cl, 537 Cl [(M+H) ]; HRMS C33H40ClO2S [(M+H) ] Expected 535.2432, Found 535.2423.

161

[3,5-bis(Allyloxy)-2-(2-chlorohept-6-en-1-yl)phenyl](phenyl)sulfide 164o

As described in general procedure D, 91ad (95.5 mg, 0.320 mmol), 1,6-heptadiene (162 mg, 1.70 mmol) and FeCl3 (217 mg, 1.35 mmol), after purification by column chromatography (20% CHCl3 in hexanes) gave 164o (70.5 mg, 0.164 mmol, 52%) as a colourless oil; δH (400 MHz, CDCl3) 1.31 - 1.44 (1 H, m, CH2), 1.56 - 1.72 (3 H, m, CH2),

1.88 - 2.01 (2 H, m, CH2CH=CH2), 3.18 (1 H, dd, J 13.9, 7.3 Hz, ArCH2CHCl), 3.27 (1 H, dd, J 13.9, 7.3 Hz, ArCH2CHCl), 4.17 – 4.25 (1 H, m, CHCl), 4.28 (2 H, dt, J 5.3, 1.3 Hz,

OCH2), 4.44 (2 H, dt, J 5.0, 1.5 Hz, OCH2), 4.82 - 4.93 (2 H, m, CH=CH2), 5.14 (1 H, dq,

J 10.6, 1.3 Hz, OCH2CH=CH2), 5.17 - 5.25 (2 H, m, OCH2CH=CH2), 5.35 (1 H, dq, J

17.2, 1.5 Hz, OCH2CH=CH2), 5.68 (1 H, ddt, J 17.0, 10.2, 6.7 Hz, CH=CH2), 5.86 (1 H, ddt, J 17.2, 10.6, 5.3 Hz, OCH2CH=CH2), 5.96 (1 H, ddt, J 17.2, 10.5, 5.0 Hz,

OCH2CH=CH2), 6.31 - 6.34 (2 H, m, aryl H), 7.10 - 7.23 (5 H, m, aryl H); δC (100 MHz,

CDCl3) 25.9 (CH2), 33.1 (CH2CH=CH2), 36.4 (ArCH2CHCl), 37.1 (CH2), 62.9 (CHCl),

68.8 (OCH2), 69.0 (OCH2), 99.8 (aryl C-H), 109.7 (aryl C-H), 114.6 (CH=CH2), 117.3

(OCH2CH=CH2), 118.0 (OCH2CH=CH2), 121.2 (aryl Cq), 126.7 (aryl C-H), 129.1 (aryl C-

H), 130.3 (aryl C-H), 132.8 (OCH2CH=CH2), 132.9 (OCH2CH=CH2), 136.1 (aryl Cq), -1 136.9 (aryl Cq), 138.4 (CH=CH2), 157.9 (aryl Cq), 158.2 (aryl Cq); νmax (thin film/cm ) 919 (m), 1024 (m), 1045 (m), 1141 (s), 1172 (s), 1275 (m), 1417 9m), 1439 (m), 1477 (m), 1569 (s), 1595 (s), 2859 (w), 2927 (w), 3075 (w); MS (APCI) m/z 429 35Cl, 431 37Cl + + [(M+H) ]; HRMS C25H30ClO2S [(M+H) ] Expected 429.1650, Found 429.1657.

162

[2-(2-Bromooctyl)-3,5-dimethoxyphenyl](phenyl)sulfide 144

FeBr3 (130 mg, 0.440 mmol) was added to a stirred mixture of 91b (50.0 mg, 0.203 mmol) and 1-octene (160 μL, 1.02 mmol) in CH2Cl2 (2 mL) under N2 atmosphere. The mixture was stirred for 1.5 h. The reaction mixture was then quenched with H2O (2 ml) and diluted with CH2Cl2 (2 mL). The organic layer was then washed twice more with H2O (2 ml) and the combined aqueous washes extracted with CH2Cl2 (3 × 2 mL). The combined organic extracts were dried with Na2SO4, filtered and the solvent removed in vacuo. The crude mixture was then passed through a silica plug with CHCl3 eluent. The crude product was purified by column chromatography on silica gel (30% CHCl3 in hexanes) to give 144

(17.4 mg, 39.8 µmol, 20%) as a colourless oil; δH (500 MHz, CDCl3) 0.89 (3 H, t, J 6.9 Hz,

CH2CH3), 1.20 - 1.43 (7 H, m, CH2), 1.56 - 1.67 (1 H, m, CH2), 1.72 - 1.81 (1 H, m, CH2),

1.81 - 1.89 (1 H, m, CH2), 3.37 (1 H, dd, J 13.9, 7.6 Hz, ArCH2CHBr), 3.47 (1 H, dd, J

13.9, 7.3 Hz, ArCH2CHBr), 3.69 (3 H, s, OCH3), 3.84 (3 H, m, OCH3), 4.38 - 4.45 (1 H, m, CHBr), 6.42 (1 H, d, J 2.5 Hz, aryl H), 6.45 (1 H, d, J 2.5 Hz, aryl H), 7.20 - 7.32 (5 H, m, aryl H); δC (125 MHz, CDCl3) 14.1 (CH3), 22.6 (CH2), 27.8 (CH2), 28.6 (CH2), 31.7

(CH2), 37.0 (ArCH2CHBr), 38.1 (CH2), 55.3 (OCH3), 55.6 (OCH3), 57.4 (CHBr), 98.3

(aryl C-H), 108.9 (aryl C-H), 121.9 (aryl Cq), 126.7 (aryl C-H), 129.1 (aryl C-H), 130.0

(aryl C-H), 136.3 (aryl Cq), 136.5 (aryl Cq), 159.0 (aryl Cq), 159.3 (aryl Cq); νmax (thin film/cm-1) 1047 (s), 1156 (s), 1196 (s), 1459 (w), 1596 (s), 2856 (w), 2920 (w); MS (ES+) 79 81 + + m/z 437 Br, 439 Br [(M+H) ]; HRMS C22H30O2BrS [(M+H) ] Expected 437.1144, Found 437.1143.

163

1-[2,4-Dimethoxy-6-(phenylsulfanyl)phenyl]octan-2-yl nitrate 178a

Ceric ammonium nitrate (223 mg, 0.407 mmol) was added to a stirred mixture of 91b (50.0 mg, 0.203 mmol) and 1-octene (160 μL, 1.02 mmol) in MeCN (2 mL) and stirred for 2 h.

The reaction mixture was then quenched with H2O (2 ml) and diluted with EtOAc (5 mL).

The organic layer was then washed twice more with H2O (2 ml). The aqueous layer was extracted with EtOAc (3 × 2 mL). The combined organic extracts were dried with Na2SO4, filtered and solvent removed in vacuo. The crude product was then purified by column chromatography on silica gel (50% CHCl3 in hexanes) to give 178a (39.8 mg, 94.9 µmol,

47%) as a colourless oil; δH (500 MHz, CDCl3) 0.88 (3 H, t, J 6.9 Hz, CH3), 1.19 - 1.38 (7

H, m, CH2), 1.43 (1 H, m, CH2), 1.63 - 1.70 (2 H, m, CH2), 3.14 (1 H, dd, J 14.2, 5.4 Hz,

ArCH2CH(ONO2)), 3.21 (1 H, dd, J 14.2, 7.6 Hz, ArCH2CH(ONO2)CH2), 3.68 (3 H, s,

OCH3), 3.83 (3 H, s, OCH3), 5.31 - 5.39 (1 H, m, CH(ONO2)), 6.40 (1 H, d, J 2.2 Hz, aryl

H), 6.42 (1 H, d, J 2.2 Hz, aryl H), 7.19 - 7.32 (5 H, m, aryl H); δC (500 MHz, CDCl3) 14.0

(CH3), 22.5 (CH2), 25.3 (CH2), 29.0 (CH2), 30.6 (ArCH2CH(ONO2)), 31.7 (CH2), 32.5

(CH2), 55.3 (OCH3), 55.6 (OCH3), 84.5 (CH(ONO2)), 98.2 (aryl C-H), 108.9 (aryl C-H),

119.2 (aryl Cq), 126.7 (aryl C-H), 129.2 (aryl C-H), 130.1 (aryl C-H), 136.0 (aryl Cq), -1 136.7 (aryl Cq), 159.3 (aryl Cq), 159.5 (aryl Cq); νmax (thin film/cm ) 1046 (s), 1147 (s), 1196 (m), 1274 (s), 1459 (m), 1571 (s), 1596 (s), 1620 (s), 2857 (w), 2930 (w); MS (ES+) + + m/z 420 [(M+H) ]; HRMS C22H29O2S [(M−NO3) ] Expected 357.1888, Found 357.1879.

5.8 Manipulation of Products General Procedure E

A solution of n-BuLi (1.60 M in hexanes, 1.2 eq.) was added to a solution of 99a (0.1 M in THF) precooled to −78 °C. The mixture was warmed to room temperature, quenched with the corresponding electrophile (9 eq.) and left to stir for 10 min., after which sat. aq.

NH4Cl (2 mL) and EtOAc (2 mL) were added. The organic layer was then washed with sat. aq. NH4Cl (2 × 2 ml). The aqueous layers were extracted with EtOAc (2 × 2 mL). The combined organic extracts were dried with Na2SO4, filtered and solvent removed in vacuo.

164

2-(2-Chlorooctyl)-1,5-dimethoxy-3-(phenylsulfonyl)benzene 181

m-CPBA (≤77%, 87.4 mg, 0.390 mmol) was added to a solution of 99a (50.0 mg, 0.127 mmol) in CH2Cl2 (1 mL). The mixture was stirred under reflux for 18 h and then quenched with aq. NaHCO3 (2 mL). The aqueous layer was washed with CH2Cl2 (3 × 2 mL) and the combined organic extracts were dried with MgSO4, filtered and the solvent removed in vacuo. The crude product was purified by column chromatography (20% EtOAc in hexanes) to give 181 (52.6 mg, 0.124 mmol, 95%) as a colourless oil; δH (500 MHz,

CDCl3) 0.87 (3 H, t, J 7.1 Hz, CH3), 1.11 - 1.36 (7 H, m, CH2), 1.45 - 1.58 (3 H, m, CH2),

3.21 (1 H, dd, J 13.6, 7.3 Hz, ArCH2CHCl), 3.28 (1 H, dd, J 13.6, 7.6 Hz, ArCH2CHCl),

3.80 (3 H, s, OCH3), 3.89 (3 H, s, OCH3), 4.25 - 4.34 (1 H, m, CHCl), 6.67 (1 H, d, J 2.5 Hz, aryl H), 7.40 (1 H, d, J 2.5 Hz, aryl H), 7.50 (2 H, t, J 7.3 Hz, aryl H), 7.58 (1 H, t, J

7.3 Hz, aryl H), 7.86 (2 H, d, J 7.3 Hz, aryl H); δC (125 MHz, CDCl3) 14.1 (CH3), 22.6

(CH2), 26.8 (CH2), 28.7 (CH2), 31.7 (CH2), 34.5 (ArCH2CHCl), 37.4 (CH2), 55.8 (OCH3),

55.9 (OCH3), 63.0 (CHCl), 103.4 (aryl C-H), 105.5 (aryl C-H), 119.6 (aryl Cq), 127.4 (aryl

C-H), 129.2 (aryl C-H), 133.2 (aryl C-H), 141.1 (aryl Cq), 141.9 (aryl Cq), 159.1 (aryl Cq), -1 160.1 (aryl Cq); νmax (thin film/cm ) 1041 (m), 1057 (w), 1154 (s), 1204 (m), 1305 (s), 1461 (m), 1600 (m), 2856 (w), 2930 (m); MS (ES+) m/z 447 35Cl, 449 37Cl [(M+Na)+]; + HRMS C22H29O4SClNa [(M+Na) ] Expected 447.1385, Found 447.1373.

[2-(2-Chlorooctyl)-3,5-dimethoxyphenyl-4-d](phenyl)sulfide 184a

As described in general procedure E, the reaction of 99a (50.0 mg, 0.127 mmol) was quenched with MeOD (48.0 μL, 1.17 mmol) and, after purification by column chromatography (30% CHCl3 in hexanes), gave 184a (49.6 mg, 0.126 mmol, 99%) as a

165 colourless oil; δH (400 MHz, CDCl3) 0.88 (3 H, t, J 6.9 Hz, CH3), 1.16 - 1.44 (7 H, m,

CH2), 1.53 - 1.65 (1 H, m, CH2), 1.66 - 1.77 (2 H, m, CH2), 3.23 (1 H, dd, J 13.8, 7.0 Hz,

ArCH2CHCl), 3.33 (1 H, dd, J 13.8, 7.5 Hz, ArCH2CHCl), 3.68 (3 H, s, OCH3), 3.83 (3 H, s, OCH3), 4.23 - 4.32 (1 H, m, CHCl), 6.44 (1 H, s, aryl H), 7.17 - 7.33 (5 H, m, aryl H); δC

(100 MHz, CDCl3) 14.1 (CH3), 22.7 (CH2), 26.7 (CH2), 28.8 (CH2), 31.8 (CH2), 36.3

(ArCH2CHCl), 37.7 (CH2), 55.3 (OCH3), 55.6 (OCH3), 63.4 (CHCl), 98.0 (t, J 24.2 Hz, aryl C-D), 108.8 (aryl C-H), 121.3 (aryl Cq), 126.6 (aryl C-H), 129.2 (aryl C-H), 130.0

(aryl C-H), 136.4 (aryl Cq), 136.5 (aryl Cq), 159.0 (aryl Cq), 159.2 (aryl Cq); νmax (thin film/cm-1) 1046 (s), 1094 (s), 1146 (m), 1199 (s), 1295 (m), 1387 (m), 1458 (m), 1565 (s), 1587 (s), 2856 (w), 2929 (m); MS (ES+) m/z 394 35Cl, 396 37Cl [(M+H)+]; HRMS + C22H29DO2ClS [(M+H) ] Expected 394.1718, Found 394.1703.

[2-(2-Chlorooctyl)-4-iodo-3,5-dimethoxyphenyl](phenyl)sulfide 184b

As described in general procedure E, the reaction of 99a (50.0 mg, 0.127 mmol) was quenched with I2 (1.17 mL, 1.17 M in THF, 1.17 mmol) and, after purification by column chromatography (30% CHCl3 in hexanes), gave 184b (64.0 mg, 0.123 mmol, 95%) as a yellow oil; δH (500 MHz, CDCl3) 0.88 (3 H, t, J 6.9 Hz, CH3), 1.19 - 1.43 (7 H, m, CH2),

1.53 - 1.63 (1 H, m, CH2), 1.67 - 1.80 (2 H, m, CH2), 3.24 (1 H, dd, J 13.9, 6.6 Hz,

ArCH2CHCl), 3.36 (1 H, dd, J 13.9, 7.7 Hz, ArCH2CHCl), 3.68 (3 H, s, OCH3), 3.85 (3 H, s, OCH3), 4.31 - 4.39 (1 H, m, CHCl), 6.51 (1 H, s, aryl H), 7.24 - 7.36 (5 H, m, aryl H); δC

(125 MHz, CDCl3) 14.1 (CH3), 22.6 (CH2), 26.7 (CH2), 28.7 (CH2), 31.7 (CH2), 37.7

(CH2), 37.9 (ArCH2CHCl), 56.5 (OCH3), 61.1 (OCH3), 62.9 (CHCl), 83.5 (aryl Cq), 110.9

(aryl C-H), 126.4 (aryl Cq), 127.3 (aryl C-H), 129.4 (aryl C-H), 130.7 (aryl C-H), 135.4, -1 (aryl Cq), 138.0 (aryl Cq), 158.2 (aryl Cq), 160.3 (aryl Cq); νmax (thin film/cm ) 1018 (w), 1086 (s), 1136 (m), 1198 (w), 1372 (m), 1456 (m), 1567 (m), 2855 (w), 2930 (m); MS + 35 37 + + (ES ) m/z 541 Cl, 543 Cl [(M+Na) ]; HRMS C22H29O2ClIS [(M+H) ] Expected 519.0616, Found 519.0610.

166

[2-(2-Chlorooctyl)-3,5-dimethoxy-4-methylphenyl](phenyl)sulfide 184c

As described in general procedure E, the reaction of 99a (50.0 mg, 0.127 mmol) was quenched with MeI (73.0 μL, 1.17 mmol) and, after purification by column chromatography (30% CHCl3 in hexanes), gave 184c (46.1 mg, 0.113 mmol, 87%) as a colourless oil; δH (500 MHz, CDCl3) 0.88 (3 H, t, J 6.9 Hz, CH3) 1.18 - 1.41 (7 H, m,

CH2), 1.51-1.63 (1 H, m, CH2), 1.66 - 1.78 (2 H, m, CH2), 2.19 (3 H, s, ArCH3), 3.19 (1 H, dd, J 13.7, 6.8 Hz, ArCH2CHCl), 3.31 (1 H, dd, J 13.7, 7.6 Hz, ArCH2CHCl), 3.70 (3 H, s,

OCH3), 3.75 (3 H, s, OCH3), 4.28 - 4.36 (1 H, m, CHCl), 6.70 (1 H, s, aryl H), 7.15 - 7.21

(3 H, m, aryl H), 7.24 - 7.29 (2 H, m, aryl H); δC (125 MHz, CDCl3) 9.6 (ArCH3), 14.1

(CH3), 22.6 (CH2), 26.7 (CH2), 28.7 (CH2), 31.7 (CH2), 37.1 (ArCH2CHCl), 37.8 (CH2),

55.6 (OCH3), 60.1 (OCH3), 63.6 (CHCl), 112.2 (aryl C-H), 120.5 (aryl Cq), 126.0 (aryl C-

H), 126.6 (aryl Cq), 128.6 (aryl C-H), 129.0 (aryl C-H), 131.6 (aryl Cq), 137.4 (aryl Cq), -1 157.6 (aryl Cq), 158.5 (aryl Cq); νmax (thin film/cm ) 1024 (m), 1120 (s), 1192 (w), 1268 (w), 1388(w), 1438 (m), 1464 (m), 1583 (m), 2856 (w), 2929 (m); MS (ES+) m/z 407 35Cl, 37 + + 409 Cl [(M+H) ]; HRMS C23H31O2S [(M-Cl) ] Expected 371.2045, Found 371.2039.

(E)-[3,5-Dimethoxy-2-(oct-1-en-1-yl)phenyl](phenyl)sulfide 185 , (E)-[3,5-dimethoxy-2-(oct-2-en-1-yl)phenyl](phenyl)sulfide 186 and [2-(2-ethoxyoctyl)-3,5-dimethoxyphenyl](phenyl)sulfide 215

A solution of NaOEt in EtOH (21 wt%, 100 μL, 0.254 mmol) was added to a solution of 99a (50.0 mg, 0.127 mmol) in EtOH (1.2 mL). The solution was stirred under reflux for 18 h, then cooled to room temperature and quenched with H2O (2 mL) and diluted with

EtOAc (5 mL). The organic phase was washed with H2O (3 × 2 mL), dried over MgSO4,

167 filtered and solvent removed in vacuo. The crude mixture was purified by column chromatography (10% EtOAc in hexanes) to give 185 (24.6 mg, 69.0 µmol, 53 %), 186

(15.3 mg, 42.9 µmol 33%) and 215 (4.2 mg, 10.4 µmol, 8%) as colourless oils; For 185, δH

(500 MHz, CDCl3) 0.89 (3 H, t, J 6.6 Hz, CH3), 1.23 - 1.37 (6 H, m, CH2), 1.37 - 1.45 (2

H, m, CH2), 2.19 (2 H, qd, J 6.9, 1.3 Hz, CH=CHCH2CH2), 3.66 (3 H, s, OCH3), 3.83 (3

H, s, OCH3), 6.27 (1 H, dt, J 16.1, 6.9 Hz, ArCH=CHCH2), 6.35 (1 H, d, J 2.5 Hz, aryl H),

6.39 (1 H, d, J 2.5 Hz, aryl H), 6.53 (1 H, dt, J 16.1, 1.3 Hz, ArCH=CHCH2), 7.21 - 7.33 (5

H, m, aryl H); δC (125 MHz, CDCl3) 14.2 (CH3), 22.7 (CH2), 28.9 (CH2), 29.4 (CH2), 31.8

(CH2), 34.1 (CH=CHCH2CH2), 55.3 (OCH3), 55.6 (OCH3), 98.0 (aryl C-H), 107.8 (aryl C-

H), 121.0 (aryl Cq), 122.7 (ArCH=CHCH2), 126.9 (aryl C-H), 129.1 (aryl C-H), 131.1 (aryl

C-H), 135.7 (aryl Cq), 136.1 (aryl Cq), 136.6 (ArCH=CHCH2), 158.6 (aryl Cq), 158.7 (aryl -1 Cq); νmax (thin film/cm ) 1046 (s), 1153 (s), 1200 (m), 1210 (m), 1298 (m), 1407 (w), 1434 (w), 1459 (m), 1563 (s), 1593 (s), 2854 (w), 2925 (m), 2954 (w), 3000 (w); MS (ES+) m/z + + 357 [(M+H) ]; HRMS C22H29O2S [(M+H) ] Expected 357.1883, Found 357.1887; For

186, δH (400 MHz, CDCl3) 0.87 (3 H, t, J 7.0 Hz, CH3), 1.16 - 1.36 (6 H, m, CH2), 1.91 (2

H, q, J 6.6 Hz, CH=CHCH2CH2), 3.49 (2 H, d, J 5.8 Hz, ArCH2CH=CH), 3.68 (3 H, s,

OCH3), 3.82 (3 H, s, OCH3), 5.37 (1 H, dt, J 15.3, 6.6 Hz, CH=CHCH2CH2), 5.45 (1 H, dt,

J 15.3, 5.8 Hz, ArCH2CH=CH), 6.41 (1 H, d, J 2.3 Hz, aryl H), 6.42 (1 H, d, J 2.3 Hz, aryl

H), 7.16 - 7.31 (5 H, m, aryl H); δC (100 MHz, CDCl3) 14.1 (CH3), 22.5 (CH2), 29.1 (CH2),

30.2 (ArCH2CHCH), 31.4 (CH2), 32.5 (CHCHCH2), 55.3 (OCH3), 55.7 (OCH3), 98.4 (aryl

C-H), 108.6 (aryl C-H), 123.8 (aryl Cq), 126.4 (aryl C-H), 127.3 (CH2CH=CHCH2), 129.0

(aryl C-H), 130.1 (aryl C-H), 131.2 (CH2CH=CHCH2), 135.5 (aryl Cq), 136.6 (aryl Cq), -1 158.7 (aryl Cq), 158.8 (aryl Cq); νmax (thin film/cm ) 1050 (s), 1144 (s), 1166 (w), 1205 (m) 1274 (w), 1296 (w), 1409 (w), 1437 (w), 1460 (m), 1477 (m), 1572 (s), 1596 (s), 2854 + + + (w), 2925 (m), 2955 (w); MS (ES ) m/z 357 [(M+H) ]; HRMS C22H29O2S [(M+H) ]

Expected 357.1883, Found 357.1886; For 215, δH (400 MHz, CDCl3) 0.87 (3 H, t, J 6.9

Hz, CH3), 1.12 (3 H, t, J 7.0 Hz, OCH2CH3), 1.17 - 1.33 (7 H, m, CH2), 1.35 - 1.54 (3 H, m, CH2), 2.91 (1 H, dd, J 13.2, 7.2 Hz, ArCH2CH(OEt)), 3.07 (1 H, dd, J 13.2, 6.1 Hz,

ArCH2CH(OEt)), 3.39 - 3.55 (3 H, m, OCH2CH3 + CH(OEt)), 3.68 (3 H, s, OCH3), 3.82 (3

H, s, OCH3), 6.39 (1 H, d, J 2.5 Hz, aryl H), 6.41 (1 H, d, J 2.5 Hz, aryl H), 7.17 – 7.32 (5

H, m, aryl H); δC (100 MHz, CDCl3) 14.1 (CH3), 15.7 (OCH2CH3), 22.7 (CH2), 26.0

(CH2), 29.5 (CH2), 32.0 (CH2), 32.4 (ArCH2CH(OEt)), 34.8 (CH2), 55.3 (OCH3), 55.6

(OCH3), 64.9 (OCH2CH3), 79.6 (CH(OEt)), 98.2 (aryl C-H), 108.6 (aryl C-H), 122.4 (aryl

Cq), 126.4 (aryl C-H), 129.1 (aryl C-H), 130.0 (aryl C-H), 136.3 (aryl Cq), 136.8 (aryl Cq), 168

-1 158.8 (aryl Cq), 159.2 (aryl Cq); νmax (thin film/cm ) 1050 (s), 1148 (s), 1195 (m), 1295 (w), 1408 (w), 1438 (m), 1461 (m), 1477 (m), 1571 (s), 1597 (s), 2855 (m), 2927 (s); MS + + + (ES ) m/z 425 [(M+Na) ]; HRMS C24H35O3S [(M+H) ] Expected 403.2301, Found 403.2303. [2-(2-Azidooctyl)-3,5-dimethoxyphenyl](phenyl)sulfide 187

NaN3 (42.3 mg, 0.651 mmol) was added to a solution of 99a (50.0 mg, 0.127 mmol) in DMF (1.3 mL) and heated to 80 °C for 18 h. The mixture was cooled to room temperature and diluted with EtOAc (5 mL) and 10% aq. LiCl (5 mL) was added. The organic phase was washed with 10% aq. LiCl (3 × 5 mL), dried over MgSO4, filtered and the solvent removed in vacuo. The crude product was purified by column chromatography (10%

EtOAc in hexanes) to give 187 (22.9 mg, 57.3 µmol, 44%) as a colourless oil; δH (500

MHz, CDCl3) 0.89 (3 H, t, J 6.9 Hz, CH3), 1.21 - 1.38 (7 H, m, CH2), 1.44 - 1.60 ( 3 H, m,

CH2), 2.98 (1 H, dd, J 13.6, 6.0 Hz, ArCH2CH(N3)), 3.09 (1 H, dd, J 13.6, 8.2 Hz,

ArCH2CH(N3)), 3.50 - 3.58 (1 H, m, CH(N3)), 3.69 (3 H, s, OCH3), 3.84 (3 H, s, OCH3), 6.42 (1 H, d, J 2.5 Hz, aryl H), 6.43 (1 H, d, J 2.5 Hz, aryl H), 7.19 - 7.32 (5 H, m, aryl H);

δC (125 MHz, CDCl3) 14.1 (CH3), 22.6 (CH2), 26.2 (CH2), 29.0 (CH2), 31.7 (CH2), 32.3

(ArCH2CH(N3)), 34.2 (CH2), 55.3 (OCH3), 55.6 (OCH3), 62.9 (CH(N3)), 98.2 (aryl C-H),

108.8 (aryl C-H), 121.0 (aryl Cq), 126.6 (aryl C-H), 129.1 (aryl C-H), 130.0 (aryl C-H), -1 136.2 (aryl Cq), 136.3 (aryl Cq), 159.1 (aryl Cq), 159.3 (aryl Cq); νmax (thin film/cm ) 1048 (s), 1146 (s), 1197 (m), 1276 (w), 1460 (m), 1571 (s), 1597 (s), 2100 (s), 2856 (w), 2929 + + + (m); MS (ES ) m/z 400 [(M+H) ]; HRMS C22H30O2N3S [(M+H) ] Expected 400.2053, Found 400.2056.

169

(3,5-Dimethoxy-2-octylphenyl)(3-methoxyphenyl)sulfide 189

AIBN (1.64 mg, 10.0 µmol) and Bu3SnH (64.6 μL, 0.240 mmol) were added to a solution of 164e (50.0 mg, 0.127 mmol) in benzene (1 mL). The solution was stirred under reflux for 18 h, then cooled to room temperature and solvent removed in vacuo. The crude product mixture was then passed through a plug of 10% K2CO3/silica using first hexanes, then EtOAc as eluents.207 The solvent was then removed in vacuo and the resultant crude product purified by column chromatography (30% CHCl3 in hexanes) to give 189 (27.9 mg, 71.8 µmol, 55%) as a colourless oil; δH (400 MHz, CDCl3) 0.83 - 0.92 (3 H, t, J 7.0

Hz, CH3), 1.18 - 1.38 (10 H, m, CH2), 1.39 - 1.51 (2 H, m, ArCH2CH2), 2.69 - 2.78 (2 H, m, ArCH2CH2), 3.70 (3 H, s, OCH3), 3.76 (3 H, s, OCH3), 3.81 (3 H, s, OCH3), 6.41 (1 H, d, J 2.5 Hz, aryl H), 6.46 (1 H, d, J 2.5 Hz, aryl H), 6.71 - 6.76 (1 H, m, aryl H), 6.79 (1 H, t, J 2.0 Hz, aryl H), 6.82 (1 H, d, J 7.8 Hz, aryl H), 7.18 (1 H, t, J 7.8 Hz, aryl H); δC (100

MHz, CDCl3) 14.1 (CH3), 22.7 (CH2), 27.3 (ArCH2CH2), 29.3 (CH2), 29.4 (CH2), 29.8

(CH2), 29.9 (CH2), 31.9 (CH2), 55.2 (OCH3), 55.2 (OCH3), 55.6 (OCH3), 98.6 (aryl C-H),

108.8 (aryl C-H), 112.0 (aryl C-H), 114.9 (aryl C-H), 121.9 (aryl C-H), 126.4 (aryl Cq),

129.8 (aryl C-H), 134.4 (aryl Cq), 138.2 (aryl Cq), 158.4 (aryl Cq). 158.8 (aryl Cq), 159.9 -1 (aryl Cq); νmax (thin film/cm ) 1047 (s), 1147 (s), 1195 (w), 1230 (w), 1245 (w), 1282 (w), 1462 (m), 1476 (m), 1570 (s), 1590 (s), 2853 (w), 2925 (m), 2954 (m), 2999 (w); MS (ES+) + + m/z 389 [(M+H) ]; HRMS C23H33O3S [(M+H) ] Expected 389.2162, Found 389.2150.

170

5.9 Synthesis of Dihydrobenzofurans

2-Hexyl-4-(phenylsulfanyl)-2,3-dihydrobenzofuran-6-ol 191a

165 The compound was prepared according to a literature procedure. Pd(PPh3)4 (25.3 mg, 21.9 µmol) was added to a solution of 164j (85.6 mg, 0.192 mmol) in MeOH (2 mL) under

N2. After 5 min. of stirring, K2CO3 (170.8 mg, 1.20 mmol) was added and the resulting mixture was stirred for 4 h. The mixture was then concentrated in vacuo, before treating with 1 N HCl (2 mL), extracting with CH2Cl2 (3 × 2 mL), washing with brine (3 × 2 mL), drying over MgSO4 and concentrating in vacuo. The crude product was purified by column chromatography (20% EtOAc in hexanes) to give 191a (33.4 mg, 0.102 mmol, 53%) as a yellow oil; δH (500 MHz, CDCl3) 0.89 (3 H, t, J 6.5 Hz, CH3), 1.23 - 1.37 (7 H, m, CH2),

1.41 - 1.49 (1 H, m, CH2), 1.59 - 1.68 (1 H, m, CH2), 1.74 - 1.84 (1 H, m, CH2), 2.64 (1 H, dd, J 15.5, 7.6 Hz, ArCH2CH(O)), 3.08 (1 H, dd, J 15.5, 8.9 Hz, ArCH2CH(O)), 4.66 (1 H, s, OH) 4.74 - 4.83 (1 H, m, CH(O)), 6.14 (1 H, s, aryl H), 6.19 (1 H, s, aryl H), 7.24 - 7.38

(5 H, m, aryl H); δC (125 MHz, CDCl3) 14.1 (CH3), 22.6 (CH2), 25.2 (CH2), 29.1 (CH2),

31.7 (CH2), 34.3 (ArCH2CH(O)), 36.1 (CH2), 84.6 (CH2CH(O)), 96.4 (aryl C-H), 108.5

(aryl C-H), 120.4 (aryl Cq), 127.2 (aryl C-H), 129.2 (aryl C-H), 131.2 (aryl C-H), 132.3 -1 (aryl Cq) 133.9 (aryl Cq) 156.2 (aryl Cq) 161.0 (aryl Cq); νmax (thin film/cm ) 994 (w), 1025 (s), 1113 (w), 1174 (w), 1262 (s), 1377 (s), 1439 (w), 1478 (w), 1585 (s), 1609 (s), 2853 − + + (w), 2923 (w), 3367 (w, br); MS (ES ) m/z 327 [(M−H) ]; HRMS C20H23O2S [(M−H) ] Expected 327.1419, Found 327.1419.

General Procedure F – Pd-catalysed deallylation/cyclisation 166

Morpholine (2.2 eq.) was added to a stirred mixture of the corresponding sulfide (1.0 eq.),

Pd(PPh3)4 (0.1 eq.) and either NaBH4 or NaH (2.40 eq.) in THF (0.1 M) at room temperature and stirred for 16 h. The reaction was then cooled to 0 °C and 1 N HCl (10 mL) was added slowly. The aqueous layer was extracted with CH2Cl2 (3 × 10 mL) and the

171 combined organic extracts were then washed with brine (10 mL), dried over MgSO4, filtered and the solvent removed in vacuo.

2-Butyl-4-(phenylsulfanyl)-2,3-dihydrobenzofuran-6-ol 191b

As described in general procedure F, morpholine (23.0 µL, 0.263 mmol), 164k (50.0 mg,

0.112 mmol), Pd(PPh3)4 (13.9 mg, 12.0 µmol) and NaBH4 (10.9 mg, 0.288 mmol), after purification by column chromatography on silica gel (10% EtOAc in hexanes) gave 191b

(30.1 mg, 0.100 mmol, 84%) as a pale yellow oil; δH (400 MHz, CDCl3) 0.90 (3 H, t, J 6.8

Hz, CH3), 1.29 - 1.49 (4 H, m, CH2), 1.58 - 1.71 (1 H, m, CH(O)CH2CH2), 1.72 - 1.86 (1

H, m, CH(O)CH2CH2), 2.65 (1 H, dd, J 15.4, 7.7 Hz, ArCH2CH(O)), 3.08 (1 H, dd, J 15.4,

8.9 Hz, ArCH2CH(O)), 4.73 - 4.89 (2 H, m, CH(O) + ArOH), 6.14 (1 H, d, J 2.3 Hz, aryl

H), 6.19 (1 H, d, J 2.3 Hz, aryl H), 7.24 - 7.37 (5 H, m, aryl H); δC (100 MHz, CDCl3) 14.0

(CH3), 22.6 (CH2), 27.3 (CH2), 34.2 (ArCH2CH(O)), 35.8 (CH(O)CH2CH2), 84.5 (CH(O)),

96.4 (aryl C-H), 108.6 (aryl C-H), 120.2 (aryl Cq), 127.2 (aryl C-H), 129.2 (aryl C-H),

131.2 (aryl C-H), 132.3 (aryl Cq), 134.0 (aryl Cq), 156.3 (aryl Cq), 160.9 (aryl Cq); νmax (thin film/cm-1) 994 (s), 1111 (s), 1216 (m), 1354 (w), 1439 (s), 1477 (s), 1591 (s), 1609 (s), 2848 (m), 2916 (m), 2955 (m), 3404 (s, br, O-H stretch); MS (ES+) m/z 301 [(M+H)+]; + HRMS C18H21O2S [(M+H) ] Expected 301.1257, Found 301.1255.

2-(3-Nitropropyl)-4-(phenylsulfanyl)-2,3-dihydrobenzofuran-6-ol 191c

As described in general procedure F, morpholine (20.0 µL, 0.229 mmol), 164l (41.8 mg,

93.3 µmol), Pd(PPh3)4 (10.3 mg, 8.91 µmol) and NaBH4 (8.6 mg, 0.227 mmol), after purification by column chromatography on silica gel (20% EtOAc in hexanes) gave 191c

172

(25.2 mg, 76.0 µmol, 82%) as a yellow oil; δH (400 MHz, CDCl3) 1.71 - 1.87 (2 H, m,

CH2), 2.09 - 2.29 (2 H, m, CH2), 2.64 (1 H, dd, J 15.6, 7.3 Hz, ArCH2CH(O)), 3.12 (1 H, dd, J 15.6, 9.0 Hz, ArCH2CH(O)), 4.39 - 4.53 (2 H, m, CH(O) + ArOH), 4.69 - 4.79 (2 H, m, CH2NO2), 6.17 (1 H, d, J 2.3 Hz, aryl H), 6.19 (1 H, d, J 2.3 Hz, aryl H), 7.28 - 7.37 (5

H, m, aryl H); δC (100 MHz, CDCl3) 23.5 (CH2), 32.6 (CH2), 34.3 (ArCH2CH(O)), 75.2

(CH2NO2), 83.0 (CH(O)), 96.6 (aryl C-H), 109.0 (aryl C-H), 119.4 (aryl Cq), 127.4 (aryl C-

H), 129.3 (aryl C-H), 131.4 (aryl C-H), 132.7 (aryl Cq), 133.8 (aryl Cq), 156.6 (aryl Cq), -1 160.5 (aryl Cq); νmax (thin film/cm ) 993 (s), 1117 (s), 1221 (m), 1377 (m), 1437 (s), 1477 (s), 1549 (s), 1609 (s), 2852 (m), 2934 (m), 3060 (m), 3419 (s, br, O-H stretch); MS + + (APCI) m/z 332 [(M+H) ]; HRMS C17H18O4NS [(M+H) ] Expected 332.0951, Found 332.0936.

2-(3-Bromopropyl)-4-(phenylsulfanyl)-2,3-dihydrobenzofuran-6-ol 191d

As described in general procedure F, morpholine (24 µL, 0.274 mmol), 164m (60.7 mg,

0.126 mmol), Pd(PPh3)4 (14.9 mg, 12.9 µmol) and NaBH4 (11.8 mg, 0.312 mmol), after purification by column chromatography on silica gel (10% EtOAc in hexanes) gave 191d

(36.3 mg, 99.4 µmol, 79%) as a colourless oil; δH (400 MHz, CDCl3) 1.78 - 2.14 (4 H, m,

CH2), 2.66 (1 H, dd, J 15.6, 7.3 Hz, ArCH2CH(O)), 3.11 (1 H, dd, J 15.6, 9.1 Hz,

ArCH2CH(O)), 3.40 - 3.52 (2 H, m, CH2Br), 4.76 (1 H, s, ArOH), 4.82 (1 H, dtd, J 9.1, 7.3, 5.3 Hz, CH(O)), 6.16 (1 H, d, J 2.0 Hz, aryl H), 6.19 (1 H, d, J 2.0 Hz, aryl H), 7.25 -

7.37 (5 H, m, aryl H); δC (100 MHz, CDCl3) 28.6 (CH2), 33.4 (CH2Br), 34.3

(ArCH2CH(O)), 34.6 (CH2), 83.3 (CH(O)), 96.5 (aryl C-H), 108.9 (aryl C-H), 119.8 (aryl

Cq), 127.4 (aryl C-H), 129.3 (aryl C-H), 131.3 (aryl C-H), 132.5 (aryl Cq), 133.9 (aryl Cq), -1 156.4 (aryl Cq), 160.7 (aryl Cq); νmax (thin film/cm ) 992 (s), 1113 (s), 1253 (w), 1437 (s), 1476 (m), 1591 (m), 1607 (m), 2849 (w), 2939 (w), 3396 (m, br, O-H stretch); MS (APCI) 79 81 + + m/z 365 Br, 367 Br [(M+H) ]; HRMS C17H18O2BrS [(M+H) ] Expected 365.0205, Found 365.0188.

173

2-(7-Phenylheptyl)-4-(phenylsulfanyl)-2,3-dihydrobenzofuran-6-ol 191e

As described in general procedure F, morpholine (18.0 µL, 0.206 mmol), 164n (52.0 mg,

97.2 µmol), Pd(PPh3)4 (12.1 mg, 10.5 µmol) and NaBH4 (9.00 mg, 0.238 mmol), after purification by column chromatography on silica gel (10% EtOAc in hexanes) gave 191e

(33.1 mg, 79.1 µmol, 81%) as a colourless oil; δH (400 MHz, CDCl3) 1.22 – 1.44 (8 H, m,

CH2), 1.48 – 1.62 (3 H, m, CH2), 1.65 – 1.78 (1 H, m, CH(O)CH2CH2), 2.50 – 2.62 (3 H, m, ArCH2CH(O) + ArCH2CH2), 3.01 (1 H, dd, J 15.4, 8.9 Hz, ArCH2CH(O)), 4.62 – 4.77 (2 H, m, CH(O) + OH), 6.06 (1 H, d, J 2.3 Hz, aryl H), 6.10 (1 H, d, J 2.3 Hz, aryl H), 7.09

– 7.15 (3 H, m, aryl H), 7.17 – 7.30 (7 H, m, aryl H); δC (100 MHz, CDCl3) 25.2 (CH2),

29.2 (CH2), 29.3 (CH2), 29.4 (CH2), 31.5 (CH2), 34.3 (ArCH2CH(O)), 36.0 (ArCH2CH2),

36.1 (ArCH2CH(O)CH2), 84.6 (CH(O)), 96.6 (aryl C-H), 108.8 (aryl C-H), 120.4 (aryl Cq), 125.6 (aryl C-H), 127.3 (aryl C-H), 128.3 (aryl C-H), 128.4 (aryl C-H), 129.3 (aryl C-H),

131.2 (aryl C-H), 132.3 (aryl Cq), 134.1 (aryl Cq), 142.9 (aryl Cq), 156.4 (aryl Cq), 161.0 -1 (aryl Cq); νmax (thin film/cm ) 993 (s), 1114 (vs), 1174 (w), 1220 (w), 1266 (w), 1353 (w), 1438 (s), 1477 (s), 1591 (s), 1607 (s), 2853 (m), 2927 (s), 3924 (w), 3402 (br); MS (APCI) + + m/z 419 [(M+H) ]; HRMS C27H31O2S [(M+H) ] Expected 419.2027, Found 419.2039.

6-(Allyloxy)-2-butyl-4-(phenylsulfanyl)-2,3-dihydrobenzofuran 192

As described in general procedure F, morpholine (23.0 µL, 0.263 mmol), 164k (50.0 mg,

0.112 mmol), Pd(PPh3)4 (13.9 mg, 12.0 µmol) and NaH (11.6 mg, 0.290 mmol, 60% dispersion in mineral oil), after purification by column chromatography on silica gel (10%

EtOAc in hexanes) gave 192 (35.1 mg, 0.103 mmol, 92%) as a colourless oil; δH

(400 MHz, CDCl3) 0.92 (3 H, t, J 7.0 Hz, CH3), 1.30 - 1.48 (4 H, m, CH2), 1.59 - 1.69 (1 174

H, m, CH(O)CH2CH2), 1.73 - 1.84 (1 H, m, CH(O)CH2CH2), 2.65 (1 H, dd, J 15.4, 7.7 Hz,

ArCH2CH(O)), 3.08 (1 H, dd, J 15.4, 8.9 Hz, ArCH2CH(O)), 4.42 (2 H, dt, J 5.3, 1.5 Hz,

OCH2), 4.73 - 4.83 (1 H, m, CH(O)), 5.25 (1 H, dq, J 10.5, 1.5 Hz, CH=CH2), 5.34 (1 H, dq, J 17.3, 1.5 Hz, CH=CH2) 5.99 (1 H, ddt, J 17.3, 10.5, 5.3 Hz, CH=CH2), 6.30 (2 H, s, aryl H), 7.22 - 7.35 (5 H, m, aryl H); δC (100 MHz, CDCl3) 14.0 (CH3), 22.6 (CH2), 27.4

(CH2), 34.4 (ArCH2CH(O)), 35.8 (CH(O)CH2CH2), 69.1 (OCH2), 84.4 (CH(O)), 96.1 (aryl

C-H), 109.0 (aryl C-H), 117.8 (CH=CH2), 120.8 (aryl Cq), 126.9 (aryl C-H), 129.2 (aryl C-

H), 130.4 (aryl C-H), 131.6 (aryl Cq), 133.1 (CH=CH2), 134.6 (aryl Cq), 159.6 (aryl Cq), -1 160.9 (aryl Cq); νmax (thin film/cm ) 925 (m), 980 (s), 1024 (s), 1114 (s), 1181 (m), 1423 (m), 1477 (s), 1578 (s), 1606 (s), 2859 (w), 2929 (m), 2954 (m); MS (APCI) m/z 341 + + [(M+H) ]; HRMS C21H25O2S [(M+H) ] Expected 341.1570, Found 341.1567.

5.10 Cross-Coupling of Dihydrobenzofurans

2-Butyl-4-(phenylsulfanyl)-2,3-dihydrobenzofuran-6-yl trifluoromethanesulfonate 193

The compound was prepared according to a literature procedure.208 Sodium tert-butoxide (187 mg, 1.95 mmol) was added to a stirred solution of N-phenyl- bis(trifluoromethanesulfonimide) (696 mg, 1.95 mmol) and 191b (532 mg, 1.77 mmol) in THF (18 mL) at 0 °C. The mixture was stirred for 1 h at 0 °C, then warmed to room temperature and stirred for a further 1 h. The mixture was then quenched with H2O (20 mL) and the aqueous layer extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with brine (30 mL), dried with MgSO4, filtered and the solvent removed in vacuo. The crude product was purified by column chromatography on silica gel

(10% Et2O in hexanes) to give 193 (666 mg, 1.54 mmol, 87%) as a colourless oil; δH (400

MHz, CDCl3) 0.94 (3 H, t, J 7.1 Hz, CH3), 1.31 - 1.51 (4 H, m, CH2), 1.62 - 1.74 (1 H, m,

CH(O)CH2CH2), 1.76 - 1.89 (1 H, m, CH(O)CH2CH2), 2.73 (1 H, dd, J 16.1, 7.5 Hz,

ArCH2CH(O)), 3.17 (1 H, dd, J 16.1, 9.2 Hz, ArCH2CH(O)), 4.83 - 4.93 (1 H, m, CH(O)), 6.39 (1 H, d, J 2.2 Hz, aryl H), 6.51 (1 H, d, J 2.2 Hz, aryl H), 7.35 - 7.43 (5 H, m, aryl H);

δC (100 MHz, CDCl3) 14.0 (CH3), 22.5 (CH2), 27.3 (CH2), 34.3 (ArCH2CH(O)), 35.8

175

(CH(O)CH2CH2), 85.2 (CH(O)), 101.3 (aryl C-H), 112.9 (aryl C-H), 127.1 (aryl Cq), 128.5

(aryl C-H), 129.6 (aryl C-H), 131.8 (aryl Cq), 132.5 (aryl C-H), 135.0 (aryl Cq), 149.6 (aryl -1 Cq), 160.6 (aryl Cq); νmax (thin film/cm ) 983 (s), 1092 (m), 1140 (s), 1209 (vs, C-F stretch?),1 1420 (s), 1592 (m), 2861 (w), 2933 (w), 2957 (w); MS (ES+) m/z 433 [(M+H)+]; + HRMS C19H20F3O4S2 [(M+H) ] Expected 433.0750, Found 433.0749.

General Procedure G – Pd-catalysed Suzuki coupling 168

Pd(PPh3)4 (11.6 mg, 10.0 µmol) and corresponding boronic acid (0.200 mmol) were added to a microwave vial with Teflon-lined septum pre-flushed with N2. K2CO3 (2.00 M in H2O, 1 mL) and 193 (43 mg, 0.100 mmol) in 1,4-dioxane (1 mL) were then added and the resulting mixture was heated to 135 °C and stirred for 5 h. The mixture was then cooled, diluted with H2O (15 mL) and extracted with CH2Cl2 (3 × 15 mL). The combined organic extracts were dried with MgSO4, filtered and the solvent removed in vacuo. The crude product was purified by column chromatography on silica gel.

2-Butyl-4-(phenylsulfanyl)-6-(p-tolyl)-2,3-dihydrobenzofuran 194a

As described in general procedure G, 193 (44.1 mg, 0.102 mmol) and 4- methylphenylboronic acid (27.0 mg, 0.199 mmol), after purification by column chromatography (2% Et2O in hexanes) gave 194a (34.4 mg, 91.8 µmol, 90%) as a white solid; m.p 59.9-61.2 °C; δH (400 MHz, CDCl3) 0.95 (3 H, t, J 6.8 Hz, CH3), 1.33 - 1.52 (4

H, m, CH2), 1.61 - 1.72 (1 H, m, (CH(O)CH2CH2)), 1.78 - 1.89 (1 H, m, (CH(O)CH2CH2)),

2.39 (3 H, s, ArCH3), 2.75 (1 H, dd, J 16.1, 7.5 Hz, ArCH2CH(O)), 3.18 (1 H, dd, J 16.1,

9.0 Hz, ArCH2CH(O)), 4.77 - 4.87 (1 H, m, CH(O)), 6.93 (1 H, d, J 1.5 Hz, aryl H), 7.03

(1 H, d, J 1.5 Hz, aryl H), 7.19 - 7.34 (7 H, m, aryl H), 7.38 - 7.43 (2 H, m, aryl H); δC (100

MHz, CDCl3) 14.0 (CH3), 21.1 (ArCH3), 22.6 (CH2), 27.4 (CH2), 34.9 (ArCH2CH(O)),

35.8 (CH(O)CH2CH2), 83.9 (CH(O)), 107.2 (aryl C-H), 122.3 (aryl C-H), 126.7 (aryl C-

H), 126.8 (aryl C-H), 127.9 (aryl Cq), 129.2 (aryl C-H), 129.4 (aryl C-H), 130.0 (aryl C-H),

131.2 (aryl Cq), 135.0 (aryl Cq), 137.2 (aryl Cq), 137.7 (aryl Cq), 142.4 (aryl Cq), 160.5

176

-1 (aryl Cq); νmax (thin film/cm ) 814 (vs), 950 (m), 1206 (m), 1468 (s), 1561 (s), 1578 (s), + + 2858 (m), 2929 (s), 2954 (s); MS (APCI) m/z 375 [(M+H) ]; HRMS C25H27OS [(M+H) ] Expected 375.1777, Found 375.1775.

3-[2-Butyl-4-(phenylsulfanyl)-2,3-dihydrobenzofuran-6-yl]pyridine 194b

As described in general procedure G, 193 (43.0 mg, 99.4 µmol) and 3-pyridylboronic acid

(24.5 mg, 0.199 mmol), after purification by column chromatography (50% Et2O in hexanes) gave 194b (25.7 mg, 71.1 µmol, 71%) as a colourless oil; δH (400 MHz, CDCl3)

0.93 (3 H, t, J 7.0 Hz, CH3), 1.33 - 1.52 (4 H, m, CH2), 1.61 - 1.73 (1 H, m,

(CH(O)CH2CH2), 1.77 - 1.90 (1 H, m, (CH(O)CH2CH2), 2.76 (1 H, dd, J 16.3, 7.5 Hz,

ArCH2CH(O)), 3.19 (1 H, dd, J 16.3, 9.0 Hz, ArCH2CH(O)), 4.79 - 4.90 (1 H, m, CH(O)), 6.88 (1 H, d, J 1.5 Hz, aryl H), 6.94 (1 H, d, J 1.5 Hz, aryl H), 7.21 - 7.40 (6 H, m, aryl H), 7.76 (1 H, dt, J 8.0, 2.0 Hz, aryl H), 8.56 (1 H, d, J 3.0 Hz, aryl H), 8.73 (1 H, br. s., aryl

H); δC (100 MHz, CDCl3) 14.0 (CH3), 22.5 (CH2), 27.3 (CH2), 34.8 (ArCH2CH(O)), 35.8

(CH(O)CH2CH2), 84.1 (CH(O)), 106.9 (aryl C-H), 121.6 (aryl C-H), 123.5 (aryl C-H),

121.2 (aryl C-H), 128.6 (aryl Cq), 129.3 (aryl C-H), 130.7 (aryl C-H), 132.4 (aryl Cq),

134.2 (aryl C-H), 136.1 (aryl Cq), 138.9 (aryl Cq), 148.1 (aryl C-H), 148.5 (aryl C-H), -1 160.6 (aryl Cq); νmax (thin film/cm ) 946 (s), 1023 (m), 1218 (s), 1293 (w), 1399 (m), 1426 (s), 1463 (m), 1577 (s), 2858 (w), 2929 (m), 2954 (m); MS (ES+) m/z 362 [(M+H)+]; + HRMS C23H24ONS [(M+H) ] Expected 362.1573, Found 362.1566.

177

2-Butyl-4-(phenylsulfanyl)-6-(2-thienyl)-2,3-dihydrobenzofuran 194c

As described in general procedure G, 193 (42.8 mg, 99.0 µmol) and 2-thienylboronic acid

(25.6 mg, 0.200 mmol), after purification by column chromatography (2% Et2O in hexanes) gave 194c (31.2 mg, 85.1 µmol, 87%) as a colourless oil; δH (400 MHz, CDCl3)

0.93 (3 H, t, J 7.0 Hz, CH3), 1.32 - 1.50 (4 H, m, CH2), 1.60 - 1.70 (1 H, m,

(CH(O)CH2CH2), 1.75 - 1.87 (1 H, m, (CH(O)CH2CH2), 2.71 (1 H, dd, J 16.3, 7.5 Hz,

ArCH2CH(O)), 3.14 (1 H, dd, J 16.3, 9.0 Hz, ArCH2CH(O)), 4.81 (1 H, dtd, J 9.0, 7.5, 5.9 Hz, CH(O)), 6.96 (1 H, d, J 1.5 Hz, aryl H), 7.04 (1 H, dd, J 5.1, 3.6 Hz, aryl H), 7.06 (1 H, d, J 1.5 Hz, aryl H), 7.20 (1 H, dd, J 3.6, 1.1 Hz, aryl H), 7.22 - 7.34 (6 H, m, aryl H);

δC (100 MHz, CDCl3) 14.0 (CH3), 22.6 (CH2), 27.3 (CH2), 34.9 (ArCH2CH(O)), 35.8

(CH(O)CH2CH2), 84.0 (CH(O)), 106.1 (aryl C-H), 121.1 (aryl C-H), 123.2 (aryl C-H),

124.8 (aryl C-H), 126.8 (aryl C-H), 127.8 (aryl C-H), 128.4 (aryl Cq), 129.2 (aryl C-H),

130.1 (aryl C-H), 131.6 (aryl Cq), 134.7 (aryl Cq), 135.3 (aryl Cq), 143.8 (aryl Cq), 160.5 -1 (aryl Cq); νmax (thin film/cm ) 932 (m), 1023 (m), 1224 (s), 1413 (m), 1476 (m), 1569 (s), 1603 (m), 2858 (w), 2930 (m), 2953 (m); MS (APCI) m/z 367 [(M+H)+]; HRMS + C22H23OS2 [(M+H) ] Expected 367.1185, Found 367.1186.

2-Butyl-6-(phenylethynyl)-4-(phenylsulfanyl)-2,3-dihydrobenzofuran 195

168 The compound was prepared according to a literature procedure. Et3N (1.13 mL, 1.00 mmol) was added to a microwave vial with Teflon-lined septum pre-flushed with N2 and containing a stirred mixture of PdCl2(PPh3)2 (7.00 mg, 9.97 µmol), phenylacetylene (20.0 mg, 0.196 mmol) and 193 (43.8 mg, 0.101 mmol) in DMF (0.5 mL). The mixture was heated to 90 °C and stirred for 18 h. The mixture was then cooled to room temperature and 178 diluted with H2O. The aqueous layer was extracted with Et2O (3 × 10 mL) and the combined organic extracts were washed with 10 aq. LiCl (15 mL), dried with MgSO4, filtered and the solvent removed in vacuo. The crude product was purified by column chromatography on silica gel (10% CHCl3 in hexanes) to give 195 (36.2 mg, 94.1 µmol,

94%) as a pale yellow oil; δH (400 MHz, CDCl3) 0.93 (3 H, t, J 6.9 Hz, CH3), 1.32 - 1.47

(4 H, m, CH2), 1.61 - 1.69 (1 H, m, CH(O)CH2CH2), 1.76 - 1.83 (1 H, m, CH(O)CH2CH2),

2.73 (1 H, dd, J 16.4, 7.5 Hz, ArCH2CH(O)), 3.16 (1 H, dd, J 16.4, 9.1 Hz, ArCH2CH(O)), 4.76 - 4.84 (1 H, m, CH(O)), 6.83 (1 H, d, J 0.9 Hz, aryl H), 6.96 (1 H, d, J 0.9 Hz, aryl H),

7.24 - 7.39 (8 H, m, aryl H), 7.47 - 7.52 (2 H, m, aryl H); δC (125 MHz, CDCl3) 14.0

(CH3), 22.5 (CH2), 27.3 (CH2), 35.0 (ArCH2CH(O)), 35.7 (CH(O)CH2CH2), 83.9 (CH(O)),

89.0 (ArC≡CAr), 89.1 (ArC≡CAr), 111.2 (aryl C-H), 123.1 (aryl Cq), 123.6 (aryl Cq), 126.5 (aryl C-H), 127.1 (aryl C-H), 128.2 (aryl C-H), 128.3 (aryl C-H), 129.3 (aryl C-H),

129.7 (aryl Cq), 130.6 (aryl C-H), 131.6 (aryl C-H), 131.7 (aryl Cq), 134.3 (aryl Cq), 159.8 -1 (aryl Cq); νmax (thin film/cm ) 755 (vs), 987 (m), 1220 (s), 1410 (m), 1562 (s), 1600 (m), + + + 2858 (w), 2929 (m), 2955 (m); MS (ES ) m/z 385 [(M+H) ]; HRMS C26H25OS [(M+H) ] Expected 385.1621, Found 385.1621.

General Procedure H – Ni-catalysed Kumada-Corriu coupling72

Ni(PPh3)2Cl2 (6.54 mg, 10 µmol) was added to a microwave vial with Teflon-lined septum before evacuating and backfilling with Ar (3 cycles). The corresponding sulfide (0.100 mmol), benzene (1.5 mL) and Grignard reagent solution (0.300 mmol) were then added at room temperature and the mixture was heated to 80 °C and stirred for 24 h. The reaction mixture was then cooled to room temperature and quenched with sat. aq. NH4Cl (10 mL). The aqueous layer was then extracted with EtOAc (3 × 10 mL) and the combined organic extracts were dried with MgSO4, filtered and the solvent removed in vacuo. The crude product was purified by column chromatography on silica gel.

179

2-Butyl-4-methyl-6-(p-tolyl)-2,3-dihydrobenzofuran 198a

As described in general procedure H, 194a (37.5 mg, 0.100 mmol), methylmagnesium chloride (3 M in THF, 0.100 mL, 0.300 mmol) and Ni(PPh3)2Cl2 (6.55 mg, 10 µmol), after column chromatography on silica gel (10% toluene in hexanes) gave 198a (20.9 mg, 74.5

µmol, 75%) as a white solid; m.p. 44.1-45.2 °C; δH (400 MHz, CDCl3) 0.96 (3 H, t, J 7.0

Hz, CH3), 1.36 - 1.59 (4 H, m, CH2), 1.66 - 1.77 (1 H, m, CH(O)CH2CH2), 1.83 - 1.95 (1

H, m, CH(O)CH2CH2), 2.29 (3 H, s, ArCH3), 2.40 (3 H, s, ArCH3), 2.80 (1 H, dd, J 15.4,

7.9 Hz, ArCH2CH(O)), 3.23 (1 H, dd, J 15.4, 8.9 Hz, ArCH2CH(O)), 4.79 – 4.89 (1 H, m, CH(O)), 6.83 (1 H, s, aryl H), 6.89 (1 H, s, aryl H), 7.20 – 7.25 (2 H, m, aryl H), 7.44 -

7.48 (2 H, m, aryl H); δC (100 MHz, CDCl3) 14.0 (CH3), 19.1 (ArCH3), 21.1 (ArCH3), 22.6

(CH2), 27.6 (CH2), 34.3 (ArCH2CH(O)), 36.0 (CH(O)CH2CH2), 83.6 (CH(O)), 105.2 (aryl

C-H), 120.2 (aryl C-H), 124.9 (aryl Cq), 126.9 (aryl C-H), 129.3 (aryl C-H), 134.7 (aryl -1 Cq), 136.8 (aryl Cq), 138.6 (aryl Cq), 141.5 (aryl Cq), 159.9 (aryl Cq); νmax (thin film/cm ) 814 (vs), 975 (s), 1204 (m), 1479 (s), 1598 (s), 2858 (m), 2929 (s), 2954 (s), 3024 (w); MS + + (APCI) m/z 281 [(M+H) ]; HRMS C20H25O [(M+H) ] Expected 281.1900, Found 281.1893.

2-Butyl-4-(2-thienyl)-6-(p-tolyl)-2,3-dihydrobenzofuran 198b

As described in general procedure H, 194a (35.3 mg, 94.2 µmol), 2-thienylmagnesium bromide (1 M in THF, 0.300 mL, 0.300 mmol) and Ni(PPh3)2Cl2 (6.50 mg, 10.0 µmol), after column chromatography on silica gel (20% CHCl3 in hexanes) gave 198b (24.3 mg,

69.7 µmol, 74%) as a yellow solid; m.p. 75.1-76.4 °C; δH (500 MHz, CDCl3) 0.97 (3 H, t, J

6.9 Hz, CH3), 1.37 - 1.59 (4 H, m, CH2), 1.70 - 1.80 (1 H, m, CH(O)CH2CH2), 1.84 - 1.96

(1 H, m, CH(O)CH2CH2), 2.41 (3 H, s, ArCH3), 3.09 (1 H, dd, J 15.6, 7.6 Hz,

180

ArCH2CH(O)), 3.53 (1 H, dd, J 15.6, 9.0 Hz, ArCH2CH(O)), 4.84 - 4.92 (1 H, m, CH(O)), 6.95 (1 H, d, J 1.3 Hz, aryl H), 7.13 (1 H, dd, J 5.0, 3.5 Hz, aryl H), 7.24 - 7.28 (2 H, m, aryl H), 7.30 - 7.34 (2 H, m, aryl H), 7.36 (1 H, dd, J 5.0, 1.1 Hz, aryl H), 7.51 (2 H, d, J

7.9 Hz, aryl H); δC (125 MHz, CDCl3) 14.0 (CH3), 21.1 (ArCH3), 22.6 (CH2), 27.6 (CH2),

36.0 (CH(O)CH2CH2), 36.2 (ArCH2CH(O)), 83.7 (CH(O)), 107.0 (aryl C-H), 118.3 (aryl

C-H), 122.7 (aryl Cq), 124.9 (aryl C-H), 125.1 (aryl C-H), 127.0 (aryl C-H), 127.6 (aryl C-

H), 129.4 (aryl C-H), 131.5 (aryl Cq), 137.2 (aryl Cq), 138.2 (aryl Cq), 142.1 (aryl Cq), -1 143.0 (aryl Cq), 160.9 (aryl Cq); νmax (thin film/cm ) 977 (s), 1045 (w), 1102 (w), 1171 (w), 1201 (s), 1218 (w), 1254 (m), 1297 (m), 1363 (w), 1400 (m), 1420 (s), 1436 (m), 1473 (m), 1516 (w), 1584 (s), 1611 (m), 2858 (w), 2928 (m), 2953 (m), 3023 (w); MS (APCI) + + m/z 349 [(M+H) ]; HRMS C23H25OS [(M+H) ] Expected 349.1621, Found 349.1606.

2-Butyl-4-(4-methoxyphenyl)-6-(p-tolyl)-2,3-dihydrobenzofuran 198c

As described in general procedure H, 194a (35.5 mg, 94.8 µmol), 4- methoxyphenylmagnesium bromide (0.5 M in THF, 0.600 mL, 0.300 mmol) and

Ni(PPh3)2Cl2 (6.54 mg, 10 µmol), after column chromatography on silica gel (5% Et2O in hexanes) gave 198c (22.6 mg, 60.7 µmol, 64%) as a white solid; m.p. 69.8-70.7 °C; δH

(400 MHz, CDCl3) 0.95 (3 H, t, J 7.2 Hz, CH3), 1.34 - 1.57 (4 H, m, CH2), 1.66 - 1.77 (1

H, m, CH(O)CH2CH2), 1.85 - 1.96 (1 H, m, CH(O)CH2CH2), 2.41 (3 H, s, ArCH3), 2.98 (1

H, dd, J 15.7, 8.0 Hz, ArCH2CH(O)), 3.38 (1 H, dd, J 15.7, 8.7 Hz, ArCH2CH(O)), 3.88 (3

H, s, OCH3), 4.78 - 4.88 (1 H, m, CH(O)), 6.95 - 7.03 (3 H, m, aryl H), 7.12 (1 H, d, J 1.5 Hz, aryl H), 7.25 (2 H, d, J 8.0 Hz, aryl H), 7.43 - 7.49 (2 H, m, aryl H), 7.52 (2 H, d, J 8.0

Hz, aryl H); δC (100 MHz, CDCl3) 14.0 (CH3), 21.1 (ArCH3), 22.6 (CH2), 27.6 (CH2), 35.4

(ArCH2CH(O)), 35.8 (CH(O)CH2CH2), 55.3 (OCH3), 83.8 (CH(O)), 106.5 (aryl C-H),

113.8 (aryl C-H), 119.4 (aryl C-H), 123.5 (aryl Cq), 127.0 (aryl C-H), 129.2 (aryl C-H),

129.4 (aryl C-H), 133.0 (aryl Cq), 137.0 (aryl Cq), 138.4 (aryl Cq), 138.5 (aryl Cq), 141.9 -1 (aryl Cq), 158.8 (aryl Cq), 160.5 (aryl Cq); νmax (thin film/cm ) 814 (vs), 938 (m), 1034 (m), 1108 (m), 1176 (m), 1246 (s), 1290 (m), 1466 (m), 1513 (s), 1609 (m), 2835 (w),

181

2858 (w), 2929 (w), 2935 (w), 2996 (w), 3029 (w); MS (APCI) m/z 373 [(M+H)+]; HRMS + C26H29O2 [(M+H) ] Expected 373.2162, Found 373.2144.

2-Butyl-4-cyclopropyl-6-(2-thienyl)-2,3-dihydrobenzofuran 198d

As described in general procedure H, 194c (33.0 mg, 90.0 µmol), cyclopropylmagnesium bromide (0.5 M in THF, 0.600 mL, 0.300 mmol) and Ni(PPh3)2Cl2 (6.54 mg, 10 µmol), after column chromatography on silica gel (10% toluene in hexanes) gave 198d (19.2 mg,

64.3 µmol, 72%) as a colourless oil; δH (400 MHz, CDCl3) 0.73 - 0.79 (2 H, m,

CH(CH2)2), 0.92 - 1.00 (5 H, m, CH3 + CH(CH2)2), 1.36 - 1.55 (4 H, m, CH2), 1.66 - 1.96

(3 H, m, CH(O)CH2CH2 + CH(CH2)2), 2.90 (1 H, dd, J 15.6, 7.5 Hz, ArCH2CH(O)), 3.35

(1 H, dd, J 15.6, 8.8 Hz, ArCH2CH(O)), 4.84 (1 H, dtd, J 8.8, 7.5, 6.1 Hz, CH(O)), 6.63 (1 H, d, J 1.5 Hz, aryl H), 6.85 (1 H, d, J 1.5 Hz, aryl H), 7.02 - 7.07 (1 H, m, aryl H), 7.20 -

7.24 (2 H, m, aryl H); δC (100 MHz, CDCl3) 7.80 (CH(CH2)2), 13.1 (CH(CH2)2), 14.0

(CH3), 22.6 (CH2), 27.6 (CH2), 34.2 ((ArCH2CH(O)), 36.0 (CH(O)CH2CH2), 83.8 (CH(O)), 104.3 (aryl C-H), 113.9 (aryl C-H), 122.8 (aryl C-H), 124.2 (aryl C-H), 125.9

(aryl Cq), 127.8 (aryl C-H), 134.6 (aryl Cq), 140.6 (aryl Cq), 145.0 (aryl Cq), 159.7 (aryl -1 Cq); νmax (thin film/cm ) 823 (s), 905 (m), 992 (m), 1023 (s), 1223 (s), 1425 (s), 1432 (s), 1483 (w), 1589 (s), 1613 (m), 2858 (m), 2930 (s), 2953 (s), 3003 (w), 3081 (w); MS + + (APCI) m/z 299 [(M+H) ]; HRMS C19H23OS [(M+H) ] Expected 299.1464, Found 299.1451.

4-Benzyl-2-butyl-6-(2-thienyl)-2,3-dihydrobenzofuran 198e

As described in general procedure H, 194c (33.0 mg, 90.0 mmol), benzylmagnesium chloride (1.82 M in THF, 0.165 mL, 0.300 mmol) and Ni(PPh3)2Cl2 (6.54 mg, 10.0 µmol), after column chromatography on silica gel (15% toluene in hexanes) gave 198e (27.4 mg,

182

78.6 µmol, 88%) as a white solid; m.p. 35.3-36.8 °C; δH (400 MHz, CDCl3) 0.93 (3 H, t, J

7.3 Hz, CH3), 1.32 - 1.52 (4 H, m, CH2), 1.59 - 1.72 (1 H, m, CH(O)CH2CH2), 1.75 - 1.88

(1 H, m, CH(O)CH2CH2), 2.66 (1 H, dd, J 15.7, 7.7 Hz, ArCH2CH(O)), 3.10 (1 H, dd, J

15.7, 8.9 Hz, ArCH2CH(O)), 3.94 (2 H, s, ArCH2Ar), 4.78 (1 H, dtd, J 8.9, 7.7, 6.0 Hz, CH(O)), 6.93 (1 H, d, J 1.5 Hz, aryl H), 6.97 (1 H, d, J 1.5 Hz, aryl H), 7.05 (1 H, dd, J

5.1, 3.6 Hz, aryl H), 7.17 - 7.26 (5 H, m, aryl H), 7.28 - 7.33 (2 H, m, aryl H); δC (100

MHz, CDCl3) 14.0 (CH3), 22.6 (CH2), 27.5 (CH2), 34.2 (ArCH2CH(O)), 35.9

(CH(O)CH2CH2), 39.7 (ArCH2Ar), 83.8 (CH(O)), 105.0 (aryl C-H), 119.3 (aryl C-H),

122.9 (aryl C-H), 124.3 (aryl C-H), 125.7 (aryl Cq), 126.2 (aryl C-H), 127.8 (aryl C-H),

128.5 (aryl C-H), 128.7 (aryl C-H), 134.6 (aryl Cq), 137.7 (aryl Cq), 139.6 (aryl Cq), 144.7 -1 (aryl Cq), 160.3 (aryl Cq); νmax (thin film/cm ) 841 (m), 971 (w), 1030 (w), 1222 (s), 1434 (s), 1590 (s), 1614 (w), 2858 (w), 2929 (m), 2954 (m), 3026 (w), 3061 (w); MS (APCI) m/z + + 349 [(M+H) ]; HRMS C23H25OS [(M+H) ] Expected 349.1621, Found 349.1605.

General Procedure I – Raney Ni desulfurisation

A solution of the corresponding sulfide (0.100 mmol) in EtOH (1 mL) was added dropwise to a suspension of Raney Nickel in EtOH (1 mL). The reaction was stirred at room temperature for 1 h and then filtered through Celite® 545 (Et2O eluent). The solvent was then removed in vacuo, and the crude product was purified by column chromatography.

1-(2-Chlorohexyl)-2,4-dimethoxybenzene 182 and 1-hexyl-2,4-dimethoxybenzene 183

As described in general procedure I, 99a (40.1 mg, 0.110 mmol), Raney Nickel (700 mg of slurry), after column chromatography on silica gel (10% CHCl3 in hexanes) gave 182 (22.8 mg, 88.8 µmol, 81%) and 183 (4.10 mg, 18.4 µmol, 11%) as colourless oils; For 182, δH

(500 MHz, CDCl3) 0.91 (3 H, t, J 7.2 Hz, CH3), 1.19 – 1.46 (3 H, m, CH2), 1.52 – 1.62 (1

H, m, CH2), 1.63 – 1.72 (1 H, m, ArCH2CH(Cl)CH2), 1.73 – 1.82 (1 H, m,

ArCH2CH(Cl)CH2), 2.93 (1 H, dd, J 13.7, 7.6 Hz, ArCH2), 3.04 (1 H, dd, 13.7, 6.3 Hz,

ArCH2), 3.81 (3 H, s, OCH3), 3.82 (3 H, s, OCH3), 4.15 – 4.22 (1 H, m, CHCl), 6.42 – 6.47

(2 H, m, aryl H), 7.08 (1 H, d, J 7.8 Hz, aryl H); δC (125 MHz, CDCl3) 14.0 (CH3), 22.2

183

(CH2), 28.6 (CH2), 37.5 (ArCH2CH(Cl)CH2), 39.4 (ArCH2), 55.2 (OCH3), 55.3 (OCH3),

63.4 (CHCl), 98.4 (aryl C-H), 103.7 (aryl C-H), 119.0 (aryl Cq), 131.6 (aryl C-H), 158.4 -1 (aryl Cq), 159.8 (aryl Cq); νmax (thin film/cm ) 935 (w), 1036 (s), 1131 (m), 1155 (s), 1207 (s), 1287 (m), 1437 (w), 1464 (m), 1506 (s), 1587 (m), 1613 (m), 2836 (w), 2858 (w), 2928 35 37 + + (w), 2955 (w); MS (APCI) m/z 257 Cl, 259 Cl [(M+H) ]; HRMS C14H22O2Cl [(M+H) ]

Expected 257.1303, Found 257.1299; For 183, δH (500 MHz, CDCl3) 0.89 (3 H, t, J 6.7

Hz, CH3), 1.19 – 1.37 (6 H, m, CH2), 1.49 – 1.57 (2 H, m, ArCH2CH2), 2.53 (2 H, t, J 7.6

Hz, ArCH2), 3.80 (6 H, s, OCH3), 6.40 – 6.46 (2 H, m, aryl H), 7.03 (1 H, d, J 8.2 Hz, aryl

H); δC (125 MHz, CDCl3) 13.9 (CH3), 22.4 (CH2), 29.2 (ArCH2), 29.5 (CH2), 29.8 (CH2),

31.5 (CH2), 55.0 (OCH3), 55.1 (OCH3), 98.2 (aryl C-H), 103.4 (aryl C-H), 123.5 (aryl Cq), -1 129.5 (aryl C-H), 158.0 (aryl Cq), 158.6 (aryl Cq); νmax (thin film/cm ) 923 (w), 1040 (m), 1134 (m), 1155 (s), 1207 (s), 1259 (w), 1288 (w), 1463 (m), 1505 (s), 1587 (w), 1613 (w), + + 2852 (w), 2921 (m), 2953 (w); MS (APCI) m/z 223 [(M+H) ]; HRMS C14H22O2 [(M+H) ] Expected 223.1693, Found 223.1691.

2-Butyl-2,3-dihydrobenzofuran-6-ol 196

As described by general procedure I, 191b (53.8 mg, 0.179 mmol), Raney Nickel (700 mg of slurry), after column chromatography on silica gel (10% EtOAc in hexanes) gave 196

(33.3 mg, 0.173 mmol, 97%) as a colourless oil; δH (400 MHz, CDCl3) 0.94 (3 H, t, J 7.2

Hz, CH3), 1.33 – 1.54 (4 H, m, CH2), 1.61 – 1.73 (1 H, m, ArCH2CH(O)CH2), 1.76 – 1.91

(1 H, m, ArCH2CH(O)CH2), 2.78 (1 H, dd, J 15.1, 7.8 Hz, ArCH2), 3.19 (1 H, dd, J 15.1,

8.8 Hz, ArCH2), 4.74 – 4.84 (1 H, m, CH(O)), 4.91 (1 H, s, OH), 6.27 – 6.33 (2 H, m, aryl

H), 6.94 – 7.00 (1 H, m, aryl H); δC (100 MHz, CDCl3) 14.0 (CH3), 22.6 (CH2), 27.5

(CH2), 34.7 (ArCH2CH(O)), 35.7 (CH(O)CH2CH2), 84.6 (CH(O)), 97.5 (aryl C-H), 106.8

(aryl C-H) 119.1 (aryl Cq), 125.0 (aryl C-H), 155.9 (aryl Cq), 160.8 (aryl Cq); νmax (thin film/cm-1) 964 (s), 1096 (s), 1136 (s), 1186 (m), 1214 (m), 1269 (w), 1352 (w), 1458 (s), 1497 (s), 1606 (m), 1622 (m), 2859 (w), 2930 (w), 2956 (w), 3388 (br, w, O-H stretch); + + MS (APCI) m/z 193 [(M+H) ]; HRMS C12H17O2 [(M+H) ] Expected 193.1223, Found 193.1215.

184

2-Butyl-6-(p-tolyl)-2,3-dihydrobenzofuran 197

As described by general procedure I, 194a (37.0 mg, 98.8 µmol), Raney Nickel (700 mg of slurry), after column chromatography on silica gel (10% CHCl3 in hexanes) gave 197 (23.5 mg, 88.2 µmol, 89%) as a colourless oil; δH (500 MHz, CDCl3) 0.97 (3 H, t, J 7.0 Hz,

CH2CH3), 1.37 – 1.59 (4 H, m, CH2), 1.66 – 1.78 (1 H, m, ArCH2CH(O)CH2), 1.83 – 1.95

(1 H, m, ArCH2CH(O)CH2), 2.41 (3 H, s, ArCH3), 2.91 (1 H, dd, J 15.4, 7.8 Hz, ArCH2),

3.31 (1 H, dd, J 15.4, 8.9 Hz, ArCH2), 4.78 – 4.88 (1 H, m, CH(O)), 7.00 (1 H, s, aryl H), 7.06 (1 H, d, J 7.6 Hz, aryl H), 7.20 (1 H, d, J 7.6 Hz, aryl H), 7.24 (2 H, d, J 8.1 Hz, aryl

H), 7.48 (2 H, d, J 8.1 Hz, aryl H); δC (125 MHz, CDCl3) 13.8 (CH2CH3), 20.8 (ArCH3),

22.4 (CH2), 27.4 (CH2), 35.0 (ArCH2), 35.6 (ArCH2CH(O)CH2), 83.6 (CH(O)), 107.6 (aryl

C-H), 118.8 (aryl C-H), 124.7 (aryl C-H), 125.6 (aryl Cq), 126.7 (aryl C-H), 129.1 (aryl C- -1 H), 136.6 (aryl Cq), 138.2 (aryl Cq), 141.3 (aryl Cq), 160.0 (aryl Cq); νmax (thin film/cm ) 971 (s), 1110 (w), 1166 (w), 1204 (m), 1295 (m), 1378 (w), 1431 (m), 1483 (s), 1568 (w), 1588 (w), 1618 (w), 2858 (w), 2928 (w), 2954 (w); MS (APCI) m/z 267 [(M+H)+]; HRMS + C19H23O [(M+H) ] Expected 267.1743, Found 267.1740.

5.11 Towards the Truce-Smiles Rearrangement (2-Allylphenyl)(phenyl)sulfide 64 88c

An oven dried metal-capped microwave reactor with a Teflon-lined septum was flushed with N2, before adding a solution containing diphenyl sulfoxide (500 mg, 2.47 mmol) in

CH2Cl2 (20 mL). Allyl TMS (1.00 mL, 6.29 mmol) and triflic anhydride (0.622 mL, 3.70 mmol) were added sequentially at room temperature and the reaction mixture was then heated for 1 h at 60 °C in a microwave reactor. After cooling to room temperature, the solution was quenched with sat. aq. NaHCO3 (25 mL) and the aqueous layer was extracted

185 with CH2Cl2 (2 × 10 mL). The combined organic layer was washed successively with water (3 × 10 mL) and brine (10 mL), dried with MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (n-hexane) to yield 88c (339 mg, 1.50 mmol, 60% yield) as a colourless oil; δH (400 MHz, CDCl3)

3.57 (2 H, dt, J 6.6, 1.5 Hz, ArCH2), 4.93 - 5.14 (2 H, m, CH=CH2), 5.85 - 6.05 (1 H, m,

CH=CH2), 7.03 - 7.41 (9 H, m, aryl H); δC (100 MHz, CDCl3) 38.1 (ArCH2), 116.0

(CH=CH2), 126.5 (aryl C-H), 127.0 (aryl C-H), 128.1 (aryl C-H), 128.9 (aryl C-H), 129.8

(aryl C-H), 129.9 (aryl C-H), 133.5 (aryl C-H), 133.7 (aryl Cq), 136.5 (CH=CH2), 136.7

(aryl Cq), 142.0 (aryl Cq).

1-Allyl-2-(phenylsulfonyl)benzene 204

Ammonium molybdate (25.8 mg, 0.132 mmol), followed by 30% aq. H2O2 (0.794 mL, 7.04 mmol) were added to a solution of 88c (100 mg, 0.442 mmol) in MeCN (5 mL) at 0 °C. The mixture was warmed to room temperature and stirred for 16 h. The reaction was quenched by adding Na2SO3 (901 mg, 7.15 mmol) and stirred for a further 40 min. The solvent was then removed in vacuo, the residue dissolved in CH2Cl2 (15 mL) and sat. aq.

NH4Cl (10 mL) added. The aqueous phase was extracted with CH2Cl2 (3 × 15 mL) and the combined organic layers were dried over MgSO4, filtered and solvent removed in vacuo. The crude product was purified by column chromatography on silica gel (10% EtOAc in hexanes) to give 204 (66 mg, 0.255 mmol, 58%) as a white solid; m.p. 51.2 – 52.5 °C; δH

(400 MHz, CDCl3) 3.65 (2 H, dt, J 6.6, 1.5 Hz, ArCH2), 4.91 (1 H, dq, J 16.9, 1.5 Hz,

CH=CH2), 4.97 (1 H, dq, J 10.1, 1.5 Hz, CH=CH2), 5.69 (1 H, ddt, J 16.9, 10.1, 6.6 Hz,

CH=CH2), 7.32 (1 H, dd, J 7.6, 0.8 Hz, aryl H), 7.43 (1 H, td, J 7.6, 1.3 Hz, aryl H), 7.47 -

7.61 (4 H, m, aryl H), 7.83 - 7.90 (2 H, m, aryl H), 8.24 (1 H, dd, J 7.9, 1.4 Hz, aryl H); δC

(100 MHz, CDCl3) 36.4 (ArCH2), 116.9 (CH=CH2), 126.7 (aryl C-H), 127.5 (aryl C-H), 129.1 (aryl C-H), 129.5 (aryl C-H), 131.7 (aryl C-H), 133.0 (aryl C-H), 133.6 (aryl C-H), -1 135.5 (CH=CH2), 138.6 (aryl Cq), 139.9 (aryl Cq), 141.7 (aryl Cq); νmax (thin film/cm ) 1153 (vs, S=O sym), 1306 (s, S=O asym), 1446 (m), 2979 (vw), 3063 (vw); MS (ES+) m/z + + 259 [(M+H) ]; HRMS C15H15O2S [(M+H) ] Expected 259.0793, Found 259.0801.

186

1-(Methylsulfonyl)-2-(1-phenylallyl)benzene 207

A solution of 204 (50.0 mg, 0.194 mmol) in THF (1.5 mL) was added dropwise to a mixture of n-BuLi (1.60 M in hexanes, 0.150 mL, 0.240 mmol) in THF (0.5 mL) at −78 °C. The resulting mixture was warmed to room temperature, with stirring, and then heated to 60 °C and stirred for 16 h. The mixture was cooled to room temperature, MeI (24.2 µL, 0.388 mmol) added, reheated to 60 °C and stirred for a further 5 h. The solution was then cooled to room temperature, quenched with sat. aq. NH4Cl (10 mL) and EtOAc added (15 mL). The aqueous layer was extracted with EtOAc (3 × 15 mL) and the combined organic extracts were dried with MgSO4, filtered and solvent removed in vacuo. The crude product was purified by column chromatography (10% EtOAc in hexanes) to give 207 (36.0 mg,

0.132 mmol, 70%) as a colourless oil; δH (400 MHz, CDCl3) 2.85 (3 H, s, SO2CH3), 4.90

(1 H, dt, J 17.2, 1.4 Hz, CH=CH2), 5.35 (1 H, dt, J 10.3, 1.4 Hz, CH=CH2), 6.13 (1 H, dt, J

6.1, 1.4 Hz, (Ar)2CH), 6.33 (1 H, ddd, J 17.2, 10.3, 6.1 Hz, CH=CH2), 7.20 - 7.26 (3 H, m, aryl H), 7.28 - 7.35 (2 H, m, aryl H), 7.39 - 7.46 (2 H, m, aryl H), 7.59 (1 H, td, J 7.5, 1.5

Hz, aryl H), 8.14 (1 H, dd, J 7.9, 1.3 Hz, aryl H); δC (100 MHz, CDCl3) 44.8 (SO2CH3),

48.1 ((Ar2)CH), 117.9 (CH=CH2), 126.8 (aryl C-H), 127.2 (aryl C-H), 128.6 (aryl C-H),

128.9 (aryl C-H), 129.8 (aryl C-H), 131.9 (aryl C-H), 133.7 (aryl C-H), 138.7 (aryl Cq), -1 140.2 (CH=CH2), 142.0 (aryl Cq), 142.7 (aryl Cq); νmax (thin film/cm ) 1147 (vs, S=O sym), 1305 (s, S=O asym), 2927 (w), 3027 (w), 3061 (w); MS (ES+) m/z 273 [(M+H)+]; + HRMS C16H17O2S [(M+H) ] Expected 273.0949, Found 273.0945.

(E)-1-(Phenylsulfonyl)-2-(prop-1-en-1-yl)benzene 208

A solution of 204 (50 mg, 0.194 mmol) in THF (1.5 mL) was added dropwise to a mixture of NaNH2 (9.00 mg, 0.231 mmol) in THF (0.5 mL) at −78 °C. The resulting mixture was warmed to room temperature, with stirring, and then heated to 60 °C and stirred for 16 h.

187

The mixture was then cooled to room temperature, quenched with sat. aq. NH4Cl (10 mL) and EtOAc added (15 mL). The aqueous layer was extracted with EtOAc (3 × 15 mL) and the combined organic extracts were dried with MgSO4, filtered and solvent removed in vacuo. The crude product was purified by column chromatography (10% EtOAc in hexanes) to give 208 (42 mg, 0.163 mmol, 86%) as a white solid; m.p. 91.1 – 92.7 °C; δH

(400 MHz, CDCl3) 1.83 (3 H, dd, J 6.5, 1.5 Hz, CH3), 5.93 (1 H, dq, J 15.6, 6.5 Hz,

CH=CHCH3), 7.16 (1 H, dq, J 15.6, 1.5 Hz, ArCH=CH), 7.38 - 7.60 (6 H, m, aryl H), 7.83

- 7.89 (2 H, m, aryl H), 8.22 (1 H, dd, J 7.9, 1.1 Hz, aryl H); δC (100 MHz, CDCl3) 18.7

(CH3), 124.4 (aryl C-H), 127.0 (aryl C-H), 127.3 (ArCH=CH), 127.7 (aryl C-H), 128.4

(aryl C-H), 128.8 (aryl C-H), 131.2 (CH=CHCH3), 133.0 (aryl C-H), 133.7 (aryl C-H), -1 136.9 (aryl Cq), 138.3 (aryl Cq), 141.6 (aryl Cq); νmax (thin film/cm ) 1150 (vs, S=O, sym), 1303 (s, S=O asym), 2852 (vw), 2912 (vw), 3061 (vw); MS (ES+) m/z 259 [(M+H)+]; + HRMS C15H15O2S [(M+H) ] Expected 259.0793, Found 259.0794.

188

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