Sulfoxide Directed Metal-Free Cross Coupling: Propargylation of Aromatic and Heteroaromatic Systems

Sulfoxide Directed Metal-free Cross Coupling: Propargylation of Aromatic and Heteroaromatic Systems

A dissertation submitted to The University of Manchester for the degree of Master of Science by Research in the Faculty of Engineering and Physical Science.

2015

Yuntong Zhang

School of Chemistry Contents List of Tables: ...... 4 List of Abbreviations ...... 5 Abstract ...... 9 Declaration ...... 10 Copyright Statement ...... 11 Acknowledgement ...... 12 Chapter 1: Introduction ...... 13 1.1 Pummerer and Pummerer-type Reactions...... 13 1.1.1 The Classical Pummerer Rearrangement ...... 13 1.1.2 Additive and Vinylogous Pummerer Reactions ...... 14 1.1.3 Interrupted Pummerer Reactions ...... 18 1.2 Pummerer-Type Reactions Extended to Aromatic Systems . 24 1.2.1 Aromatic and Hetero-aromatic Pummerer-type Reactions ...... 24 1.2.2 Ortho Alkylations of Aryl and Heteroaryl Systems .... 29 1.3 Beyond Classical Pummerer Reaction Electrophiles ...... 35 1.4 Application of Pummerer-type Reactions in Total Synthesis ………………………………………………………………………………………….36 1.5 Previous Work and Proposed Work ...... 38 Chapter 2: Results and Discussion...... 39 2.1 Synthesis of Starting Materials ...... 39 2.1.1 Synthesis of Sulfoxides ...... 39 2.1.2 Synthesis of Silanes ...... 40 2.1.3 Sulfoxide-directed Metal-free Propargylation of Arenes …………………………………………………………………………………41 2.2 Propargylation of Thiophene ...... 42 2.3 Cyclisation of the Products of Metal-free Propargylation .... 44 2.4 Cyclisation of Propargyl Thiophenyl Sulfide ...... 51 2.5 Conclusions and Future Work ...... 53 Chapter 3: Experimental ...... 55 3.1 General Procedure 1: bis-sulfide formation ...... 56 2

3.2 General Procedure 2: bis-sulfide oxidation ...... 57 3.3 General Procedure 3: sulfide oxidation ...... 58 3.4 General Procedure 4: alkynyl silane synthesis ...... 60 3.5 General Procedure 5: propargylation of aromatic systems ... 61 3.6 General Procedure 6: propargylation of thiophenes ...... 63 3.7 General Procedure 7: iodine mediated cyclization to vinyl benzothiophene ...... 69 3.8 General Procedure 8: iodine mediated two directional cyclisation ...... 73 3.9 General Procedure 9: iodine mediated cyclisation to vinyl iodide ...... 76 References ...... 77

List of Tables:

Table 1: NMR experiments of propargylation reaction process ...... 44

Table 2: Optimising of iodine mediated cyclisation ...... 47

Table 3: Optimisation of two directional heterocyclisation ...... 50

List of Abbreviations

Ac acyl

AIBN 2,2’-bis(isobutyronitrile)

aq. aqueous

Ar aryl 2,2’-bis(diphenylphosphino-1,1’- BINAP binaphthyl)

Bn benzyl

Boc t-butoxycarbonyl

br. broad (NMR)

Bu butyl

Bz benzoyl cerium(IV) ammonium CAN nitrate

cat. catalytic

CI chemical ionisation

C celsius

d doublet (NMR)

δ chemical shift (NMR)

DCE 1,2-dichloroethane 2,3-dichloro-5,6-dicyano-p- DDQ benzoquinone

DMF N,N-dimethylformamide

DMSO dimethylsulfoxide dimethyl(methylthio)sulfonium DMTSF tetrafluoroborate

DPPE ethylenebis(diphenylphosphine) dr diastereoisomeric ratio

DTBP di-tert-butylpyridine

DTBB 4,4-di-tert-butylbiphenyl

E electrophile ee enantiomeric excess

EDG electron donating group

EG ethylene glycol

EI electron ionisation equiv. equivalent positive/negative ion electrospray ES+/ES- (MS)

Et ethyl

EWG electron withdrawing group fluorous solid phase FSPE extraction g gram h hour

HFIP 1,1,1,3,3,3-hexafluoroisopropanol

HMPA hexamethylphosphoramide high resolution mass HRMS spectrum

Hz hertz

IBX o-iodoxybenzoic acid i-Pr isopropyl

IR infrared 6

J coupling constant (NMR)

M Molar m multiplet (NMR) m-CPBA m-chloroperbenzoic acid

Me methyl mg milligram

MHz megahertz min minutes mL millilitre mmol millimole

MOM methoxymethyl mp melting point

MS mass spectrum

MW micro wave m/z mass/charge ratio (MS)

NCS N-chlorosuccinimide

Nf2O nonafluorobutanesulfonic anhydride

NMR nuclear magnetic resonance

Nu nucleophile

Ph phenyl

PIFA iodobenzene-I,I-bis(trifluoroacetate)

PMB p-methoxybenzyl ppm parts per million 7

Pr propyl

PTSA p-toluenesulfonic acid

Pyr. pyridine q quartet (NMR) quin quintet (NMR) F R perfluoroalkyl rt room temperature s singlet (NMR) sxt sextet (NMR) 2- SEM (trimethylsilyl)ethoxymethyl t triplet (NMR) tetrabutylammonium TBAF fluoride

TBS tert-butyldimethylsilyl

TFA trifluoroacetic acid

TFAA trifluoroacetic anhydride

Tf trifluoromethanesulfonyl

THF tetrahydrofuran

TIPS triisopropylsilyl N,N,N’,N’- TMEDA tetramethylethylenediamine

TMS trimethylsilyl

Tol tolyl

Ts tosyl

Abstract

This thesis describes the development of an interrupted Pummerer reaction and its application in aromatic and hereroaromatic carbon-hydrogen substitution. During the development of the approach, a wide range of aryl and heteroaryl sulfoxides has been synthesised in order to investigate the scope of ortho-propargylation.

Good to excellent yields of propargyl aromatic and heteroaromatic products have been obtained. Moreover, propargylated substrates can be treated with iodine undergoing 5-exo-dig cyclisation leading to benzothiophenes and thienylthiophenes, which have industrially-significant applications in organic materials, pharmaceuticals and chemosensors. Under different conditions, different functionalised benzothiophenes can be obtained. Further extending this reaction in two directional cyclisation of propargyl naphthalene sulfides gives napthodithiophenes motif found in organic materials.

Declaration

No portion of the work referred to in the dissertation has been submitted in support of an application for another degree or qualification of this or any other university or other institute of learning.

Part of this work has been published in peer reviewed journals: A. J. Eberhart, H. J. Shrives, E. Álvarez, A. Carrër, Y. Zhang and D. J. Procter, ‘Sulfoxide-directed metal-free ortho-propargylation of aromatics and heteroaromatics.’ Chem. Eur. J. 2015, 21, 7428-7434.

A. J. Eberhart, H. Shrives, Y. Zhang, A. Carrër, A. Parry, D. Tate, M. J. Turner, D. J. Procter ‘Sulfoxide-directed metal-free cross-couplings in the expedient synthesis of benzothiophene-based organic materials’ Chem. Sci. 2015, DOI: 10.1039/C5SC03823E.

The author of this dissertation (including any appendices and/or schedules to this dissertation) owns any copyright in it (the “Copyright”) and s/he has given The University of Manchester the right to use such Copyright for any administrative, promotional, educational and/or teaching purposes.

Copies of this dissertation, either in full or in extracts, may be made only in accordance with the regulations of the John Rylands University Library of Manchester. Details of these regulations may be obtained from the Librarian. This page must form part of any such copies made.

The ownership of any patents, designs, trade marks and any and all other intellectual property rights except for the Copyright (the “Intellectual Property Rights”) and any reproductions of copyright works, for example graphs and tables (“Reproductions”), which may be described in this dissertation, may not be owned by the author and may be owned by third parties. Such Intellectual Property Rights and Reproductions cannot and must not be made available for use without the prior written permission of the owner(s) of the relevant Intellectual Property Rights and/or Reproductions.

Further information on the conditions under which disclosure, publication and exploitation of this dissertation, the Copyright and any Intellectual Property Rights and/or Reproductions described in it may take place is available from the Head of the School of Chemistry.

Acknowledgement

At the beginning, I am very grateful for my supervisor Prof. David Procter giving me chance study in the University of Manchester and I really appreciate his help on my study and life.

Sincere thanks to my lab work and English supervisor Harry Shrives. He is very patient with my work and gives me a lot of help apart from chemistry. His optimism towards life and encouragement definitely helped me a lot in my one year study here.

I would also like to say thanks to Dr. Alex Pulis, Dr. Nicolas Kern, Dr Xavier Just

Baringo, Dr Jose Antonio Fernandez Salas, Dr Jie An, Mateusz Plesniak, Craig

Cavanagh, Huanming Huang and the rest of Procter group member. In particular, many thanks to Mateusz Plesniak, Dr. Nicolas Kern and Craig Cavanagh for teaching me interesting and significant chemistry theory very often. Their help helped me a lot on analysing chemistry problem in different areas.

Chapter 1: Introduction

1.1 Pummerer and Pummerer-type Reactions

The selective formation of carbon-aryl and -heteroaryl bonds is one of the highest targets in synthetic chemistry because of their importance in the synthesis of pharmaceuticals, agrochemicals, and functional materials. The Pummerer rearrangement was first reported by Rudolf Pummerer in 1903.[1-3] Since the 1960s, the Pummerer rearrangement has evolved to be an indispensable method for the synthetic community. Recently, the Pummerer reaction has been extended to deliver a broad range of synthetic transformations including the regioselective functionalisation of aryl and heteroaryl systems.[4-6] This introduction will give a brief description of advances in Pummerer-type reactions, before focusing on related interrupted, aryl- and heteroaryl-Pummerer-type reactions.

1.1.1 The Classical Pummerer Rearrangement

The classical Pummerer rearrangement involves O-activation of an alkyl sulfoxide 1 (Scheme 1) through treatment with a suitable electrophile and elimination to give thionium ion 2, which is followed by a nucleophilic attack at the α-position. In general, the sulfoxide is activated using acetic anhydride (Ac2O), trifluoromethanesulfonic anhydride (Tf2O), silyl chlorides and Lewis acidic metals. However, thionium ions can be obtained through direct activation of sulfides using oxidants like N-chlorosuccinimide (NCS) or hypervalent iodine- [7] [8] based initiators such as PhI(OTf)2 , PhI(CN)OTf (Stang’s reagent) and tol- [9] IF2 . ‘Overoxidation’ is rarely observed due to both steric and electronic differences between the starting and final sulfide substrates. Selection of the activator depends on the characteristics of the substrate and the reagent’s compatibility with nucleophiles in the Pummerer sequence. Recent advances in electrophilic activators have broadened the scope of nucleophiles that can be used. Arenes, alkenes, alkynes, amines, phosphites, phenols and acetates have been widely used as nucleophiles in Pummerer type reactions due to the unreactive combination of initiator and nucleophiles.[4]

Scheme 1

Recently, Winkler et al.[10] reported a route to the tetracyclic core of cytotoxic nakadomarin A (6) (Scheme 2) using a classical Pummerer reaction as the key step to achieve intramolecular carbon-carbon coupling. In the proposed mechanism, dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF) activates the thioacetal first, followed by elimination to obtain thionium ion 5, which undergoes cascade cyclisation and elimination of thioethanol to yield the target core 6 stereoselectively in 50%.

Scheme 2

1.1.2 Additive and Vinylogous Pummerer Reactions

The classical Pummerer reaction was soon extended to substrates with α,β- unsaturated sulfoxides. Sulfoxides adjacent to alkenyl or aromatic moieties efficiently extend the electrophilicity of the thionium ion intermediate along the

14 conjugated molecular framework, which provides different options for nucleophilic attack.

1.1.2.1 Additive Pummerer Reactions

In the additive Pummerer-type reactions, as shown in Scheme 3, vinyl sulfoxide 7 is first activated by an electrophile to give sulfonium salt 8. Nucleophilic attack causes the elimination to yield thionium ion 9, followed by second nucleophilic addition to obtain the double addition product 10.

Scheme 3

The additive Pummerer-type mechanism was first reported by Stoodley in 1972.[11] This substrate possessing a cyclic vinyl sulfoxide 11 (Scheme 4) features sites for double addition. Activated by acetyl chloride, sulfonium ion 13 was formed from intramolecular cyclization of intermediate 12 by hydroxyl addition. The second addition subsequently occurred through chloride attack on 13 give adduct 14.

Scheme 4

One particularly interesting example using an additive Pummerer-type reaction in the synthesis of 4’-thionucleosides was reported by Haraguchi (Scheme 5).[12]

Vinyl sulfoxide 15 was activated by Ac2O assisted with BF3∙OEt2 in the presence of TMSOAc to give diacetate glycosyl donor 16. The diacetate glycosyl donor 16 was obtained with high β-selectivity and subsequently formed the thionium ion 17, which underwent β face nucleophilic addition to yield 4’-thionucleosides 18 in 93%.

Scheme 5

1.1.2.2 Vinylogous Pummerer Reactions

In Vinylogous Pummerer reactions, α,β-unsaturated sulfoxides 19 (Scheme 6) bearing a γ-proton can undergo E2-like elimination of acyloxysulfonium salt 20 to give a conjugated thionium ion 21. Either the α- or γ-position can be attacked by a nucleophile to deliver α-substituted 22 or conjugate adduct 23.

Scheme 6

In 1975, Uda and co-workers described a vinylogous Pummerer reaction of sulfoxide 24. They demonstrated that 24 (Scheme 7), upon O-activation by Ac2O, gave sulfonium ion intermediate 25, which underwent elimination to yield extended thionium ion 26. Acetate addition occured at the γ-position of 26 instead of the α-position of 26 to obtain adduct 27.[13]

Scheme 7

However, under several circumstances, it is difficult to differentiate the vinylogous Pummerer reaction from nucleophilic coupling. Yorimitsu and Oshima have demonstrated that arylketene dithioacetal monoxides 28 (Scheme 8), upon O- activation by Tf2O in the presence of an aromatic nucleophile, underwent Friedel- Crafts arylation of dicationic species 30 followed by elimination from 31 to obtain 32. Solvent screening studies show a preference for polar solvents which would encourage the formation of double cationic intermediate 30. Electron rich rings gave arylation products 32a-b with high yields and electron deficient rings 32c-d delivered moderate yields. However, the vinylogous Pummerer reaction pathway could happen and lead to the same product 32. The arene could attack instead of formation of the dicationic intermediate. The intermediate 31 then loses a proton to give 32.[14]

Scheme 8

1.1.3 Interrupted Pummerer Reactions

Under certain circumstances, a competitive interrupted Pummerer-type pathway can occur, especially for substrates lacking α-protons. In this pathway, sulfoxide

33 (Scheme 9) is activated by an electrophile and directly attacked at sulfur by a nucleophile to give sulfonium ion 35 instead of forming a thionium ion. In some cases, sulfonium salts like 35 can be isolated after quenching the reaction. In some 2 cases, the reaction can undergo displacement of R CH2 to obtain sulfide 36.

Scheme 9

Yuste, Ruano and co-workers have utilized an interrupted Pummerer-type reaction in a process to obtain α-hydroxy-β-amino alcohols (Scheme 10).[15] Sulfoxide 37 was treated with TFAA and sym-collidine to give either sulfonium salts 38 or sulfuranes 39 through intramolecular nucleophilic attack. Compounds 38 or 39 underwent inter- or intra-molecular processes respectively to yield the same product 40, which was further hydrolysed to give protected alcohol 41 in high yield. 18

Scheme 10

Oshima and Yorimitsu have highlighted a ring closing process using an intramolecular interrupted Pummerer-type reaction to give highly substituted benzo[b]thiophenes. Treatment of arylketene bis(methylthio)acetal monoxide 42

(Scheme 11) with Tf2O gave phenyl and methylthio group stabilised dicationic thionium ion 43, which was assumed to undergo Friedel-Crafts-type intramolecular aromatic substitution to achieve C-S coupling, followed by rearomatization to obtain highly substituted benzo[b]thiophenes 44. Interestingly, both E and Z isomers 42 gave the same experimental result when treated under the same conditions. This outcome supports the existence of a dicationic thionium intermediate 43 due to free bond rotation possible in this intermediate.[16]

Scheme 11

Oshima and Yorimitsu have developed a synthetic strategy using 2-(2,2,2- trifuoroethylidene)-1,3-dithiane monoxide 45 (Scheme 12) as a trifluoromethylketene equivalent. This reaction combines an interrupted- Pummerer-type reaction with a [3,3]-sigmatropic rearrangement to obtain products of α-allylation of α-trifluoromethyl ketones. Allylic silanes were used as a nucleophile to attack activated sulfoxide 46 to give sulfonium salt intermediate 47, followed by [3,3]-sigmatropic rearrangement and deprotonation to provide α- allylated trifluoromethylketene equivalent 48.[17]

Scheme 12

Oshima and Yorimitsu reported a similar interrupted Pummerer-type reaction involving ketones (Scheme 13).[18] Aromatic and aliphatic ketones were chosen as the nucleophile. The reaction was proposed to proceed by direct attack of an enolate oxygen onto the Tf2O activated 2-(2,2,2-trifuoroethylidene)-1,3-dithiane monoxide 45 to provide sulfonium salt 46, followed by [3,3]-sigmatropic rearrangement and proton elimination to give 50, which could be further hydrolysed to yield thio esters 51 in high yield.

Scheme 13

Furthermore, the similar substrate 52 was exposed to phenol under mild conditions to give highly substituted benzofurans (Scheme 14).[18] The first two steps were similar to the procedure described above. Activated 53 was attacked by nucleophilic phenolic oxygen to give sulfonium salt intermediate 54. Thio-Claisen sigmatropic rearrangement follows to yield thionium ion 55. Then 55 underwent cyclisation and rearomatisation via the loss of thiomethanol to obtain benzofurans 56. It is worth noting that p-methoxyphenol was too reactive and gave the triflated product 57 instead of delivering the expected product.

Scheme 14

Xu and Li have recently demonstrated a novel sulfur mediated C-H substitution process.[19] Tri- and disubstituted Olefins underwent allylic C-H alkylation through a one-pot transition-metal-free procedure. Olefins 58 (Scheme 15) undergo an interrupted Pummerer-type reaction to give sulfonium salt 60. Then deprotonation either by KOtBu or KOTf gave sulfur ylide 61, which underwent a [2,3]- rearrangement to form alkylated product 59. According to the report, electron rich cyclohexene 59e favour alkylation when compared with electron poor cyclohexene 59f. However, electron rich methoxy substituted acyclic olefin 59g was produced in only 32% yield, whereas electron poor acyclic olefins 59h was obtained with a yield of 73%.

Scheme 15

1.2 Pummerer-Type Reactions Extended to Aromatic Systems

1.2.1 Aromatic and Hetero-aromatic Pummerer-type Reactions

Substitution of aromatic and hetero-aromatic systems is one of the most popular topics in synthetic chemistry due to their wide applications in many pharmaceuticals, agrochemicals, and functional materials. With the development of Pummerer type reactions, sulfur-mediated aromatic and hetero-aromatic electrophilic substitution have been investigated due to their metal-free and regioselective nature. Aromatic substrates bearing electron donating groups can either undergo the classical or vinylogous Pummerer pathway to give 1 or 3 substituted products (Scheme 16). While unsubstituted benzenes generally yield ortho or para substituted rings. However, there are only a few examples describing para substituted aromatic Pummerer reactions. The reason for this might be that the interrupted Pummerer reaction is more competitive than vinylogous Pummerer type addition on aromatic systems.

Scheme 16

Feldman and co-workers have used sulfur-mediated cyclisation to obtain spirocyclic oxindoles (Scheme 17).[20] Indole-2-sulfoxides 60, upon O-activation by Tf2O, were proposed to undergo vinylogous Pummerer reactions to give 61,

24 followed by deprotonation to give 62. Interestingly, carbon-carbon coupling was not observed when using substrate 63 (Scheme 18) under the same conditions. Instead, the nitrogen atom reacted at C3 of indole to give spiroazetidine 64.[21]

Scheme 17

Scheme 18

Kita et al. investigated an efficient synthesis of para-quinones using para- sulfinylphenols 65 as starting materials (Scheme 19).[22] Sulfoxide 65 was activated with TFAA to give sulfonium salt 66. Thionium ion 67, generated from 66 is attacked by trifluoroacetate at C1 to deliver intermediate 68. Loss of trifluoroacetate and then hydrolysis by water produced para-quinone 69 with a yield of 84%.

Scheme 19

Kita and co-workers have also reported a synthesis of highly substituted indoles using aromatic Pummerer reactions (Scheme 20).[23] Protected sulfinyl aniline 70 was activated by TFAA to give sulfonium salt intermediate 71, followed by deprotonation to deliver thionium ion 72. Carbon-carbon bond formation was achieved by 1,4-addition of alkene nucleophile to generate carbocation 73. Rearomatisation and cyclisation gave saturated heterocycle 74 in good yield. Intermediate 74 can undergo further oxidation process with DDQ in refluxing benzene to produce 2,3,5-substituted indoles 75.

Scheme 20

Jung demonstrated an intramolecular process using an aromatic Pummerer type reaction to produce spirocyclic hexadienone 79 (Scheme 21).[24] Ortho-substituted sulfoxide 76, upon activation, generated 77 which further delivered 78. The methyl groups of 76 prevented 1,4-addition. A classical Pummerer type reaction occured instead to give spirocyclic hexadienone 79 in 94% yield.

Scheme 21

1.2.2 Ortho Alkylations of Aryl and Heteroaryl Systems

Recently the Magnier group reported the synthesis of sulfilimines employing interrupted Pummerer-type reactions (Scheme 22).[25] Perfluoroalkyl sulfoxides

80, activated by Tf2O giving 81, were thought to be attacked by a nitrile in a Ritter- type reaction. The formation of intermediate 82 was tracked by quenching the reaction at −15°C to obtain acylsulfilimines 85.[26] Elimination of triflic acid from 82 and rearomatisation produced ortho functionalised aryl sulfides 83a-f. Interestingly, when p-tolyl sulfoxide was employed as the starting material, sulfide 84 was obtained through extended vinylogous Pummerer-type reaction.

Scheme 22 29

The Maulide group has reported a sulfoxide mediated α-arylation of carbonyl compounds. The reaction is thought to proceed by an interrupted Pummerer reaction pathway, followed by [3,3]-sigmatropic rearrangement to realise arylation. Diphenyl sulfoxide 86 (Scheme 23) was treated with TFAA at room temperature in the presence of β-ketoester 87a. The enol 87b attacks the activated sulfoxide to generate sulfonium salts 88, which are thought to undergo a [3,3]- sigmatropic rearrangement and rearomatisation to produce arylated cyclic β- ketoester 89 in good yield.[27]

Scheme 23

A similar process has been reported by Kita and co-workers based on thiophene and furan systems. The proposed mechanism proceeds by activating 2-sulfoxide heterocycles 90 (Scheme 24) and 3-sulfoxide heterocycles 92 with TFAA. Then a vinylogous Pummerer addition follows to deliver ortho-alkylated product 91 and 93 (red pathway).[28] However, an interrupted Pummerer sequence could also be

30 considered that would give the same regioselectivity (blue pathway). For example, the ketone can tautomerize to form enol 95 which can react with the activated sulfoxide 94 to generate sulfonium salt 96. A [3,3]-sigmatropic rearrangement and rearomatisation would produce the same product 91.

Scheme 24

In the past few years, the Procter group have developed a methodology using sulfoxides as a directing group to mediate allylation and propargylation of a wide scope of aryl and heteroaryl systems. At the beginning, allylic silanes were employed as the nucleophile. Sulfoxide 97 (Scheme 25), activated by Tf2O at room temperature, is thought to be attacked by allylic silane to generate sulfonium salt 98. The intermediate sulfonium salt 98 has been partially characterised by 1H NMR. When the temperature is raised, [3,3]-sigmatropic rearrangement and 31 rearomatisation proceeded within one hour to deliver ortho-allylated products 99a- g.[29]

Scheme 25

Looking for further application of this methodology, Procter and co-workers optimised conditions for the allylation of heteroaromatic systems. Under mild conditions, allylated thiophenes, furans 100 (Scheme 26), pyrroles and pyrazoles 101 (Scheme 27) were successfully obtained.[30] Due to the electron rich nature of these systems, lower temperature and a milder activator were needed to avoid side reactions.

Scheme 26

Scheme 27

Inspired by the interrupted Pummerer allylation, the Procter group later employed propargyl silanes as nucleophiles to achieve the ortho-propargylation of aromatic systems (Scheme 28).[31] This metal-free regioselective process avoids the generation of allenyl products and use of harsh conditions and metals. Sulfoxides

102 were activated by Tf2O at room temperature to give interrupted Pummerer 33 product allenyl sulfonium salts 103, which could be isolated at room temperature. The [3,3]-sigmatropic rearrangement occurred upon heating, which after rearomatisation gave propargylated products 104. The reaction worked well in electron rich and poor aromatic systems. Different propargyl silanes gave the product in high yield.

Scheme 28

1.3 Beyond Classical Pummerer Reaction Electrophiles

In 2014, the Maulide group reported α-arylation of amides using an activated amide as the electrophile to obtain α-arylated amide 112 (Scheme 29).[32] Amide

105 was preactivated by Tf2O and 2-iodopyridine in the absence of sulfoxide. The activation process first formed intermediate 106 which converted to either iminium dication 107 or keteniminium intermediate 108. Both intermediates favoured a similar low energy pathway to give cationic intermediate 109. Diphenyl sulfoxide was added to the activated amide to afford nucleophilic attack at 0°C. A charge accelerated [3,3]-sigmatropic rearrangement and rearomatisation produced the α- arylated amide 112. In the general process of Pummerer type reactions, oxygen of the sulfoxide which after activation generally show unreactive property in the rest reaction sequence. However, this α-arylation of amides employed the sulfoxide oxygen to capture intermediate 107 or 108 to form amide 112 without losing the oxygen through activation with an electrophile and displacement.

Scheme 29

In the same year, Maulide reported the Bronsted acid catalysed redox arylation of oxazolidinone ynamides (Scheme 30).[33] A similar reaction process was employed to that of the α-aryation of amides. Preactivation of ynamide 113 gave high energy 35 intermediate 114, which was attacked by diphenyl sulfoxide delivering sulfonium salt 115. Oxidation of the α-carbon of ynamide 113 and reduction of sulfoxide occurs during the rearrangement process, followed by rearomatisation to produce final product 116.

Scheme 30

1.4 Application of Pummerer-type Reactions in Total Synthesis

The total synthesis of antibiotic (±)-γ-rubromycin 124 (Scheme 31) using two aromatic Pummerer-type reactions was reported by Kita et al.[34] The central bisbenzannelated spiroketal motif is essential to its pharmacological activity. In their synthetic strategy, two Pummerer-type reactions were employed. 117 was first converted into silyl ether in order to dissolve in acetonitrile. After activation of sulfoxide 117, enol ether attacks sulfonium salt 118 through a 1,3-addition pathway, followed by cyclisation to give spiroketal 120. After deprotection and oxidation of sulfide 120, a second Pummerer reaction was employed. The sulfonium intermediate was thought to react via a classical Pummerer-type pathway, followed by elimination of the sulfanyl group and acid mediated ketal rearrangement to produce 123. A further 7 steps furnished (±)-γ-rubromycin 124.

Scheme 31

1.5 Previous Work and Proposed Work

This project focuses on developing metal-free processes using sulfoxides as directing groups to orchestrate ortho carbon-carbon bond formation in aromatic and heteroaromatic systems. Based on previous work on the metal-free propargylation of aryl sulfoxides in the Procter group, this project will further investigate the utility of propargylations on heteroaromatic systems as shown in Scheme 32.

Scheme 32

This project will also exploit the selective manipulation of propargyl products in order to give industrially-important benzothiophene and thiothiophene motifs, which have applications in organic materials, pharmaceuticals and chemosensors (Scheme 33).[35]

Scheme 33

Chapter 2: Results and Discussion

2.1 Synthesis of Starting Materials

2.1.1 Synthesis of Sulfoxides

In order to prepare propargyl aromatic and heteroaromatic sulfides, a wide scope of sulfoxides were synthesised. Based on known methods, sulfoxides were directly obtained by m-CPBA oxidation of precursor sulfides. With regard to aromatic sulfides 130, apart from commercially available sulfides, 130 were formed via deprotonation of thiol 129 and methylation with methyl iodide. Further oxidation gave sulfoxides 131 in good overall yields (Scheme 34).

Scheme 34

1,5-Bis(hexylsulfinyl)naphthalene was later synthesised from commercially available naphthalene-1,5-diol 132 (Scheme 35). 132 was substituted by hexanethiol under acidic conditions, through a stabilised carbocation intermediate, to give bisulfide 133 in 75% yield. The water byproduct removed using a Dean- Stark apparatus in order to prevent the forming of 132 in the reverse reaction. Temperature sensitive m-CPBA oxidation gave the desired disulfoxide 134 in low yield and as a mixture of diastereomers.

Scheme 35

Based on known methods,[36] thiophenyl sulfoxides 137 were obtained by lithiation of the corresponding bromides 135, followed by addition of a suitable electrophile to give sulfides 136. The similar oxidation process as described above delivered thiophenyl sulfoxides 137. (Scheme 36)

Scheme 36

2.1.2 Synthesis of Silanes

A series of nucleophilic silane coupling partners was synthesised in order to further investigate the scope of the metal free coupling and the effect of steric hindrance in the silane. Silane 139 was prepared from terminal alkyne 138 by lithiation and alkylation in a yield of 87% on a 7 gram scale (Scheme 37). In order to investigate the two directional arylation of propargyl silanes, 1,4-bis(trimethylsilyl)but-2-yne 141 was synthesised via established methods.[37] The low yield of this reaction was probably due to Li metal oxidation preventing the reaction (Scheme 38).

Scheme 37

Scheme 38

2.1.3 Sulfoxide-directed Metal-free Propargylation of Arenes

In order to investigate of the scope of vinyl benzothiophene formation, a range of propargyl benzenes 143 was required. Using the optimised conditions[31] previously established within the group, propargyl benzenes 143 were obtained in good yields on gram scale (Scheme 39). Furthermore, propargylation of bissulfinyl naphthalene 144 and 134 were successful with the same conditions giving isomers 145 and 146 respectively in good yields (Scheme 40). These compounds were designed with longer alkyl chains in order to improve the solubility in further cyclisation reactions.

Scheme 39

Scheme 40

2.2 Propargylation of Thiophene

From previous work in the group, the propargylation of thiophene sulfoxides was found to occur at low temperatures. Propargylation of thiophenyl sulfoxide 137c gave propargyl product 147 in moderate yield. 2-Sulfoxide thiophene 137b and 3- sulfoxide thiophene 137a bearing acidic protons in the activated sulfoxide gave 148 and 149 in moderate yield possibly due to the competitive classical Pummerer pathway (Scheme 41).

Scheme 41

NMR experiments were carried out in order to elucidate the reaction process and find a starting point for optimising these conditions. Excitingly, setting the reaction at −40 °C in deuterated MeCN gave full conversion of sulfoxide 137a to intermediate 150 (Scheme 42). As shown in Table 1, with an increase in temperature from −40 °C to room temperature, intermediate 150 rearranged to give high yields of product 149. Furthermore, when the same reaction was activated at −40 °C and warmed to room temperature within 2 hours, only 37% of desired product 149 was formed by 1H NMR. The intermediate 150 might decompose into sulfide or classical Pummerer reaction product, which leads us to believe that the thiophene propargylation reaction is very sensitive to temperature. The rearrangement process needs a relatively low temperature to start and slow warming to control this process.

Table 1: NMR experiments of propargylation reaction process

Time (h) Situ temperature (°C) Product 149a 0 −40 0% 4 −10 29% 9 5 51% 24 5 90% 31 20 92%

1 a: Yield determined by H NMR using MeNO3 as internal standard

Scheme 42

With the best conditions in hand, propargylation with bisilane 141 (Scheme 43) was investigated for the first time. The product thiophene 151 could be used as nucleophile in a second propargylation with sulfoxide 137a to give bis- propargylation product 152. The first propargylation product 151 was isolated in moderate yield because of its poor stability on silica gel. Unfortunately, the second propargylation product 152 was not obtained, possibly due to the steric hindrance of thiophene sulfide 151 making the interrupted Pummerer addition unfavourable.

Scheme 43

2.3 Cyclisation of the Products of Metal-free Propargylation

Previous work in the group showed that ortho-methylthio propargyl benzenes react with I2 to give three different benzothiophene products depending on the reaction

44 conditions employed (Scheme 44). Under an atmosphere of O2, with 0.7 equivalent of I2, sulfides 153 cyclised to give ketones 154. Without O2 and with addition of hydrogen atom donor, 1,4-cyclohexadiene, a stoichiometric amount of I2 gave alkanes 156. The best conditions for forming ketones 154 and alkanes 156 have already been established previously in the group. Another interesting reaction was found when 153 was treated with I2 and a base, under argon atmosphere, and alkenes 155 were obtained with low yield.

Scheme 44

With the initial conditions found by previous group members, heterocyclisation of substrate 143b (Scheme 45) bearing methyl groups on the aromatic ring and substrate 143d bearing an electron withdrawing group were investigated. Cyclised products 157 and 159 were obtained in low yield when treated with I2 and CsCO3 as additive. Moreover, the purification operation is difficult because the side products 158 and 160 have very similar Rf with desired alkene.

Scheme 45

In order to obtain good yields of alkenyl benzothiophenes (Scheme 46), a series of optimisation experiments was conducted (Table 2). Under an argon atmosphere, sulfide 143a was treated with I2, additives and solvents in order to get a high yield of alkenyl benzothiophene 161. Toluene was first selected as solvent because of its ability to dissolve aromatic compounds. Previous conditions that involved the use of CsCO3 as a base gave moderate yields. Increasing the amount of base by adding an organic base like 2,6-DTBP and Et3N produced more product. Addition of 2.2 equivalents of Et3N gave the best NMR yield of 68%. However, increasing the amount of Et3N to more than 2.2 equivalent decreased the yield of desired product. Interestingly, adding water into the reaction gave the same yield as that obtained when CsCO3 was used. Further investigation showed addition of methanol gave a 92% yield. The rationale for adding methanol is because it has a similar pKa to water and is miscible with DCE.

Scheme 46

Table 2: Optimising of iodine mediated cyclisation

Entry Additive Equivalent Solvent Yield (%)a

1 CsCO3 1.2 Toluene 46

2 2,6-DTBP 2 Toluene 54

3 DBU 2 Toluene Starting material

4 Et3N 3 Toluene 44

5 Et3N 2.2 1,2-Dichloroethane 68

6 - - Et3N Starting material

7 H2O 100 Toluene 45

8 MeOH 100 1,2-Dichloroethane 92b

1 a: Yield determined by H NMR using MeNO3 as internal standard b: isolated yield

With optimised conditions, the scope of substrates was investigated. The substrate bearing methyl group in the para position gave desired product 162 in good yield. Products 163, 164 and 159 with electron withdrawing groups were only obtained with moderate yields, which might be caused by reducing the nucleophilicity of sulfur in the starting material. A substrate possessing an electron rich ring underwent successful cyclisation to deliver 165. Without substitution para to sulfide, the substrate bearing two methyl group was cyclised in high yield to give 157. Moreover, a substrate breaing meta fluorine substitution gave the cyclised product 166 in excellent yield. This reaction also worked well for a substrate bearing a naphthalene motif to give 167 in high yield (Scheme 47).

Scheme 47

A proposed mechanism is described in Scheme 48. The product of metal-free cross-coupling 143a is believed to undergo 5-exo-dig iodine mediated cyclisation to give a vinyl iodide, which after loss of methyl iodide gave 168 which was observed by NMR. This may explain the low yield obtained for substrates bearing para electron withdrawing groups as they would lower the nucleophilicity of sulfur. When heating the reaction to 80 °C, tautomerisation follows to give 169 and elimination of hydrogen iodide gives alkene 161. However, the role of MeOH is still unclear at this time.

Scheme 48

Benzothiophene-based architectures are crucial components in valuable organic materials. In general, organic materials are prepared in classical pathways by employing metal-catalysed methods for cross coulping.[35] Among benzothiophene motifs, benzodithiophenes (BDTs)[36] and napthodithiophenes (NDTs)[37] have been exploited as high performance organic semiconductors. With the methodologies developed by Procter group, these materials could be synthesised using our metal-free cross coupling approach. The naphthalene products of two directional propargylation 145 were treated the same conditions in order to get napthodithiophene (NDTs) 170 (Scheme 49). Unfortunately, these conditions gave the desired product in low NMR yield and the product decomposed on silica gel. Reducing the concentration of the reaction mixture did not help, but lower concentration guaranteed all the starting material dissolved in the solvent. When the reaction was stirred at room temperature overnight before heating to make sure all starting materials convert to vinyl iodide intermediate, the yield increased to 42% and shorter heating time gave the desired product in 51% NMR yield. The product was thought to decompose due to the hydrogen iodide which was generated in the reaction process. Therefore, 2.2 equivalents of CsCO3 was added with MeOH in order to neutralise the acid generated during the reaction. Unfortunately, this did not improve the situation. Without adding any additives and heating the reaction for only a short time gave 170 in an acceptable 65% isolated yield (Table 3).

Scheme 49

Table 3: Optimisation of two directional heterocyclisation

I entry solvent conc. 2 additives (equiv.) Cond. Yielda (equiv.) 1 DCE 0.01 2.2 MeOH (200) 18 h 80 °C 38%

2 DCE 0.005 2.2 MeOH (200) 18 h 80 °C 36%

3 DCE 0.005 2.2 MeOH (200) 18 h rt, 8h 80 °C 42%

4 DCE 0.005 2.2 MeOH (200) 18 h rt, 3h 80 °C 51% MeOH (200) and 5 DCE 0.005 2.2 18 h rt, 3h 80 °C 18% Cs2CO3 (2.2) 6 DCE 0.005 2.2 MeOH (200) 1 h 80 °C 65% b

1 a: yield determined by H NMR using MeNO3 as internal standard b: isolated yield

When the optimised conditions were applied to the other isomer 146 (Scheme 50), two directional cyclised product 171 was obtained in 84% yield. This isomer was found to have better solubility in the solvent system which might be the reason for the higher yield obtained.

Scheme 50

2.4 Cyclisation of Propargyl Thiophenyl Sulfide

Organic materials have attracted significant attention as a result of their great performance and solution processability.[35] Thiophenes, oligothiophenes and polythiophenes are one of the most popular classes organic electronic semiconductors. However, relatively high cost and the need for metal catalysed coupling processes and the metal contamination that can result make their production challenging. This project investigated cyclisation of thiophenyl sulfide 149 using the conditions optimised for benzene motifs. Unfortunately, high temperature gave no cyclised thienylthiophene product. Propargyl thiophene might be sensitive to harsh condition and therefore decomposed (Scheme 52).

Scheme 52

When sulfide 149 was treated with excess iodine at room temperature, vinyl iodide was 173 formed in low yield. NOE studies showed spin polarization transfer between H1 and H2 suggesting that the E-alkene was formed (Scheme 53). The mechanism of this reaction is thought to proceed via the vinyl iodide 174 (Scheme 54) by a process analogous to that observed for benzene substrate. The mild conditions prevent 174 from tautomerising and aromatising. A second iodine is believed to react with iodide 174 to give diiodide 175, followed by tautomerisation producing 176. Elimination of hydrogen iodide delivers product 173.

Scheme 53

Scheme 54

2.5 Conclusions and Future Work

Iodine mediated cyclisation in the presence of methanol produced vinyl benzothiophenes in good yields. The two directional cyclisation reactions were also carried out in in good yields (Scheme 49-50). However, the mechanism of this reaction is still not clear. Further study will focus on the role of methanol in this reaction (Scheme 55).

Scheme 55

With regard to the iodine mediated cyclisation of propargyl thiophene to give vinyl iodide 173, a similar process could be applied on benzene propargylation products. Lower temperature might be able to prevent vinyl iodide 168 from undergoing tautomerisation and allow it to further react with iodine to give 177 (Scheme 56).

Scheme 56

Manipulation of vinyl iodide thieno[3,2-b]thiophene 173 will be further investigated. Elimination of hydrogen iodide will give alkyne 178. Stille, Hiyama, Kumada, Negishi and Sonogashira Coupling would give a wide range of thienylthiophene 179 (Scheme 57).

Scheme 57

Two directional cyclisation leading to highly conjugated heteroaromatic systems could be realised based on a similar mechanism. Commercially available bisbromide 180 (Scheme 58) could give 181, followed by two directional iodine mediated cyclisation producing 182. Elimination of hydrogen iodide could give extended conjugated product 183. Metal catalysed cross-couplings could then give highly conjugated 184, which might be the first of a family of promising organic electronic materials.

Scheme 58

Chapter 3: Experimental

General Information

All experiments were performed under an atmosphere of nitrogen, using anhydrous solvents, unless stated otherwise. THF was distilled from sodium / benzophenone. Dichloromethane was distilled from CaH2. Triethylamine was distilled from CaH2.

1H NMR and 13C NMR were recorded using 300, 400 and 500 MHz spectrometers, with chemical shift values being reported in ppm relative to residual chloroform

(H = 7.27 or C = 77.2). All coupling constants (J) are reported in Hertz (Hz). Mass spectra were obtained using positive and negative electrospray (ES±), gas chromatography (GC) methodology using EI or Atmospheric Pressure Chemical Ionisation (APCI). Infra-red spectra were recorded as evaporated films or neat using a FT/IR spectrometer. Column chromatography was carried out using 35 – 70 μ, 60A silica gel. Routine TLC analysis was carried out on aluminium sheets coated with silica gel 60 F254, 0.2 mm thickness and plates were viewed using a 254 mm ultraviolet lamp and dipped in aqueous potassium permanganate or p- anisaldehyde.

Reagents were either purchased directly from commercial suppliers or prepared according to literature procedures.

3.1 General Procedure 1: bis-sulfide formation

1,5-Bis(Hexylsulfanyl)naphthalene 133[39]

A solution containing naphthalene-1,5-diol (3.20 g, 20.0 mmol), 1-hexanethiol

(6.21 mL, 44.0 mmol) and p-toluenesulfonic acid (1.90 g, 10.0 mmol) in toluene

(115 mL) were refluxed in a flask equipped with a Dean-Stark apparatus for 48 h.

The reaction was then quenched with aqueous NaHCO3 (50 mL) and extracted with Et2O (3  75 mL) and the combined organic layers dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 2% EtOAc in n-hexane to yield the product (5.41 g, 15.0

−1 mmol, 75% yield) as a yellow solid (mp: 48 - 52 °C); νmax (neat)/cm 2951, 2924,

2853, 1575, 1492, 1465, 1431, 1389, 1374, 1311, 1219, 1193, 1151, 1063, 797,

770, 746, 729; δH (500 MHz, CDCl3) 0.88 (6H, t, J = 6.9, 2  CH3), 1.24 - 1.34

(8H, m, 4  CH2), 1.45 (4H, quin, J = 7.6, 2  SCH2CH2CH2), 1.67 (4H, quin, J =

7.5, 2  SCH2CH2), 2.98 (4H, t, J = 7.6, 2  SCH2), 7.47 (2H, t, J = 8.0, 2  Ar-

H), 7.57 (2H, d, J = 7.3, 2  Ar-H), 8.31 (2H, d, J = 8.4, 2  Ar-H); δC (125 MHz,

CDCl3) 14.3 (2  CH3), 22.8 (2  CH2), 28.8 (2  SCH2CH2CH2), 29.3 (2 

SCH2CH2), 31.6 (2  CH2), 34.5 (2  SCH2), 123.9 (2  Ar-CH), 126.2 (2  Ar-

CH), 127.8 (2  Ar-CH), 133.4 (2  Ar-C), 135.1 (2  Ar-C); m/z (EI) M, 360;

(Found: M, 360.1946. C22H32S2 requires M, 360.1940).

3.2 General Procedure 2: bis-sulfide oxidation

1,5-Bis(Hexylsulfinyl)naphthalene 134

To a solution of 1,5-bis(hexylsulfanyl)naphthalene (3.0 g, 8.32 mmol) in CH2Cl2

(42.0 mL) a solution of m-CPBA (2.05 g, 9.15 mmol) in CH2Cl2 (183 mL) was added at −78 °C in 30 min. The reaction was warmed to room temperature in 1 h before adding a second portion of m-CPBA (2.05 g, 9.15 mmol) in CH2Cl2 (183 mL) in 30 min at −78 °C. After allowing the reaction mixture to reach room temperature in 1 h it was stirred for a further 1 h before quenching with aqueous

NaHCO3 (100 mL) and extraction with CH2Cl2 (2  75 mL). The combined organic layers were dried (Na2SO4) and concentrated in the high vacuum. The crude product was purified by column chromatography on silica gel eluting with

30% Et2O in CHCl3 to yield the product (1.26 g, 2.99 mmol, 36% yield) as a white

−1 solid (mp: 103 - 107 °C); νmax (neat)/cm 2949, 2921, 2856, 1498, 1466, 1403,

1390, 1338, 1275, 1261, 1193, 1155, 1113, 1074, 1036, 970, 791, 764, 750, 724;

δH (500 MHz, CDCl3) 0.79 - 0.91 (6H, m, 2  CH3), 1.19 - 1.31 (8H, m, 4  CH2),

1.32 - 1.53 (4H, m, 2  CH2), 1.59 - 1.74 (2H, m, 2  SCH2CHaCHb), 1.79 - 1.95

(2H, m, 2  SCH2CHaCHb), 2.75 - 2.88 (2H, m, 2  SCHaCHb), 2.94 - 3.07 (2H, m, 2  SCHaCHb), 7.71 - 7.82 (2H, m, 2  Ar-H), 8.03 - 8.13 (2H, m, 2  Ar-H),

8.16 - 8.27 (2H, m, 2  Ar-H); δC (125 MHz, CDCl3) 14.1 (2  CH3), 22.5 (2 

SCH2CH2, 2  CH2), 28.4 (2  SCH2CH2CH2), 31.5 (2  CH2), 56.4 (2  SCH2),

123.9 (2  Ar-CH), 124.5 (2  Ar-CH), 127.1 (2  Ar-CH), 129.1 (2  Ar-C), 141.8

(2  Ar-C); m/z (ES+) M + H, 393; (Found: M + Na, 415.1741. C22H32O2S2Na requires M, 415.1736).

3.3 General Procedure 3: sulfide oxidation

3-(Methylsulfinyl)thiophene 137a[36]

To a solution of 3-(methylthio)thiophene (0.65 g, 5.00 mmol) in CH2Cl2 (10 mL) at 0 °C, was added dropwise a solution of m-CPBA (1.00 g, 4.5 mmol) in CH2Cl2.

The resulting mixture was stirred at 0 °C for 1 h before warming to room temperature after which it was stirred for a further 1 h. The reaction was quenched with saturated NaHCO3 solution (10 mL) and the layers separated. The aqueous layer was washed with dichloromethane (3  5 mL) and the combined organic layers dried with MgSO4 and the solvent removed in the high vacuum. The resulting crude mixture was purified by column chromatography (30% ethyl acetate in chloroform) to give product as a clear oil (0.474 g, 3.24 mmol, 65 %);

δH (300 MHz, CDCl3) 7.74 (1H, dd, J = 2.9, 1.2 Hz, ArCH), 7.48 (1H, dd, J = 5.1,

3.0 Hz, ArCH), 7.25 (1H, dd, J = 5.3, 1.3 Hz, ArCH), 2.78 (3H, s, SCH3); δC (75

MHz, CDCl3) 144.6 (ArC), 128.5 (ArCH), 125.4 (ArCH), 122.6 (ArCH), 42.8

(SCH3); m/z (GCMS) 146.0; (measured 145.9856, C5H6OS2 requires 145.9855).

2-(Methylsulfinyl)thiophene: 137b[36]

As described in General procedure 3, to a solution of 2-(methylsulfanyl)thiophene

(0.60 g, 4.60 mmol) in CH2Cl2 (10 mL) at 0 °C, was added dropwise a solution of m-CPBA (0.79 g, 4.60 mmol) in CH2Cl2. The resulting crude mixture was purified by column chromatography eluting with chloroform: ethyl acetate (95:5) to give product as a clear oil (0.41 g, 2.62 mmol, 57 %); δH (300 MHz, CDCl3) 7.62 (1H, dd, J = 5.0, 1.2 Hz, ArCH), 7.45 (1H, dd, J = 3.7, 1.2 Hz, ArCH), 7.09 (1H, dd, J

= 5.0, 3.7 Hz, ArCH), 2.89 (3 H, s, SCH3); δC (75 MHz, CDCl3) 147.55 (ArC),

131.15 (ArC‐H), 129.62 (ArCH), 127.72 (ArCH), 44.73 (SCH3); m/z (GCMS)

146.0; (measured 145.9855, C5H6OS2 requires 145.9855)

2-(Phenylsulfinyl)thiophene: 137c

As described in General procedure 3, to a solution of 3-(phenylsulfanyl)thiophene

(0.58 g, 3 mmol) in CH2Cl2 (6 mL) at 0 °C, was added dropwise a solution of m-

CPBA (0.56 g, 2.5 mmol) in CH2Cl2. The resulting crude mixture was purified by flash column chromatography eluting with chloroform: ethyl acetate (95:5) to give

−1 product as a clear oil (0.358 g, 1.72 mmol 57 %); νmax (neat)/cm 3110, 3078,

1474, 1444, 1412, 1304, 1196, 1095, 1080, 1036, 999, 988, 971, 894, 803, 745,

684, 625; δH (300 MHz, CDCl3) 7.07 (1H, dd, J = 5.1, 1.2 Hz, HetArH), 7.39 (1H, 59 dd, J = 5.1, 3.0 Hz, HetArH), 7.45 - 7.55 (3H, m, ArH), 7.61 - 7.69 (2H, m, ArH),

7.79 (1H, dd, J 3.0, 1.2 Hz, HetArH); δC (75 MHz, CDCl3) 124.1 (ArCH), 124.6

(2 × ArCH), 127.2 (ArCH), 128.3 (ArCH), 129.2 (2 × ArCH), 131.0 (ArCH), 144.6

(ArC), 144.7 (ArC); m/z (GCMS) 208.0; (measured 208.0006, C10H8OS2 requires

208.0011).

3.4 General Procedure 4: alkynyl silane synthesis

1,4-Bis(trimethylsilyl)but-2-yne 141[38]

To a suspension of Li granules (1.00 g, 140 mmol) and DTBB (0.26 g, 1.00 mmol) in dry THF (30 ml) at –40 °C was added a solution of 1,4-dichloro-2-butyne (0.98 ml, 10 mmol) and TMSCl (3 ml, 20 mmol) in THF (30 ml) over 1.5 h using a syringe pump. The reaction mixture was then carefully hydrolysed with water and extracted with diethyl ether. The combined organic layer was washed with water, brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified using column chromatography on silica gel using 100% hexane as the eluent to

−1 give product as a clear oil (0.258 g, 1.30 mmol, 13%); νmax (neat)/cm 2955, 1247,

1181, 1142, 1054, 836, 758, 695, 672, 597; δH (400 MHz, CDCl3); 0.09 (18 H, s,

2 × Si(CH3)3), 1.45 (4 H, s, 2 × CH2); δC (100 MHz, CDCl3); −2.0 ((CH3)3Si), 7.2

(CH2), 75.6 (CC); m/z (GCMS) 198.1.

3.5 General Procedure 5: propargylation of aromatic systems

(2-(Hept-2-yn-1-yl)phenyl)(methyl)sulfane 143a[31]

An oven dried tube was flushed with N2, before adding a solution containing methylsulfinylbenzene (723 mg, 5.00 mmol) and hept-2-ynyltrimethylsilane (1.26 g, 7.50 mol) in MeCN (30 mL). Triflic anhydride (1.26 mL, 7.5 mmol) and 2,6- lutidine (1.45 mL, 12.5 mmol) were added sequentially at room temperature and the reaction mixture was then heated for 18 h at 60 °C. After cooling to room temperature, the solution was quenched with aqueous saturated NaHCO3 (10 mL) and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layer was washed successively with aqueous HCl 1.0 M (2 × 10 mL) and brine (10 mL), dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography on silica gel eluting with n-hexane gave product (870 mg, 3.99 mmol, 80% yield) as a yellow oil; δH (300 MHz, CDCl3) 0.93 (3H, t, J = 7.2, CH3),

1.36 - 1.59 (4H, m, 2 × CH2), 2.25 (2H, tt, J = 7.0, 2.2, CCH2), 2.48 (3H, s, S-CH3),

3.62 (2H, t, J = 2.2, Ph-CH2C), 7.12 - 7.26 (3H, m, Ar-H), 7.57 (1H, d, J = 7.5,

Ar-H); δC (75 MHz, CDCl3) 13.6 (CH3), 15.9 (S-CH3), 18.6 (CCH2), 22.0

(CH2CH2), 23.2 (Ph-CH2), 31.1 (CH2CH2), 76.7 (C≡C), 83.4 (C≡C), 125.2 (Ar-

CH), 125.7 (Ar-CH), 127.2 (Ar-CH), 128.2 (Ar-CH), 135.7 (Ar-C), 136.7 (Ar-C); m/z (EI) M, 218; (Found: M - CH3, 203.0886. C13H15S requires M - CH3,

203.0889).

(2-(Hept-2-yn-1-yl)-4-methylphenyl)(methyl)sulfane 143b[31]

As described in general procedure 5, 1-methyl-4-(methylsulfinyl)benzene (772 mg,

5.00 mmol), hept-2- ynyltrimethylsilane (1.01 g, 6.00 mmol), triflic anhydride

(1.26 mL, 7.50 mmol), 2,6 - lutidine (1.46 mL 12.5 mmol) and MeCN (30 mL) were heated at 80 °C for 18 h. Purification by column chromatography on silica gel eluting with n-hexane gave product (810 mg, 3.49 mmol, 70% yield) as a yellow oil; δH (300 MHz, CDCl3) 0.93 (3H, t, J = 7.2, CH3), 1.41 - 1.55 (4H, m, 2

× CH2), 2.25 (2H, tt, J = 6.9, 2.4 CCH2), 2.34 (3H, s, CH3), 2.44 (3H, s, CH3), 3.63

(2H, t, J = 2.4, Ph-CH2C), 7.05 (1H, d, J = 8.0, Ar-H), 7.16 (1H, d, J = 8.0, Ar-H),

7.37 (1H, s, Ar-H); δC (75 MHz, CDCl3) 13.6 (CH2CH3), 16.7 (CH3), 18.6 (CCH2),

21.0 (CH3), 22.0 (CH2CH2), 23.3 (Ph-CH2C), 31.1 (CH2CH2), 77.2 (C≡C), 83.2

(C≡C), 127.1 (Ar-CH), 127.9 (Ar-CH), 129.3 (Ar-CH), 133.1 (Ar-C), 135.4 (Ar-

C), 136.2 (Ar-C); m/z (CI) (M + H), 233; (Found: M - CH3, 217.1045. C14H17S requires M - CH3, 217.1045).

(2-(Hept-2-yn-1-yl)-4-(trifluoromethyl)phenyl)(methyl)sulfane 143c[31]

As described in general procedure 5, 1-(methylsulfinyl) - 4 -

(trifluoromethyl)benzene (1.04 g, 5.00 mmol), hept-2- ynyltrimethylsilane (1.26 g,

7.50 mmol), triflic anhydride (1.26 mL, 0.22 mmol), 2,6-lutidine (1.46 mL 12.5 62 mmol) and MeCN (30 mL) were heated at 70 °C for 18 h. Purification by column chromatography on silica gel eluting with hexane gave product (741.7 mg, 52 % yield) as a yellow oil; δH (400 MHz, CDCl3) 0.94 (3H, t, J = 7.3, CH3), 1.43 - 1.62

(4H, m, 2 × CH2,), 2.28 (2H, tt, J = 6.9, 2.4, CCH2), 2.52 (3H, s, S-CH3), 3.59 (2H, t, J = 2.4, Ph-CH2), 7.23 (1H, d, J = 8.1, Ar-H), 7.46 - 7.52 (1H, m, Ar-H), 7.85

(1H, s, Ar-H); δC (100 MHz, CDCl3) 13.6 (CH3), 15.0 (S-CH3), 18.5 (CCH2), 21.9

(CH2CH2), 23.1 ((Ph-CH2), 30.9 (CH2CH2), 75.5 (C≡C), 84.7 (C≡C), 123.8 (q, J

3.7, Ar-CH), 123.8 (Ar-CH), 124.6 (q, J = 3.7, Ar-CH), 124.3 (q, J = 271, CF3),

126.1 (Ar-C), 135.2 (Ar-C), 142.0 (m, Ar-C); m/z (EI) M, 286; (Found: M - CH3,

271.0769. C14H14F3S requires M - CH3, 271.0763).

3.6 General Procedure 6: propargylation of thiophenes

3-(Hept-2-yn-1-yl)-2-(phenylsulfanyl)thiophene 147

To an oven dried round bottom flask flushed with N2, was added 3‐

(phenylsulfinyl)thiophene (0.104 g, 0.50 mmol) and hept‐2‐yn‐1‐yltrimethylsilane

(0.126 g, 0.75 mmol) in MeCN (3 mL). Trifluoroacetic anhydride was then added

(0.20 mL, 1.25 mmol) at −78 °C and the reaction was stirred for 2 h. The solution was quenched with aqueous saturated NaHCO3 (6 mL) and the aqueous layer was extracted with EtOAc (3 × 5 mL). The combined organic layer was dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 100% n‐hexane to yield product as

−1 colourless oil (0.079 g, 0.28 mmol, 55 %). νmax (neat)/cm 3072, 2955, 2929, 2870,

1661, 1581, 1521, 1439, 1398, 1297, 1218, 1135, 1080, 1023, 998, 832, 737, 688;

δH (400 MHz, CDCl3) 0.92 (3H, t, J = 7.2 Hz, CH3), 1.33 ‒ 1.54 (4H, m, CH2CH2),

2.19 (2H, tt, J = 6.8, 2.4 Hz, CCH2), 3.77 (2H, t, J = 2.4 Hz, HetAr‐CH2C), 6.99

(1H, d, J = 5.2 Hz, HetAr‐H), 7.03 ‒ 7.16 (3H, m, Ar‐H), 7.24 (1H, d, J = 5.2 Hz,

HetAr‐H), 7.17 ‒ 7.26 (2H, m, Ar‐H); δC (100 MHz, CDCl3) 13.6 (CH3), 18.4

(CH2), 19.2 (CH2), 21.9 (CH2), 30.8 (CH2), 77.2 (C), 82.8 (C), 123.3 (ArCH),

123.9 (ArC), 125.5 (ArCH), 127.0 (2 × ArCH), 128.9 (2 × ArCH), 132.6 (ArCH),

137.5 (ArC), 145.3 (ArC); m/z (GCMS) 209.0 (M‐C6H5); (measured 286.0833,

C17H18S2 requires 286.0844).

3-(Hept-2-yn-1-yl)-2-(methylsulfanyl)thiophene 148

To an oven dried round bottom flask flushed with N2, was added 2‐

(methylsulfinyl)thiophene (0.093 g, 0.63 mmol) and hept‐2‐yn‐1‐yltrimethylsilane

(0.15 g, 0.90 mmol) in MeCN (3 mL). Trifluoroacetic anhydride was then added

(0.22 mL, 1.25 mmol) at −40 °C and the reaction was allowed to slowly warm to room temperature over 18 h. The solution was quenched with aqueous saturated

NaHCO3 (10 mL) and the aqueous layer was extracted with EtOAc (3 × 10 mL).

The combined organic layer was dried (MgSO4) and concentrated in high vacuum.

The crude product was purified by column chromatography on silica gel eluting with 100% n‐hexane to yield product as a colourless oil (0.056 g, 0.25 mmol, 40 %).

−1 νmax (neat)/cm 2955, 2922, 2858, 1728, 1523, 1464, 1420, 1377, 1312, 1216,

1093, 1020, 969, 877, 848, 831, 689, 651, 579; δH (400 MHz, CDCl3) 0.91 (3H, t,

J = 7.2 Hz, CH3), 1.33 ‒ 1.55 (4H, m, CH2CH2), 2.19 (2H, tt, J = 7.0, 2.4 Hz, 64

CCH2), 2.39 (3H, s, S‐CH3), 3.60 (2H, t, J = 2.4 Hz, HetAr‐CH2C), 7.12 (1H, d, J

= 5.4 Hz, HetAr‐H), 7.28 (1H, d, J = 5.4 Hz, HetAr‐H); δC (100 MHz, CDCl3) 13.6

(CH3), 18.5 (CH2), 19.0 (CH2), 21.9 (CH3), 21.9 (CH2), 31.0 (CH2), 77.4 (C), 81.5

(C), 127.1 (ArCH), 129.0 (ArCH), 130.6 (ArC), 141.4 (ArC); m/z (GCMS) 209.0

(M‐CH3); (measured 225.0780, C12H17S2 requires 225.0772).

2-(Hept-2-yn-1-yl)-3-(methylsulfanyl)thiophene 149

As described in general procedure 6, 3‐(methylsulfinyl)thiophene (0.073 g, 0.50 mmol), hept‐2‐yn‐1‐yltrimethylsilane (0.126 g, 0.75 mmol) in MeCN (3mL) and

Trifluoroacetic anhydride (0.17 mL, 1.35 mmol) was added at −40 °C and the reaction was allowed to slowly warm to room temperature over 18 h. The crude product was purified by column chromatography on silica gel eluting with 100%

−1 n‐hexane to yield product as red oil (0.67 g, 0.30 mmol, 60 %). νmax (neat)/cm

2955, 2927, 2870, 1508, 1464, 1431,1377, 1346, 1315, 1294, 1198, 1153, 1077,

969, 875, 853, 778, 704, 636,572; δH (400 MHz, CDCl3) 0.92 (3H, t, J = 7.2 Hz,

CH3), 1.38 ‒ 1.55 (4H, m, CH2CH2), 2.21 (2H, tt, J = 7.0, 2.4 Hz, CCH2), 2.38 (3H, s, S‐CH3), 3.77 (2H, t, J = 2.4 Hz, HetAr‐CH2C), 6.99 (1H, d, J = 5.3 Hz, HetAr‐

H), 7.17 (1H, d, J = 5.3 Hz, HetAr‐H); δC (100 MHz, CDCl3) 13.6 (CH3), 18.4

(CH2), 18.9 (CH3), 18.9 (CH2), 21.9 (CH2), 30.8 (CH2), 76.9 (C), 82.4 (C), 122.9

(ArCH), 128.7 (ArC), 129.9 (ArCH), 139.7 (ArC); m/z (GCMS) 224.0; (measured

224.0689, C12H16S2 requires 224.0693).

Trimethyl(4(3-(methylsulfanyl)thiophen-2-yl)but-2-yn-1-yl)silane 151

As described in general procedure 6, a mixture of methyl thienyl sulfoxide (0.03 g, 0.20 mmol) and 1,4-bis(trimethylsilyl)but-2-yne (0.06 g, 0.30 mmol) in MeCN at −40 °C was added with TFAA (0.105 g, 0.50 mmol) and the mixture left to slowly warm to room temperature over 18 h. The crude product was purified by column chromatography on silica gel eluting with 100% n-hexane to yield product

−1 (0.0237 g, 0.090 mmol, 47%); νmax (neat)/cm 2954, 2920, 1418, 1295, 1247,

1146, 970, 908, 841, 790, 759, 731, 698, 648, 608, 558; δH (400 MHz) 0.12 (9 H, s, Si(CH3)3), 1.49 (2 H, t, J = 2.7 Hz, CH2-Si ), 2.37 (3 H, s, SCH3), 3.77 (2 H, t, J

= 2.7 Hz, CH2), 6.98 (1 H, d, J = 5.1 Hz, ArCH), 7.16 (1 H, d, J = 5.3 Hz, ArCH);

δC (100 MHz) -2.0 (Si(CH3)3), 7.0 (CH2), 18.9 (CH2), 19.1 (SCH3), 75.5 (CC),

80.0 (CC), 122.7 (ArCH), 128.4 (ArC), 129.9 (ArCH), 140.4 (ArC); m/z (GCMS)

254.1; (measured 239.0373, C11H15S2Si requires 239.037)

(1,5-Di(non-2-yn-1-yl)naphthalene-2,6-diyl)bis(hexylsulfide) 145

An oven dried tube was flushed with N2, before adding a solution containing 2,6- bis(hexylsulfinyl)naphthalene (29.4 mg, 0.075 mmol), and trimethyl(non-2-yn-1-

66 yl)silane (44.5 mg, 0.225 mol) in MeCN (7.50 mL). Triflic anhydride (38.0 µL,

0.225 mmol) and 2,6-lutidine (31.0 µL, 0.263 mmol) were added sequentially at room temperature and the reaction mixture was then heated for 24 h at 80 °C. After cooling to room temperature, the solution was quenched with aqueous saturated

NaHCO3 (3 mL) and the aqueous layer was extracted with EtOAc (3  3 mL). The combined organic layer was washed successively with aqueous HCl 1.0 M (2  1 mL) and brine (3 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by preparative thin-layer chromatography eluting with 2%

EtOAc in n-hexane to yield the product (27.9 mg, 0.046 mmol, 62% yield) as a

-1 yellow solid (mp: 56 - 57 °C); νmax (neat)/cm 2955, 2920, 2870, 2854, 1567, 1468,

1459, 1433, 1377, 1275, 1267, 1260, 1112, 941, 922, 798, 789, 764, 750, 722; δH

(500 MHz, CDCl3) 0.82 - 0.92 (12H, m, 4  CH3), 1.18 - 1.35 (20H, m, 10  CH2),

1.37 - 1.48 (8H, m, 2  SCH2CH2CH2, 2  CCH2CH2), 1.64 (4H, quin, J = 7.5, 2

 SCH2CH2), 2.09 (4H, tt, J = 7.1, 2.2, 2  CCH2), 3.00 (4H, t, J = 7.3, 2  SCH2),

4.22 (4H, t, J = 2.2, 2  CCH2C), 7.62 (2H, d, J = 8.8, Ar-H), 8.06 (2H, d, J = 8.8,

Ar-H); δC (125 MHz, CDCl3) 14.0 (4  CH3), 18.9 (2  CCH2), 20.5 (2  CCH2C),

22.5 (2  CH2), 22.6 (2  CH2), 28.5 (4  CH2), 28.9 (2  CH2), 29.6 (2 

SCH2CH2), 31.3 (2  CH2), 31.4 (2  CH2), 35.2 (2  SCH2), 77.9 (C≡C), 81.6

(C≡C), 124.2 (2  Ar-CH), 129.5 (2  Ar-CH), 131.5 (2  Ar-C), 132.6 (2  Ar-

C), 135.4 (2  Ar-C); m/z (ES-) M - C6H13, 519; (Found: M, 604.4112. C40H60S2 requires M, 604.4131).

(2,6-Di(non-2-yn-1-yl)naphthalene-1,5-diyl)bis(hexylsulfide) 146

An oven dried tube was flushed with N2, before adding a solution containing 1,5- bis(hexylsulfinyl)naphthalene (1.50 g, 3.82 mmol) and trimethyl(non-2-yn-1- yl)silane (2.25 g, 11.5 mol) in MeCN (180 mL). Triflic anhydride (1.93 mL, 11.5 mmol) and 2,6-lutidine (1.55 mL, 13.4 mmol) were added sequentially at room temperature and the reaction mixture was then heated for 24 h at 80 °C. After cooling to room temperature, the solution was quenched with aqueous saturated

NaHCO3 (100 mL) and the aqueous layer was extracted with EtOAc (3  75 mL).

The combined organic layer was washed successively with aqueous HCl 1.0 M (2

 20 mL) and brine (100 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with

2% EtOAc in n-hexane to yield the product (1.37 g, 2.27 mmol, 59% yield) as a

-1 bown solid (mp: 39 - 41 °C); νmax (neat)/cm 2955, 2923, 2868, 2850, 1589, 1486,

1464, 1457, 1440, 1412, 1368, 1302, 1278, 1267, 1259, 1217, 1206, 1182, 956,

890, 813, 795, 764, 755, 726; δH (500 MHz, CDCl3) 0.84 - 0.92 (12H, m, 4  CH3),

1.18 - 1.45 (24H, m, 12  CH2), 1.54 (8H, m, 4  CH2), 2.23 (4H, tt, J = 7.1, 2.5,

2  CCH2), 2.75 (4H, t, J = 7.6, 2  SCH2), 4.14 (4H, t, J = 2.4, 2  CCH2C), 7.85

(2H, d, J = 8.8, Ar-H), 8.74 (2H, d, J = 8.8, Ar-H); δC (125 MHz, CDCl3) 14.0 (4

 CH3), 18.9 (2  CCH2), 22.5 (2  CH2), 22.6 (2  CH2), 25.2 (2  CCH2C), 28.6

(4  CH2), 29.0 (2  CH2), 29.8 (2  CH2), 31.4 (4  CH2), 36.9 (2  SCH2), 78.1

(C≡C), 82.7 (C≡C), 127.7 (2  Ar-CH), 128.0 (2  Ar-CH), 131.0 (2  Ar-C),

135.1 (2  Ar-C), 140.7 (2  Ar-C); m/z (ES+) M + H, 605; (Found: M, 604.4108.

C40H60S2 requires M, 604.4131).

3.7 General Procedure 7: iodine mediated cyclization to vinyl

benzothiophene

(E)-2-(Pent-1-en-1-yl)benzo[b]thiophene 161

Under an argon atmosphere, a solution of iodine (55.6 mg, 0.22 mmol) in Ar flushed 1,2-dichloroethane (2 mL) and MeOH (0.81 ml, 20 mmol) was added to a solution of (2-(hept-2-yn-1-yl)phenyl)(methyl)sulfide (43.6 mg, 0.20 mmol) in Ar flushed 1,2-dichloroethane (18 mL) at room temperature. The reaction mixture was stirred for 18 h at 80 °C before quenching with saturated aqueous Na2S2O3 (5 mL). The aqueous layer was then extracted with EtOAc (3 × 5 mL) and the combined organic layers washed with brine (5 mL), dried (Na2SO4) and concentrated in the high vacuum. The crude product was purified by column chromatography on silica gel eluting with n-hexane to yield the product (37.5 mg,

−1 0.18 mmol, 92 % yield) as a yellow solid (mp 38-40 °C ); νmax (neat)/cm 2957,

2926, 2871, 1456, 1436, 1224, 1148, 1012, 950, 839, 839, 743, 725; δH (500 MHz,

C6D6) 0.82 (3H, t, J = 7.3, CH3), 1.29 (2H, sxt, J = 7.3, CH2CH3), 1.95 (2H, qd, J

= 7.2, 1.4, CHCH2), 6.14 (1H, dt, J = 15.7, 7.0, CCH=CH), 6.44 (1H, dt, J = 15.7,

1.2, CCH=CH), 6.81 (1H, s, Ar-H), 7.03 (1H, td, J = 7.6, 1.3, Ar-H), 7.12 (1H, td,

J = 7.5, 1.2, Ar-H), 7.45 - 7.52 (2H, m, 2  Ar-H); δC (125 MHz, C6D6) 14.1

(CH3), 22.9 (CH2CH3), 35.6 (CHCH2), 122.1 (Ar-CH), 122.8 (Ar-CH), 123.9 (Ar-

CH), 124.9 (CCH=CH), 125.0 (2  Ar-CH), 134.1 (CCH=CH), 139.5 (Ar-C),

141.2 (Ar-C), 143.9 (Ar-C); m/z (EI) M, 202; (Found: M, 202.0802. C13H14S requires M, 202.0811).

(E)-5-Methyl-2-(pent-1-en-1-yl)benzo[b]thiophene 162

As described in general procedure 7, (2-(hept-2-yn-1-yl)-4- methylphenyl)(methyl)sulfide (46.4 mg, 0.20 mmol), iodine (55.6 mg, 0.22 mmol) and MeOH (0.81 ml, 20.0 mmol) in 1,2-dichloroethane (20 mL), after purification by column chromatography on silica gel eluting with n-hexane, gave the product

(34.7 mg, 0.16 mmol, 80% yield) as a yellow solid (mp: 47-50 °C); νmax

(neat)/cm−1 3012, 2954, 2924, 2867, 1443, 1378, 1301, 1259, 1230, 1209, 1169,

1138, 1065, 1044, 1008, 951, 889, 803, 744, 725, 694; δH (400 MHz, CDCl3) 0.98

(3 H, t, J = 7.3 Hz, CH3), 1.53 (2 H, sxt, J = 7.4 Hz, CH2CH3), 2.22 (2 H, qd, J =

7.2, 1.5 Hz, CHCH2), 2.44 (3 H, s, CH3), 6.15 (1 H, dt, J = 15.4, 7.0 Hz, CCH=CH),

6.60 (1 H, dd, J = 15.4, 0.5 Hz, CCH=CH), 6.98 (1 H, s, Ar-H), 7.10 (1 H, dd, J =

8.2, 1.1 Hz, Ar-H), 7.46 (1 H, s, Ar-H), 7.62 (1 H, d, J = 8.1 Hz, Ar-H); δC (100

MHz, CDCl3) 13.4 (CH3), 21.0 (CH2CH3), 22.0 (CH3), 34.7 (CHCH2), 120.6 (Ar-

CH), 121.4 (Ar-CH), 122.8 (Ar-CH), 123.7 (CCH=CH), 125.6 (Ar-CH), 133.2

(Ar-C), 133.6 (CCH=CH), 135.2 (Ar-C), 140.2 (Ar-C), 143.1 (Ar-C;); m/z

(GCMS) M, 216.1; (Found: M, 217.1051. C14H17S requires M, 217.1050).

(E)-4,6-Dimethyl-2-(pent-1-en-1-yl)benzo[b]thiophene 157

As described in general procedure 7, (2-(hept-2-yn-1-yl)-3,5- dimethylphenyl)(methyl)sulfide (49.2 mg, 0.20 mmol), iodine (55.6 mg, 0.22 mmol) and MeOH (0.81 ml, 20 mmol) in 1,2-dichloroethane (20 mL), after purification by column chromatography on silica gel eluting in n-hexane, gave the

−1 product (42.4 mg, 0.18 mmol, 92% yield) as a yellow oil; νmax (neat)/cm 2957,

2924, 2869, 1671, 1600, 1567, 1504, 1454, 1376, 1301, 1221, 1204, 1160, 1113,

1032, 950, 843, 757, 657; δH (400 MHz, CDCl3) 1.00 (3 H, t, J = 7.4 Hz, CH3),

1.54 (2 H, sxt, J = 7.4 Hz, CH2CH3), 2.23 (2 H, q, J = 6.9 Hz, CHCH2), 2.43 (3 H, s, CH3), 2.53 (3 H, s, CH3), 6.14 (1 H, dt, J = 15.4, 7.0 Hz, CCH=CH), 6.63 (1 H, d, J = 15.5 Hz, CCH=CH), 6.94 (1 H, s, ArC-H), 7.08 (1 H, s, ArC-H), 7.40 (1 H, s, ArC-H); δC (100 MHz, CDCl3) 13.8 (CH3), 19.4 (CH2CH3), 21.5 (CH3), 22.3

(CH3), 35.0 (CHCH2), 119.3 (ArC-H), 119.5 (ArC-H), 124.1 (ArCH), 126.6

(CCH=CH), 132.0 (ArC), 132.9 (CCH=CH), 134.3 (ArC), 137.4 (ArC), 138.7

(ArC), 141.5 (ArC); m/z (GCMS) M, 230.1; (Found: M, 230.1119. C15H18S requires M, 230.1124).

(E)-4-Fluoro-2-(pent-1-en-1-yl)benzo[b]thiophene 166

As described in general procedure 7, (2-(hept-2-yn-1-yl)-5- fluorophenyl)(methyl)sulfide (47.2 mg, 0.20 mmol), iodine (55.6 mg, 0.22 mmol) and MeOH (0.81 ml, 20.0 mmol) in 1,2-dichloroethane (20 mL), after purification by column chromatography on silica gel eluting with n-hexane, gave the product

- (40.3 mg, 0.18 mmol, 92 % yield) as a yellow solid (mp 64-65 °C); νmax (neat)/cm

1 2958, 2929, 2872, 1589, 1565, 1520, 1464, 1401, 1378, 1248, 1233, 1188, 1146,

1111, 1046, 957, 938, 851, 819, 807, 718, 586; δH (400 MHz, CDCl3) 0.97 (3 H, t, J = 7.4 Hz, CH3), 1.45 - 1.58 (2 H, m, CH2CH3), 2.21 (2 H, qd, J = 7.2, 1.5 Hz,

CHCH2), 6.13 (1 H, dt, J = 15.6, 7.0 Hz, CCH=CH), 6.58 (1 H, d, J = 15.6 Hz,

CCH=CH), 7.00 (1 H, s, ArC-H), 7.04 (1 H, td, J = 8.9, 2.4 Hz, ArC-H), 7.43 (1

H, dd, J = 8.8, 2.3 Hz, ArC-H), 7.58 (1 H, dd, J = 8.7, 5.2 Hz, ArC-H); δC (100

MHz, CDCl3); 13.7 (CH3), 22.3 (CH2CH3), 35.0 (CHCH2), 108.3 (ArCH), 113.1

(ArCH), 120.3 (ArC-H), 123.6 (CH=CHCH2), 123.9 (ArC-H), 133.9

(CH=CHCH2), 136.7 (ArC), 139.4 (ArC), 143.0 (d, J = 3.7 Hz, ArC), 160.5 (d, J

= 243.6 Hz, ArC-F); m/z (GCMS) M, 220.1; (Found: M, 220.0721. C13H13FS requires M, 220.0717).

(E)-2-(Pent-1-en-1-yl)-5-(trifluoromethyl)benzo[b]thiophene 159

Under an Ar atmosphere, a solution of iodine (55.8 mg, 0.22 mmol) in Ar flushed

1,2- dichloroethane (2 mL) and CsCO3 (78 mg, 0.24 mmol) was added to a solution of (2-(hept-2-yn-1-yl)phenyl)(methyl)sulfide (57.3 mg, 0.200 mmol) in Ar flushed

1,2-dichloroethane (18 mL) at room temperature. The reaction mixture was stirred

72 for 18 h at 80 °C before quenching with saturated aqueous Na2S2O3 (5 mL). The aqueous layer was then extracted with EtOAc (3 × 5 mL) and the combined organic layers washed with brine (5 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with n-hexane, gave the product (21.9 mg, 0.81 mmol, 41 % yield) as a yellow oil; νmax

(neat)/cm−1 2959, 2929, 1607, 1528, 1433, 1332, 1262, 1217, 1169, 1144, 1120,

1073, 1054 953, 906, 892, 812, 729, 709, 668, 650; δH (400 MHz, CDCl3) 0.99 (3

H, t, J = 7.4 Hz, CH3), 1.54 (2 H, sxt, J = 7.3 Hz, CH2CH3), 2.24 (2 H, q, J = 6.9,

CHCH2), 6.18 - 6.28 (1 H, m, CCH=CH), 6.62 (1 H, d, J = 15.8 Hz, CCH=CH),

7.10 (1 H, s, ArC-H), 7.48 (1 H, d, J = 8.5 Hz, ArC-H), 7.83 (1 H, d, J = 8.5 Hz,

ArC-H), 7.91 (1 H, s, ArC-H); δC (100 MHz, CDCl3) 13.8 (CH3), 22.2 (CH2CH3),

35.1 (CHCH2), 120.1 (ArCH), 120.4 (ArC-H), 120.8 (ArC-H), 122.5 (ArC-H),

123.5 (CCH=CH), 124.5 (q, J = 272.9Hz, CF3), 126.9 (q, J = 32.3Hz, ArC-CF3),

135.3 (CCH=CH), 139.9 (Ar-C), 141.6 (Ar-C), 145.4 (Ar-C); m/z (GCMS) M,

270.0; (Found: M, 270.0681. C14H13F3S requires M, 270.0685).

3.8 General Procedure 8: iodine mediated two directional

cyclisation

2,7-Di((E)-hept-1-en-1-yl)naphtho[1,2-b:5,6-b']dithiophene 171

To a solution of (2,6-di(non-2-yn-1-yl)naphthalene-1,5-diyl)bis(hexylsulfide)

(30.2 mg, 0.05 mmol) in Ar flushed 1,2-dichloroethane (8 mL) was added a solution of iodine (27.8 mg, 0.11 mmol) in 1,2-dichloroethane (2 mL) with methanol (0.81 ml, 5 mmol) at room temperature. The reaction mixture was put under an Ar atmosphere, stirred for 1 h at 80 °C before quenching with saturated aqueous Na2S2O3 (10 mL). The aqueous layer was then extracted with

Dichloromethane (2  10 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography on neutralised silica gel eluting with Hexane to yield the product (18.1 mg, 0.042 mmol, 84% yield) as a

−1 white solid (mp 145-147 °C); νmax (neat)/cm 2960, 2930, 2483, 1332, 1263, 1169,

1145, 1121, 1074, 1055, 953, 907, 893, 812, 729, 709, 669, 651; δH (400 MHz,

CDCl3) 0.90 - 0.99 (6 H, m, 2  CH3), 1.29 - 1.45 (4 H, m, 2  CH2CH2CH3), 1.47

- 1.61 (4H, m, 2  CH2CH2CH2), 2.27 (4H, q, J = 6.9 Hz, 2  CH=CHCH2), 6.26

(2H, dt, J = 15.5, 7.00 Hz, 2  CH=CH), 6.65 (2H, d, J = 15.7 Hz, 2  CH=CH),

7.18 (2H, s, 2  Ar-H), 7.75 (2H, d, J = 8.6 Hz, 2  Ar-H), 7.90 (2H, d, J = 8.7 Hz,

2  Ar-H); δC (100 MHz, CDCl3) 14.1 (2  CH3), 22.6 (2  CH2CH3), 28.9 (2 

CH2CH2CH3), 31.5 (2  CHCH2CH2), 33.0 (2  CH=CHCH2), 121.1 (2  Ar-CH),

122.2 (2  Ar-CH), 122.3 (2  Ar-CH), 123.6 (2  ArCH=CH), 125.8 (2  Ar-C),

133.7 (2  CCH=CH2), 136.8 (2  Ar-C), 137.6 (2  Ar-C), 142.4 (2  Ar-C); m/z

(AP+) M + H, 433.5; (Found: M + H, 433.2023. C28H32O2S2 requires M,

432.1945).

2,7-Di((E)-hept-1-en-1-yl)naphtho[2,1-b:6,5-b']dithiophene 170

As described in general procedure 8, 2,7-di((E) hept-1-en-1-yl)naphtho[2,1-b:6,5- b']dithiophene (40.9 mg, 0.088 mmol), iodine (55.7 mg, 0.022 mmol), 1,2- dichloroethane (20.0 mL) and methanol (0.40 ml, 8.80 mmol) were heated for 1 h at 80 °C. Purification by column chromatography on neutralised silica gel (1%

Et2O in Hexane) gave the product (24.6 mg, 0.057 mmol, 65% yield) as a white

-1 solid (decomp. T > 235 °C); νmax (neat)/cm 2952, 2922, 2849, 1465, 1455, 1362,

1190, 1171, 955, 876, 837, 806, 796, 725, 677; δH (400 MHz, CDCl3) 0.91 - 0.96

(6H, m, 2  CH3), 1.37 (4H, dq, J = 7.3, 3.6 Hz, 2  CH2CH2CH3), 1.49 - 1.57 (4H, m, 2  CH2CH2CH2), 2.27 (4H, q, J = 6.9 Hz, 2  CH=CHCH2), 6.26 (2H, dt, J =

15.4, 7.0 Hz, 2  CH=CH), 6.72 (2H, d, J = 15.5 Hz, 2  CH=CH), 7.72 (2H, s, 2

 Ar-H), 7.87 (2H, d, J = 8.8 Hz, 2  Ar-H), 8.12 (2H, d, J = 8.7 Hz, 2  Ar-H);

δC (100 MHz, CDCl3) 14.4 (2  CH3), 22.9 (2  CH2CH3), 29.1 (2  CH2CH2CH3),

31.8 (2  CHCH2CH2), 33.3 (2  CH=CHCH2), 119.7 (2  Ar-CH), 120.8 (2  Ar-

CH), 121.0 (2  Ar-CH), 124.1 (2  CCH=CH2), 126.6 (2  Ar-C), 134.1 (2 

CCH=CH2), 135.5 (2  Ar-C), 137.3 (2  Ar-C), 143.8 (2  Ar-C); m/z (AP+) M

+ H, 432.9; (Found: M + H, 433.2009. C28H32O2S2 requires M, 432.1945).

3.9 General Procedure 9: iodine mediated cyclisation to vinyl

iodide

(Z)-2-(1-Iodopent-1-en-1-yl)thieno[3,2-b]thiophene 173

Under an Ar atmosphere, a solution of iodine (121.5mg, 0.48 mmol) in Ar flushed

1,2- dichloroethane (4.8 mL) and H2O (0.29 ml, 16.0 mmol) was added to a solution of 2-(hept-2-yn-1-yl)-3-(methylthio)thiophene (36.0 mg, 0.16 mmol) in

Ar flushed 1,2-dichloroethane (11.2 mL) at room temperature. The reaction mixture was stirred for 18 h at room temperature before quenching with saturated aqueous Na2S2O3 (10 mL). The aqueous layer was then extracted with EtOAc (3

× 10 mL) and the combined organic layers washed with brine (10 mL), dried

(Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with n-hexane to yield the product (12.1 mg,

−1 0.036 mmol, 23% yield) as a yellow liquid; νmax (neat)/cm 2960, 2924, 2853,

1455, 1258, 1082, 1016, 863, 790, 702, 668; δH (500 MHz, CDCl3) 1.02 (3H, t, J

= 7.4 Hz, CH3), 1.54 - 1.60 (2H, m, CH2CH3), 2.34 (2H, q, J = 6.9 Hz, CH2CH3),

6.13 (1H, t, J = 6.8 Hz, CH), 7.17 (1H, dd, J = 5.4, 0.6 Hz, Ar-H), 7.35 (1H, d, J

= 5.4 Hz, Ar-H) 7.45 (1H, s, HetAr-H); δC (125 MHz, CDCl3) 13.8 (CH3), 21.7

(CH2CH3), 39.3 (CHCH2), 95.1 (CI), 119.6 (Ar-CH), 121.4 (HetAr-CH), 127.6

(Ar-CH), 137.7 (Ar-C), 138.1(Ar-C), 138.2 (CH), 147.0 (Ar-C); m/z (GCMS) M,

334; (Found: M, 333.9352. C11H11S2I requires M, 333.9341).

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