sulfoxide directed metal-free cross coupling
TRANSCRIPT
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
2
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
3
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
4
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
5
List of Abbreviations
Ac
acyl
AIBN
2,2’-bis(isobutyronitrile)
aq.
aqueous
Ar
aryl
BINAP
2,2’-bis(diphenylphosphino-1,1’-
binaphthyl)
Bn
benzyl
Boc
t-butoxycarbonyl
br.
broad (NMR)
Bu
butyl
Bz
benzoyl
CAN
cerium(IV) ammonium
nitrate
cat.
catalytic
CI
chemical ionisation
C
celsius
d
doublet (NMR)
δ
chemical shift (NMR)
DCE
1,2-dichloroethane
DDQ
2,3-dichloro-5,6-dicyano-p-
benzoquinone
DMF
N,N-dimethylformamide
DMSO
dimethylsulfoxide
DMTSF
dimethyl(methylthio)sulfonium
tetrafluoroborate
6
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
ES+/ES-
positive/negative ion electrospray
(MS)
Et
ethyl
EWG
electron withdrawing group
FSPE
fluorous solid phase
extraction
g
gram
h
hour
HFIP
1,1,1,3,3,3-hexafluoroisopropanol
HMPA
hexamethylphosphoramide
HRMS
high resolution mass
spectrum
Hz
hertz
IBX
o-iodoxybenzoic acid
i-Pr
isopropyl
IR
infrared
7
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
8
Pr
propyl
PTSA
p-toluenesulfonic acid
Pyr.
pyridine
q
quartet (NMR)
quin
quintet (NMR)
RF
perfluoroalkyl
rt
room temperature
s
singlet (NMR)
sxt
sextet (NMR)
SEM
2-
(trimethylsilyl)ethoxymethyl
t
triplet (NMR)
TBAF
tetrabutylammonium
fluoride
TBS
tert-butyldimethylsilyl
TFA
trifluoroacetic acid
TFAA
trifluoroacetic anhydride
Tf
trifluoromethanesulfonyl
THF
tetrahydrofuran
TIPS
triisopropylsilyl
TMEDA
N,N,N’,N’-
tetramethylethylenediamine
TMS
trimethylsilyl
Tol
tolyl
Ts
tosyl
9
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.
10
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.
11
Copyright Statement
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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.
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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
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and Reproductions cannot and must not be made available for use without the prior
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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.
12
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.
13
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-
based initiators such as PhI(OTf)2[7], PhI(CN)OTf (Stang’s reagent)[8] and tol-
IF2[9]. ‘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]
14
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
15
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
16
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.
17
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]
18
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
cases, the reaction can undergo displacement of R2CH2 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.
19
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]
20
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
21
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.
22
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%.
23
Scheme 15
24
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,
25
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
26
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%.
27
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.
28
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
29
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
30
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
31
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
32
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.
33
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
34
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
35
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
36
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.
37
Scheme 31
38
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
39
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.
40
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).
41
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
42
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).
43
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.
44
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%
a: Yield determined by 1H 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
45
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
46
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
47
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
a: Yield determined by 1H 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).
48
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.
49
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).
50
Scheme 49
Table 3: Optimisation of two directional heterocyclisation
entry solvent conc. I2
(equiv.) additives (equiv.) Cond. Yielda
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%
5 DCE 0.005 2.2 MeOH (200) and
Cs2CO3 (2.2) 18 h rt, 3h 80 °C 18%
6 DCE 0.005 2.2 MeOH (200) 1 h 80 °C 65% b
a: yield determined by 1H 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
51
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
52
Scheme 54
53
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
54
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
55
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.
56
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
mmol, 75% yield) as a yellow solid (mp: 48 - 52 °C); νmax (neat)/cm−1 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).
57
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
solid (mp: 103 - 107 °C); νmax (neat)/cm−1 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),
58
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).
59
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
product as a clear oil (0.358 g, 1.72 mmol 57 %); νmax (neat)/cm−1 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,
60
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
give product as a clear oil (0.258 g, 1.30 mmol, 13%); νmax (neat)/cm−1 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.
61
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).
62
(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
63
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
colourless oil (0.079 g, 0.28 mmol, 55 %). νmax (neat)/cm−1 3072, 2955, 2929, 2870,
64
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 %).
νmax (neat)/cm−1 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,
65
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%
n‐hexane to yield product as red oil (0.67 g, 0.30 mmol, 60 %). νmax (neat)/cm−1
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).
66
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
(0.0237 g, 0.090 mmol, 47%); νmax (neat)/cm−1 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-
67
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
yellow solid (mp: 56 - 57 °C); νmax (neat)/cm-1 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).
68
(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
bown solid (mp: 39 - 41 °C); νmax (neat)/cm-1 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),
69
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,
0.18 mmol, 92 % yield) as a yellow solid (mp 38-40 °C); νmax (neat)/cm−1 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-
70
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).
71
(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
product (42.4 mg, 0.18 mmol, 92% yield) as a yellow oil; νmax (neat)/cm−1 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
72
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
73
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
74
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
white solid (mp 145-147 °C); νmax (neat)/cm−1 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).
75
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
solid (decomp. T > 235 °C); νmax (neat)/cm-1 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).
76
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,
0.036 mmol, 23% yield) as a yellow liquid; νmax (neat)/cm−1 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).
77
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