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Iron-mediated C–H coupling of arylsulfides and
simple terminal alkenes
A thesis submitted to the University of Manchester
for the degree of Doctor of Philosophy (PhD) in the
Faculty of Engineering and Physical Sciences
2016
Craig W. Cavanagh
School of Chemistry
3
Contents
Index of Figures ..................................................................................................................... 6
Index of Schemes ................................................................................................................... 7
Index of Tables ..................................................................................................................... 10
Abstract ................................................................................................................................ 11
Declaration ........................................................................................................................... 12
Copyright Statement ............................................................................................................ 13
Acknowledgements .............................................................................................................. 15
Abbreviations and Definitions ............................................................................................. 16
1. Organoiron Chemistry .................................................................................................. 20
1.1 Introduction ....................................................................................................................... 20
1.2 Cross-Coupling Reactions................................................................................................. 20
1.2.1 Coupling of Alkyl Electrophiles ............................................................................... 22
1.2.2 Couplings of Aryl Electrophiles ............................................................................... 26
1.2.3 Coupling of Heteroaromatic Compounds ................................................................. 29
1.3 C–H Bond Activation ....................................................................................................... 30
1.3.1 Activation of sp2 C–H bonds ..................................................................................... 31
1.3.2 Activation of sp3 C–H bonds..................................................................................... 35
1.4 Cross Dehydrogenative Coupling ..................................................................................... 38
1.4.1 CDC of two sp3 C–H bonds ...................................................................................... 38
1.4.2 CDC between sp2 and sp
3 C–H bonds ....................................................................... 40
1.4.3 CDC in Domino Processes ........................................................................................ 42
1.5 Summary ........................................................................................................................... 44
2. Iron-mediated Coupling of Arylsulfides with Silanes .................................................. 45
2.1 Introduction to Pummerer and Pummerer-Type Reactions .............................................. 45
2.1.1 Classical Pummerer Rearrangement ......................................................................... 45
2.1.2 Aromatic Pummerer-Type Reactions ........................................................................ 46
2.2 Results and Discussion ..................................................................................................... 48
4
2.2.1 Proposed Project ....................................................................................................... 48
2.2.2 Preliminary Reaction ................................................................................................ 49
2.2.3 Synthesis of Biarylsulfide Starting Materials ........................................................... 50
2.2.4 Solvent Screen .......................................................................................................... 50
2.2.5 Oxidant Screen ......................................................................................................... 51
2.2.6 Changing The Addition Rate of Allyl Silane ............................................................ 53
2.2.7 Changing Reagent Stoichiometry ............................................................................. 54
2.2.8 Other Biaryl Sulfides ................................................................................................ 55
2.2.9 Reaction with an unfunctionalised alkene ................................................................ 56
3. Metal-catalysed Reactions of Arenes and Alkenes ...................................................... 57
3.1 Oxidative Coupling of Arenes and Alkenes ..................................................................... 57
3.1.1 Examples of Directing Groups ................................................................................. 58
3.1.2 Sulfur Directing Groups in Oxidative Alkenylations ............................................... 61
3.2 Hydroarylation of Alkenes ............................................................................................... 65
3.3 Iron-mediated Functionalisation of Alkenes..................................................................... 68
3.4 Summary ........................................................................................................................... 70
4. Iron-mediated Chloroarylation of Alkenes ................................................................... 71
4.1 This Work ......................................................................................................................... 71
4.2 Optimisation Studies ......................................................................................................... 71
4.2.1 Solvent Screen .......................................................................................................... 71
4.2.2 Oxidant Screen ......................................................................................................... 72
4.2.3 Investigation of Bases and Additives........................................................................ 74
4.2.4 Further Optimisation Studies .................................................................................... 75
4.2.5 Controlled Addition of Reagents .............................................................................. 77
4.3 Substrate Scope ................................................................................................................. 78
4.3.1 Variation of Alkene Coupling Partners .................................................................... 78
4.3.2 Variation of Arene Coupling Partners ...................................................................... 82
4.3.3 Use of Other Aryl Sulfides ....................................................................................... 85
4.4 Mechanistic Studies .......................................................................................................... 87
5
4.4.1 Proposed Mechanism ................................................................................................ 87
4.4.2 Cyclic Voltammetry .................................................................................................. 90
4.4.3 Solvent Investigations ............................................................................................... 91
4.4.4 Use of Other Oxidants ............................................................................................... 91
4.4.5 Electron Paramagnetic Resonance ............................................................................ 93
4.4.6 Alternative Mechanisms ........................................................................................... 94
4.5 Towards a Catalytic Process ............................................................................................. 96
4.5.1 Iron Catalysis ............................................................................................................ 96
4.5.2 Photoredox Catalysis................................................................................................. 97
4.6 Product Manipulation ...................................................................................................... 101
4.6.1 Formation of Dihydrobenzofuran Motifs ................................................................ 104
4.7 Summary ......................................................................................................................... 109
4.8 Future Work .................................................................................................................... 110
4.8.1 Iron-mediated Chloroarylation of Alkenes ............................................................. 110
4.8.2 Manipulation of Allylation Products – The Truce-Smiles Rearrangement ............. 112
5. Experimental ............................................................................................................... 116
5.1 General Experimental ..................................................................................................... 116
5.2 Cyclic Voltammetry ........................................................................................................ 116
5.3 Sulfide Synthesis ............................................................................................................. 117
5.4 Synthesis of Other Arenes............................................................................................... 134
5.5 Synthesis of Alkenes ....................................................................................................... 136
5.6 Iron-mediated Allylation of Arylsulfides ........................................................................ 139
5.7 Iron-mediated C-H Coupling of Arylsulfides and Terminal Alkenes ............................. 141
5.8 Manipulation of Products ................................................................................................ 164
5.9 Synthesis of Dihydrobenzofurans ................................................................................... 171
5.10 Cross-Coupling of Dihydrobenzofurans ......................................................................... 175
5.11 Towards the Truce-Smiles Rearrangement ..................................................................... 185
6. References ................................................................................................................... 189
Final word count: 53,930
6
Index of Figures
Figure 1 Activation of arene through interaction with t-BuOK and ligand ......................... 34 Figure 2 Steric clash resulting from biaryl formation ......................................................... 56 Figure 3 Unsuccessful coupling partners ............................................................................. 82
Figure 4 Proposed thioquinone-type radical cation intermediate ........................................ 86 Figure 5 Aromatic substrates that failed to undergo cross-coupling ................................... 87 Figure 6 Alternative intermediate species in chloroarylation reaction ................................ 88 Figure 7 Voltammogram for sulfides vs reference electrode .............................................. 90 Figure 8 Possible n-σ* interaction ..................................................................................... 106
7
Index of Schemes
Scheme 1 Catalytic cycle for Pd(0)-catalysed cross-coupling reaction ............................... 21 Scheme 2 Iron-catalysed Suzuki-Miyaura coupling of alkylhalides ................................... 22 Scheme 3 Proposed cycle for Fe-catalysed Suzuki-Miyaura coupling of alkyl halides ...... 23
Scheme 4 FeCl2(SciOPP)-catalysed Sonogashia-type coupling .......................................... 23 Scheme 5 Suzuki-Miyaura coupling of alkyl halides and alkynyl borates .......................... 24 Scheme 6 Fe-catalysed Kumada alkyl-alkyl cross-coupling ............................................... 24 Scheme 7 Fe-catalysed Kumada-type alkyl-alkyl cross-coupling using Fe-NHC ............... 24 Scheme 8 Proposed catalytic cycle for the alkyl-alkyl cross-coupling reaction .................. 26
Scheme 9 Fe-catalysed coupling of aryl chlorides with alkyl Grignard reagents ................ 27 Scheme 10 Selective Fe-catalysed biaryl cross-coupling .................................................... 27
Scheme 11 Proposed mechanism for biaryl coupling .......................................................... 28 Scheme 12 Cross-coupling of aryl sulfamates and tosylates with aryl Grignard reagents .. 28 Scheme 13 Use of Fe(OTf)2/SIPr for selective biaryl cross-coupling ................................. 29 Scheme 14 Fe-catalysed coupling of N-heterocyclic halides and arylmagnesium reagents 29 Scheme 15 Ligand accelerated iron-catalysed heteroaryl-heteroaryl cross-coupling .......... 30
Scheme 16 Radical clock studies showing formation of cyclised product .......................... 30 Scheme 17 Fe-catalysed arylation through directed C–H bond activation .......................... 31
Scheme 18 ortho-Arylation of aryl imines by directed C–H activation............................... 31 Scheme 19 Fe-catalysed activation of olefinic C–H bond with Grignard reagent ............... 32
Scheme 20 Proposed mechanism of direct C–H activation ................................................. 32 Scheme 21 Fe-catalysed direct arylation of aryl iodides ..................................................... 33
Scheme 22 Proposed mechanism for the iron-catalysed direct arylation of aryl iodides .... 33 Scheme 23 Iron-catalysed Suzuki-Miyaura-type C–H coupling ......................................... 34
Scheme 24 Proposed catalytic cycle for Suzuki-Miyaura-type C–H coupling .................... 35 Scheme 25 Fe-catalysed alkenylation of 2-substituted azaarenes........................................ 36 Scheme 26 Proposed intermediate in the direct-alkenylation reaction ................................ 36
Scheme 27 Fe-catalysed amidation of C–H bonds .............................................................. 37 Scheme 28 Proposed mechanism for Fe-catalysed amidation of benzylic sp
3 C–H bonds . 38
Scheme 29 Iron-catalysed CDC of benzylic C–H and 1,3-diketones .................................. 38 Scheme 30 Tentative mechanism for iron-catalysed CDC .................................................. 39 Scheme 31 Iron-catalysed CDC of cyclic alkanes and 1,3-dicarbonyl compounds ............ 40
Scheme 32 Iron-catalysed CDC α- to heteroatoms .............................................................. 40 Scheme 33 Iron-catalysed CDA of benzylic C–H bonds ..................................................... 41
Scheme 34 Proposed mechanism for the CDA reaction ...................................................... 41 Scheme 35 Iron-catalysed direct functionalisation of benzylic C–H bonds ........................ 42
Scheme 36 Iron-catalysed oxidative coupling of alkylamides with arenes ......................... 42 Scheme 37 Vinylaromatic generation via iron-catalysed sp
3 C–H functionalisation .......... 43
Scheme 38 Proposed mechanism for generation of vinylaromatics .................................... 43 Scheme 39 Classical Pummerer Rearrangment ................................................................... 45 Scheme 40 1,4 addition to p-sulfinylphenols to give dihydroxybenzofurans ...................... 46
Scheme 41 Nucleophilic ortho-allylation of aryl sulfoxides ............................................... 47 Scheme 42 Mechanism of ortho-allylation of aryl sulfoxides ............................................. 47 Scheme 43 Proposed oxidative process for nucleophilic cross-coupling with aryl sulfides 48 Scheme 44 Iron-catalysed oxidative coupling of biaryl sulfides ......................................... 49 Scheme 45 Model reaction conditions ................................................................................. 50
Scheme 46 Pd- and Cu-catalysed formation of biaryl sulfides ............................................ 50
Scheme 47 Reaction of 91c under standard conditions ....................................................... 55
8
Scheme 48 Reaction of 91a under standard reaction conditions ......................................... 55 Scheme 49 FeCl3-mediated chloroarylation of 1-octene ..................................................... 56 Scheme 50 Catalytic Fujiwara-Moritani reaction ................................................................ 57 Scheme 51 Mechanism for Fujiwara-Moritani reaction ...................................................... 58 Scheme 52 Pd-catalysed ortho-alkenylation of phenylacetic acids ..................................... 58
Scheme 53 Use of amino acid ligands for increased A. reactivity and B. regioselectivity . 59 Scheme 54 Sequential olefination with different alkene partners ....................................... 60 Scheme 55 Ester-directed alkenylation of arenes by A. Ackermann and B. Jeganmohan .. 60 Scheme 56 Proposed catalytic cycle for Ru-catalysed oxidative alkenylation .................... 61 Scheme 57 Screen of S-containing directing groups ........................................................... 62
Scheme 58 Pd-catalysed selective ortho-alkenylation with thioether directing groups ...... 62 Scheme 59 Controlled Rh-catalysed olefination using thioether directing groups ............. 63
Scheme 60 Rh-catalysed selective alkenylation of 2-aryl-1,3-dithianes ............................. 63 Scheme 61 Proposed catalytic cycle for sulfur-directed oxidative C–H alkenylation ........ 64 Scheme 62 Use of sulfoxides as remote directing groups for arene C–H olefination ......... 65 Scheme 63 Ru-catalysed hydroarylation of olefins through direct C–H activation ............ 65 Scheme 64 Proposed mechanism for Ru-catalysed hydroarylation of olefins .................... 66
Scheme 65 Ni-catalysed hydroarylation of alkenes using electron-deficient arenes .......... 66 Scheme 66 Linear-selective hydroarylation of olefins with electron-deficient arenes ........ 67
Scheme 67 Proposed mechanism for Ni-catalysed linear-selective hydroarylation ............ 67 Scheme 68 Iron-mediated halo-nitration of alkenes ............................................................ 68
Scheme 69 Iron(III)/NaBH4-mediated additions to unactivated alkenes ............................ 68 Scheme 70 Fe-catalysed reductive olefin coupling ............................................................. 69 Scheme 71 Mechanism for reductive olefin coupling ......................................................... 69
Scheme 72 Variation of the alkene coupling partner ........................................................... 79
Scheme 73 Proposed 5-exo-trig cyclisation of 1,6-heptadiene intermediate ...................... 80 Scheme 74 Reaction of more substituted dienes ................................................................. 80 Scheme 75 Reaction of 4,4-dimethyl-1-pentene ................................................................. 81
Scheme 76 Variation of arylsulfide in the cross-coupling ................................................... 83 Scheme 77 Attempted second chloroarylation reaction ...................................................... 84
Scheme 78 Competition experiment between 91b and 91d ................................................. 84 Scheme 79 Competition experiment between 91b and 91e ................................................. 85 Scheme 80 Proposed mechanism for coupling of biaryl sulfides and terminal olefins ....... 88
Scheme 81 Cu(II)-catalysed functionalisation directed by pyridyl group ........................... 88 Scheme 82 Proposed mechanism for Cu-catalysed functionalisation of C–H bonds .......... 89
Scheme 83 Iron-catalysed oxidative coupling/cyclisation between phenols and styrenes .. 89
Scheme 84 Proposed mechanism of cross-coupling/cyclisation ......................................... 89
Scheme 85 Use of brominated solvent to investigate halide incorporation ......................... 91 Scheme 86 Reaction of biaryl sulfide and octene with CAN .............................................. 91 Scheme 87 Fe-catalysed hydroarylation of styrenes ........................................................... 94 Scheme 88 Alternative electrophilic metalation/carbometalation reaction ......................... 95 Scheme 89 Standard photoredox catalysis cycle ................................................................. 98
Scheme 90 mCPBA oxidation to the sulfone .................................................................... 102 Scheme 91 Desulfurisation of products using Raney Ni ................................................... 102 Scheme 92 ortho-Directed metalation using various quenches ......................................... 102 Scheme 93 Elimination to give conjugated and non-conjugated alkenes .......................... 103 Scheme 94 Manipulation of alkyl chloride moiety in cross-coupled products ................. 104
Scheme 95 Proposed cyclisation of coupling products to form dihydrobenzofuran ......... 104
Scheme 96 Deallylation/cyclisation sequence to form dihydrobenzofuran ...................... 105 Scheme 97 Pd-catalysed deallylation ................................................................................ 105
9
Scheme 98 Substrate scope for dihydrobenzofuran formation .......................................... 107 Scheme 99 Triflation and Pd-catalysed couplings of dihydrobenzofuran ......................... 108 Scheme 100 Desulfurisation of dihydrobenzofurans using Raney Ni ............................... 108 Scheme 101 Ni-catalysed Kumada-Corriu cross-coupling ................................................ 109 Scheme 102 Use of vinylcyclopropane in radical clock studies ........................................ 110
Scheme 103 Preparation of vinyl cyclopropane via Wittig reaction ................................. 111 Scheme 104 Proposed conversion of chloroarylation products to dibenzothiepines ......... 111 Scheme 105 Silver-mediated dehalogenation to form sulfonium salts .............................. 112 Scheme 106 Proposed Truce-Smiles rearrangement of allylphenylsulfones ..................... 112 Scheme 107 ortho-C–H Allylation of diphenylsulfoxide .................................................. 112
Scheme 108 Selective oxidation to the allylated sulfone ................................................... 113 Scheme 109 Preliminary studies on the Truce-Smiles rearrangement .............................. 113
Scheme 110 Use of MeI as quench for intermediary metal sulfinate ................................ 114 Scheme 111 Isomerisation of the allyl unit using NaNH2 ................................................. 114 Scheme 112 Potential further manipulations of metal sulfinate intermediates .................. 115
10
Index of Tables
Table 1 Solvent screen using FeCl3 oxidant ........................................................................ 51 Table 2 Oxidant screen carried out in MeNO2 .................................................................... 52 Table 3 Slow addition of allyl TMS to mixture of 91b and FeCl3 ...................................... 53
Table 4 Changing the stoichiometry of the reaction ............................................................ 54 Table 5 Solvent screen for FeCl3-mediated reaction of 91b with 1-octene ......................... 72 Table 6 Oxidant screen for Fe(III)-mediated reaction with octene ..................................... 73 Table 7 Addition of base to reaction mixture ...................................................................... 75 Table 8 Effect of changing various parameters on the reaction .......................................... 76
Table 9 Changing the addition rate of reagents ................................................................... 78 Table 10 Screen of Ce(IV) reagents/conditions for an analogous cross-coupling .............. 93
Table 11 Screen of Lewis acids ........................................................................................... 95 Table 12 Attempts to perform the reaction with catalytic amounts of FeCl3 ...................... 97 Table 13 Initial photocatalyst screen ................................................................................... 99 Table 14 Solvent screen with Ru(bpy)3Cl2 ........................................................................ 100 Table 15 Investigation of oxidative quenchers towards a photocatalytic process ............. 101
Table 16 Improved conditions for deallylation/cyclisation cascade .................................. 106
11
Abstract
The University of Manchester
School of Chemistry
Craig Cavanagh
Doctor of Philosophy
Iron-mediated C–H coupling of arylsulfides and simple terminal alkenes
The use of directing groups in C–H functionalisation reactions provides a means to control
the regioselectivity of such processes. Previous work in the Procter group reported the
sulfoxide-directed metal-free C–H alkylation of arenes with organosilane nucleophiles.
Attempts to expand this work by carrying out a similar process directly from the sulfide
oxidation level, utilising an Fe(III) oxidant, a diarylsulfide and an alkene are discussed
herein.
During these investigations, it was discovered that the use of simple, unfunctionalised
olefins selectively gave linear products of formal chloroarylation, which represents a novel
transformation. Following optimisation studies, the reaction proceeded in good to moderate
yield under exceptionally mild conditions with a range of alkene and sulfide coupling
partners, although sulfides do require a particular oxygenation pattern in the aryl ring
undergoing coupling. Based on various experimental observations, a single electron
oxidation process is believed to be responsible for the desired reactivity.
A number of manipulations of the chlorinated products are demonstrated, including their
use in an expedient synthesis of important dihydrobenzofuran motifs. The original sulfur
directing-group has also been used as a handle for further elaboration of these interesting
structures.
12
Declaration
No portion of the work referred to in this thesis has been submitted in support of an
application for another degree or qualification of this or any other university or other
institute of learning.
Part of this work has been published in peer reviewed journals:
Cavanagh, C. W.; Aukland, M. H.; Hennessy, A.; Procter, D. J., Chem. Commun. 2015, 51,
9272.
Cavanagh, C. W.; Aukland, M. H.; Laurent, Q.; Hennessy, A.; Procter, D. J., Org. Biomol.
Chem. 2016, 14, 5286.
13
Copyright Statement
i. The author of this thesis (including any appendices and/or schedules to this
thesis) owns certain copyright or related rights in it (the “Copyright”) and s/he
has given The University of Manchester certain rights to use such Copyright,
including for administrative purposes.
ii. Copies of this thesis, either in full or in extracts and whether in hard or
electronic copy, may be made only in accordance with the Copyright, Designs
and Patents Act 1988 (as amended) and regulations issued under it or, where
appropriate, in accordance with licensing agreements which the University has
from time to time. This page must form part of any such copies made.
iii. The ownership of certain Copyright, patents, designs, trademarks and other
intellectual property (the “Intellectual Property”) and any reproductions of
copyright works in the thesis, for example graphs and tables (“Reproductions”),
which may be described in this thesis, may not be owned by the author and may
be owned by third parties. Such Intellectual Property and Reproductions cannot
and must not be made available for use without the prior written permission of
the owner(s) of the relevant Intellectual Property and/or Reproductions.
iv. Further information on the conditions under which disclosure, publication and
commercialisation of this thesis, the Copyright and any Intellectual Property
University IP Policy
(see http://documents.manchester.ac.uk/display.aspx?DocID=24420), in any
relevant Thesis restriction declarations deposited in the University Library, The
University Library’s regulations
(see http://www.library.manchester.ac.uk/about/regulations) and in The
University’s policy on Presentation of Theses.
14
Finite to fail, but infinite to venture.
For the one ship that struts the shore
Many’s the gallant, overwhelmed creature
Nodding in navies nevermore.
Emily Dickinson
15
Acknowledgements
First and foremost, I would like to thank my supervisor David for giving me the
opportunity to work in his group and for all the help and support that has been extended
over the years. I would also like to thank Syngenta for funding my PhD and my industrial
supervisor Alan for his continued input and for ensuring I was looked after during my
placement. Thanks are also due to the University of Manchester for financial support and
all of the technical staff for providing assistance when required.
Of course boundless thanks go to the members of the Procter and Greaney research groups,
past and present, who have provided companionship on this scientific journey. It has been
a pleasure to work with many of you and your adherence to Rule #1 is greatly appreciated.
Particular thanks are extended to everyone who proof-read parts of this thesis and helped
make it moderately readable.
To my compeers, Chris and Irem, I have (mostly) enjoyed our time together and am glad to
have started this stint at your side. To The Plastics, thank you so much for being so
welcoming when I first arrived and for being such good sources of laughter for the
following years. The Crossword Compatriots, Harry and Becky, thank you for providing a
link to the outside world and for the hours spent attempting ‘quick’ crosswords. Miles, I
appreciate all the help you’ve given me in those tough times and hope that your future is a
perfect shade of orange. The Syngenta Crew, your presence in the dark and lonely abyss
that is Bracknell was most opportune and I can safely say that, thanks to you all, what
could have been a major low became one of the highlights of my PhD. To our longstanding
postdocs, Xavi and Jose, thanks for your help and for attempting to understand my
lightning-fast chatter. Huanming and Kay, your patience in expanding my linguistic
knowledge is much appreciated; I can only apologise for the horrendous ways I twisted
said knowledge. Mateusz, your obsession with those born out of wedlock has provided
much amusement in those long lab hours.
I risk causing offence by attempting (and failing) to list everyone so I may as well just
cause it; if you haven’t been mentioned already, assume you don’t matter (especially
Nico!). Regardless, I wish you all luck in whatever future escapades you find yourselves.
Finally I should thank my family. You will likely never read this but I appreciate the
encouragement you have offered, even though you may not know what I am actually doing
most of the time.
16
Abbreviations and Definitions
Å 10-10
metres
Ac acetyl
Acac acetylacetone
AIBN azobisisobutyronitrile
APCI atmospheric pressure chemical ionisation
Ar aryl
Asym asymmetric
Aq. aqueous
BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene
Bipy 2,2-bipyridine
B:L branched:linear ratio
Bn benzyl
Boc tert-butoxycarbonyl
Bpz 2,2’-bipyrazine
brsm based on recovered starting material
Bu butyl
BQ benzoquinone
Bz benzoyl
CAN ceric ammonium nitrate
CAS ceric ammonium sulfate
cat. catalyst/catalytic
Cbz carboxybenzyl
CDA cross dehydrogenative arylation
CDC cross dehydrogenative coupling
CI chemical ionisation
cod 1,5-cyclooctadiene
Cp* pentamethylcyclopentadiene
CV cyclic voltammetry
Cyp cyclopentane
dba dibenzylideneacetone
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
DCE 1,2-dichloroethane
DCIB 1,2-dichloroiso-butane
DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
17
DFT density functional theory
DG directing group
DMF dimethylformamide
DMSO dimethylsulfoxide
DTBP di-tert-butyl peroxide
DTBPy 2-6-di-tert-butylpyridine
dtbbpy 4,4′-di-tert-butyl-2,2′-bipyridyl
EDG electron donating group
EDTA ethylenediaminetetraacetic acid
EI electron ionisation
ES+/ES– positive/negative ion electrospray
Et ethyl
Eq. equivalent
EWG electron withdrawing group
FTIR Fourier transform infrared spectroscopy
Gly glycine
h hour/s
HFIP hexafluoroisopropyl alcohol
HRMS high resolution mass spectrometry
i- iso-
Ile isoleucine
IMes 1,3-bis(2,4,6-trimethylphenyl)-imidazolium
IR infrared
JohnPhos (2-biphenyl)di-tert-butylphosphine
KIE kinetic isotope effect
LDA lithium diisopropylamide
M metal/molar
m meta
m/z mass/charge ratio (MS)
mCPBA meta-chloroperoxybenzoic acid
Me methyl
min. minutes
m.p. melting point
Ms mesyl
MS molecular sieves/ mass spectrometry
MW microwave/ molecular weight
18
n- normal
NBS N-bromosuccinimide
NHC N-heterocyclic carbene
NMP N-methyl-2-pyrrolidone
NMR nuclear magnetic resonance
o ortho
p para
Ph phenyl
Phen phenanthroline
PI photoionisation
Piv pivaloyl
ppm parts per million
Ppy phenylpyridine
Pr propyl
rt room temperature
s-/sec- secondary
Sat. saturated
SciOPP spin-control-intended-ortho-phenylene biphosphine
SEAr electrophilic aromatic substitution
SET single electron transfer
SHE standard hydrogen electrode
SM starting material
SN2 bimolecular nucleophilic substitution
Sym symmetric
t-/tert- tertiary
T temperature
t-AmOH tert-pentyl alcohol
TBHP tert-butyl hydroperoxide
TBAHFP tetrabutylammonium hexafluorophosphate
TBS tert-butyldimethylsilyl
TEMPO (2,2,6,6-tetramethylpiperidin-1-yl)oxyl
Tf triflyl
TFA trifluoroacetic acid
TFAA trifluoroacetic anhydride
THF tetrahydrofuran
TLC thin layer chromatography
19
TMEDA tetramethylethylenediamine
TMS trimethylsilyl
Tol toluene
Ts tosyl
Val valine
Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
Unit Abbreviations
M 106
m 10-3
µ 10-6
n 10-9
NMR Abbreviations
Singlet (s), broad singlet (br. s), apparent singlet (app. s), doublet (d), triplet (t), quartet (q),
quintet (quin), septet (sept), doublet of doublets (dd), doublet of doublet of doublets (ddd),
multiplet (m), quaternary carbon (Cq)
20
1. Organoiron Chemistry
1.1 Introduction
Throughout organic synthesis, the late transition metals, such as Pd, Rh and Au,
demonstrate powerful catalytic ability and play vital roles in many areas. Despite their
synthetic utility, most of these metals are relatively rare and come from limited and rapidly
depleting stocks. Their decreasing availability means that these reagents tend to be very
expensive and prices will only continue to rise. Also, many compounds of these elements
exhibit considerable toxicity in humans and in the environment, making their extensive use
and disposal of some long lasting concern.1
Clearly the use of these late transitions metals is not sustainable; a worrying thought
considering their utility and importance. If these elements were to run out, would it be
possible to sufficiently replace their current role in synthesis?
Thus, attention has turned toward the more readily available first row transition metals,
such as Cu and Ni. Among these metals, particular attention has been drawn to Fe: the
cheapest, most abundant, non-toxic and environmentally friendly transition metal.2 Iron
can be converted into its salts and complexes with relative ease and many iron salts are
commercially available.3 These properties make iron extremely attractive for synthesis and
catalysis.
Despite its advantages and ubiquity in many fundamental biological processes, iron was
somewhat underdeveloped in the field of catalysis until only recently. Since then the use of
iron has increased significantly and it has demonstrated some unique and novel reactivity.
It has been widely used as a Lewis acid for the activation of organic substrates and the
generation of radicals and carbocations.4
The ability of iron to play a role in many different reactions has led to its use in a number
of areas and consequently the chemical literature surrounding iron is vast. This review will
discuss recent advances in the use of iron in areas such as Fe-catalysed cross-coupling and
C–H bond activation and will serve to demonstrate some key aspects of iron’s behaviour.
1.2 Cross-Coupling Reactions
Transition metal-catalysed cross-coupling reactions are one of the most used C–C bond-
forming reactions in many areas of organic chemistry. Indeed the late transition metals, Pd
in particular, are employed extensively and couplings such as the Suzuki-Miyaura reaction
are used far and wide.
21
A general catalytic cycle for a Pd-catalysed cross-coupling reaction is shown in Scheme 1.
The first step is the oxidative addition of Pd(0) species I into a C–X bond (X can be a
number of groups such as halides or a sulfonate). This forms an organopalladium(II)
species II, which can undergo a transmetalation step with another metal species III.
Reductive elimination from the resultant organopalladium species IV gives the cross-
coupled product V and reforms the original Pd catalyst.5
Scheme 1 Catalytic cycle for Pd(0)-catalysed cross-coupling reaction
Alongside the widely used Suzuki-Miyaura reaction [where M = B(OR2)] many variations
of this mode of coupling have been reported using different organometallics, such as M =
ZnX, SnR3, Cu and Mg.
Traditionally, these types of cross-coupling reaction were limited to sp- or sp2-hybridised
α-C atoms. This was due to the initial oxidative addition being slow with sp3 carbon and
also β-H elimination competing with the desired transmetalation step in these systems,
leading to unsaturated by-products.6 A lot of work has been carried out in this area and
coupling of alkyl species is possible through the use of bulky trialkylphosphines7 or N-
heterocyclic carbene (NHC) ligands.8
The application of these reactions on large scales has made them very popular in industrial
processes, such as in the synthesis of pharmaceutical products and fine chemicals.
However, it is in these areas that a push for more green processes and materials is most
sought after. Thus, the use of iron as an alternative for the development of new catalysts is
an attractive concept and its application in many cross-coupling reactions has been
successfully realised with a range of substrates, such as alkenyl9 and aryl halides.
10
22
1.2.1 Coupling of Alkyl Electrophiles
The coupling of alkyl halides and other alkyl electrophiles has been investigated
extensively. Nakamura recently reported an iron catalysed Suzuki-Miyaura coupling of
alkyl halides 1 and arylborates 2 through the development of novel iron-phosphine
complexes 3 (Scheme 2).11
Scheme 2 Iron-catalysed Suzuki-Miyaura coupling of alkyl halides
These bisphosphine ligands were later dubbed ‘SciOPPs’ (spin-control-intended ortho-
phenylene bisphosphine).12
The bulky substituents in these phosphine complexes prevent
the formation of coordinatively saturated octahedral iron complexes and are easily
synthesised from commercially available starting materials.
The coupling reaction was shown to have a wide substrate scope, with a variety of different
functional groups in 2 being tolerated, such as OMe, Cl and F. Interestingly, the reaction
was also shown to be highly chemoselective, with the desired products still being observed
in high yields in the presence of various ester and cyano moieties, which were untouched.
A radical clock study was carried out to probe the mechanism by using
bromomethylcyclopropane as the alkyl halide partner. The corresponding ring-opened
product was observed in 99% yield, suggesting a radical mechanism was in effect (Scheme
3). The starting iron complex 3 first reacts with 2 equivalents of aryl borate to form the
active species I. Lack of biaryl formation and various mechanistic studies suggested that
iron is not reduced in this step and is still present as Fe(II). The first step in the cycle then
involves homolytic cleavage of the sp3
C–X bond to give Fe(III) species II similar to in
metal-catalysed living radical polymerisation reactions.13
II then reacts with the formed
alkyl radical via either release of an aryl radical or, more likely, ipso attack of the alkyl
radical at one of the aryl groups to yield the coupling product and Fe(II) species III.
Transmetalation of III with an aryl borate 2 then regenerates the active species I. It is
believed that the MgBr2 additive aids in this step by activating the Fe(II)–X bond. The
steric bulk of 3 prevents formation of ferrate complexes, which often show low selectivity
in coupling reactions.11
23
Scheme 3 Proposed cycle for Fe-catalysed Suzuki-Miyaura coupling of alkyl halides
Nakamura et al. later reported a Sonogashira-type coupling of unactivated alkyl halides
with alkynyl Grignard reagents using hindered Fe(SciOPP) complexes (Scheme 4).12
The
proposed mechanism involved a similar SET process to that observed in Scheme 3.
Scheme 4 FeCl2(SciOPP)-catalysed Sonogashia-type coupling
Whilst the couplings reported proceeded in high yields and, unusually, allowed for
coupling of primary and secondary alkyl halides in the presence of alkenyl triflates, low
functional group compatibility was observed and the reaction required slow addition of the
Grignard reagents at reflux. This was later improved upon by carrying out a Suzuki-
Miyaura-like coupling of alkynyl borate reagents, such as 10, similar to that discussed
earlier (Scheme 5).14
24
Scheme 5 Suzuki-Miyaura coupling of alkyl halides and alkynyl borates
These conditions allowed for a broader reaction scope and a simpler reaction procedure,
with no slow addition being required. The reaction was able to tolerate the presence of
reactive functional groups, such as nitriles and ketones, when carried out in toluene. It was
reasoned that the low polarity of toluene prevented side reactions that may occur in more
polar solvents, such as the formation of ferrate complexes.
Despite a number of reports of alkyl halides being used as coupling partners in
cross-coupling chemistry, the formation of C(sp3)-C(sp
3) bonds is still underdeveloped.
The first Fe-catalysed Kumada alkyl-alkyl cross-coupling reaction was published in 2007
by Chai et al., using Fe(OAc)2 and phosphine ligands (Scheme 6). The reaction gave
reasonable yields for coupling of unactivated primary alkyl bromides and alkyl Grignard
reagents; however, it seemed to be limited to unsubstituted long chain alkyl bromides as
the starting material.15
Scheme 6 Fe-catalysed Kumada alkyl-alkyl cross-coupling
Cárdenas et al. carried out further work on this reaction and reported the use of a novel
Fe-NHC catalytic system to couple alkyl iodides and alkylmagnesium reagents in good to
excellent yields (Scheme 7).16
Scheme 7 Fe-catalysed Kumada-type alkyl-alkyl cross-coupling using Fe-NHC
An assortment of ligands were screened, including Xantphos, the ligand reported by Chai
for the coupling of alkyl bromides, however only low yields were obtained. The use of
25
stronger σ-donor NHC ligands, generated in situ from deprotonation of imidazolium salts
with 16, led to increased yields.
The reaction itself is viable with both primary and secondary alkyl iodides; alkyl bromides
and tosylates led to lower yield and chlorides gave no reaction. Substrates containing an
ester functionality and N-Boc protected piperidines also successfully afforded cross-
coupled products. However, a major limitation in this reaction was the Grignard reagent,
with only 16 showing the desired reactivity.
Several mechanisms had been previously proposed for the coupling, such as cycles
involving Fe(I)/Fe(III),17
Fe(0)/Fe(II)18
or Fe(-II)/Fe(0).19
It has been found that the exact
pathway is dependent upon the nature of the organohalide.20
Thus extensive mechanistic
studies were carried out to attempt to elucidate the correct cycle operating.
The reaction was carried out in the absence of an electrophile and no β-elimination
products were detected, suggesting the absence of Fe hydride species. Also, by measuring
the amount of homocoupling of the Grignard reagent, the change in oxidation state of the
Fe complex by reduction of the starting salt could be deduced. The data obtained indicated
that half of the starting Fe(II) was reduced to Fe(0), formally corresponding to reduction to
Fe(I). This was confirmed by EPR spectroscopy.
Finally, radical clock experiments indicated the presence of carbon radicals in the
reactions, suggesting activation of the electrophile occurs through homolytic cleavage of
the C–I bond. These results led to a proposed catalytic cycle (Scheme 8).
The active metal complex I can evolve through either oxidative addition of the alkyl iodide
(pathway A) or transmetalation with the Grignard reagent (pathway B), with the alternate
step following in each case. It could not be stated with certainty which cycle was
operating, however initial activation of the Fe salt required addition of an excess of the
Grignard reagent compared to the amount necessary for reduction to Fe(I). This may
suggest that transmetalation to an alkyl-Fe(I) II complex may be necessary prior to the
oxidative addition. Nevertheless, reductive elimination from the Fe(III) complex IV yields
cross-coupled product and the active complex.
26
Scheme 8 Proposed catalytic cycle for the alkyl-alkyl cross-coupling reaction
Another pathway involves formation of an anionic dialkyl-Fe(I) species VII, which would
likely give easier oxidative addition (pathway C). However the trialkyl-Fe(III) species VIII
involved would give a mixture of cross-coupling and homocoupling compounds, including
homocoupling of the electrophile. The absence of these products suggests this pathway is
unlikely.16
1.2.2 Couplings of Aryl Electrophiles
The previous examples have utilised an iron-mediated radical-based mechanism, using
bromo- and iodoalkyl compounds. It has been shown that the coupling of aryl chlorides
with alkyl Grignard reagents using iron salts in the presence of additives, such as N-
methyl-2-pyrrolidone (NMP), can proceed via an ionic mechanism. These couplings were
highly efficient for primary alkyl Grignard reagents with activated, electron poor aryl
chlorides but failed for secondary Grignard reagents and more electron rich aryls.21
Recently Law et al. described the use of NHC’s as ligands in an iron-catalysed
cross-coupling of non-activated aryl chlorides with primary and secondary alkyl Grignard
reagents; expanding the scope of iron-catalysed couplings (Scheme 9).22
27
Scheme 9 Fe-catalysed coupling of aryl chlorides with alkyl Grignard reagents
The reaction gave excellent yields for the coupling of primary Grignard reagents, such as
19; however secondary alkyl Grignard reagents were not as efficient and only gave
moderate yields. The use of acyclic secondary Grignard reagents led to formation of n-
alkyl isomers in various branched:linear ratios (B:L), suggesting reversible β-H elimination
occurs in competition with desired reductive elimination. This indicates an ionic
mechanism is operating rather than a radical-based one.
Despite suffering lower yields for secondary alkyl Grignard reagents, these results are
promising as such couplings were previously unreported and have only recently been
carried out with reasonable yields and linear to branched ratios using Pd.23
Aryl-aryl cross couplings can often be challenging due to the formation of homocoupled
products of the organometallic reagent.24
However significant developments have recently
been reported in this area.
In 2007 Nakamura was able to suppress this homocoupling and demonstrated that the use
of iron fluoride salts in combination with NHC ligands helped to form the desired coupling
products.25
Results indicated that the fluoride anion is key to suppressing unwanted side
reactions. This ‘fluoride effect’ was further investigated and later reports were able to
expand the scope of the reaction (Scheme 10).26
Scheme 10 Selective Fe-catalysed biaryl cross-coupling
The ‘fluoride effect’ is believed to be due to strong coordination of the fluoride ion to the
metal centre. This is believed to suppress reduction of the metal by the organometallic
species and promotes formation of a metalate complex I. This complex can then catalyse
28
the desired biaryl cross-coupling (Scheme 11). Notably this proposed mechanism proceeds
through an unusual high-valent Fe(IV) intermediate II. DFT calculations were carried out
and this pathway was determined to be feasible. The instability of this intermediate results
in a fast reductive elimination step, which disfavours alternate pathways that could lead to
products of homocoupling. The resultant Fe(II) complex III then undergoes
transmetalation with the Grignard reagent to return active species I.
Scheme 11 Proposed mechanism for biaryl coupling
Cook et al. demonstrated a similar system for carrying out the coupling of aryl sulfamates
and tosylates 24 with aryl Grignard reagents (Scheme 12). This procedure did not use an
extra sacrificial Grignard reagent to deprotonate the NHC precursor, as was used in
Nakamura’s protocol, and added an excess of the coupling Grignard reagent to do this in
one step. A large array of aryl species were shown to successfully couple, with electron
donating and electron withdrawing substituents all being tolerated, to afford the desired
products 25.27
Scheme 12 Cross-coupling of aryl sulfamates and tosylates with aryl Grignard reagents
Duong et al. later reported a similar reaction using iron alkoxide species to carry out
selective cross-couplings. Alkoxides are known to form strong bonds to first row transition
metals and it was found that Fe2(Ot-Bu)6 was effective at carrying out the reaction. It is
29
believed that, similar to fluoride, t-butoxide may hamper reduction of Fe(III) to Fe(0) by
the Grignard reagent.28
During the investigation of different iron salts it was noticed that Fe(OTf)2 was somewhat
resistant to reduction. Following further studies it was found that the combination of
Fe(OTf)2/SIPr as a catalyst was remarkably efficient at carrying out selective biaryl cross-
coupling, in some cases surpassing previously described systems. With this method, a
variety of aryl Grignard reagents could be coupled with aryl chlorides and tosylates 27 in
good to excellent yields (Scheme 13).29
Scheme 13 Use of Fe(OTf)2/SIPr for selective biaryl cross-coupling
1.2.3 Coupling of Heteroaromatic Compounds
Recently, Knochel has achieved the cross-coupling of N-heterocyclic halides 29 with
arylmagnesium reagents 30 using FeBr3 (Scheme 14).30
Scheme 14 Fe-catalysed coupling of N-heterocyclic halides and arylmagnesium reagents
The use of heterocycles can be difficult due to interaction of the heteroatom with the metal
catalyst, which can deactivate the metal centre and prevent product formation.
Nevertheless this reaction was highly efficient and a range of differently substituted
partners 29 and 30 could be coupled. Both electron rich and electron poor substituents
were tolerated in 30, however sterically hindered reagents led to much slower reaction
times. Polar solvents appeared to hamper the reaction and apolar solvents were found to be
vital to achieving high yields, mainly by avoiding the formation of homocoupled products.
A recent serendipitous discovery demonstrated that addition of isoquinoline as a ligand can
promote this cross-coupling, leading to better yields and shorter reaction times, thus
30
increasing the range of coupling partners available. This also allowed the smooth coupling
of two heteroaryl species, such as 32 and 33 (Scheme 15).31
Scheme 15 Ligand accelerated iron-catalysed heteroaryl-heteroaryl cross-coupling
The mechanism of these couplings was not determined, however Fe(II) and Fe(III) salts
gave similar yields. Despite this, reduction of the Fe(III) catalyst in situ with i-PrMgCl
prior to the reaction deactivated the catalytic system. Radical clock studies suggest the
presence of radical intermediates, due to formation of cyclised product 35 upon reaction of
29a, and further mechanistic studies are underway (Scheme 16).31
Scheme 16 Radical clock studies showing formation of cyclised product
The discussed examples demonstrate only a small sample of iron-catalysed cross-couplings
and many more have been developed, incorporating a range of coupling partners, such as
aryl carbamates,32
alkenyl carboxylates33
and alkyl sulfides/sulfones.34
The formation of
carbon-heteroatom bonds has also been reported.35
Many of these reactions rival current
discoveries involving late transition metals and express the possibility of iron replacing
them in the future.
1.3 C–H Bond Activation
Direct C–H transformation has attracted a great deal of interest as substrates need not be
pre-functionalised to instil the necessary reactivity. This greatly increases the sustainability
of a process by reducing the number of reaction steps required. It has been shown that the
precious late transition metals are extremely useful in developing efficient C–H activation
processes. The combination of the advantages of both iron chemistry and C–H
transformation was an appealing concept and this area has recently been developed.36
31
1.3.1 Activation of sp2 C–H bonds
In 2008, Nakamura reported an iron-catalysed direct arylation through directed activation
of an aromatic C–H bond. This reaction required the use of a large excess of Grignard
reagent in conjunction with a stoichiometric amount of Zn salts (Scheme 17).37
Scheme 17 Fe-catalysed arylation through directed C–H bond activation
The reaction required 2 equivalents of Ph2Zn (formed by transmetalation from the
Grignard reagent) for reaction to occur, yet an excess was used due to a biphenyl-forming
side reaction also consuming reagent. It was found that the TMEDA additive was vital and
1,2-dichloroiso-butane (DCIB) proved an effective oxidant for the iron catalyst.
With this system a number of arylpyridines, aryl pyrimidines and arylpyrazoles were
reacted. It was also later demonstrated that arylimines, such as 38, could be used as ortho-
directing groups for this reaction to yield the corresponding ketones, such as 39 (Scheme
18).38
A range of ring substituents, such as halide, tosyl, nitrile and methoxy groups, were
tolerated in this reaction. The expensive DCIB oxidant was also later replaced by oxygen.39
Scheme 18 ortho-Arylation of aryl imines by directed C–H activation
The procedure could eventually be carried out without the need for stoichiometric Zn salts
by introducing an aromatic co-solvent and through slow addition of Grignard reagent. This
protocol allowed for increased yield of coupling compared to previous reactions.40
Nakamura et al. have also developed an iron-catalysed directed substitution reaction of an
olefinic C–H bond with a Grignard reagent using a similar procedure (Scheme 19).41
32
Scheme 19 Fe-catalysed activation of olefinic C–H bond with Grignard reagent
The reaction takes place in a syn-specific manner; however the product 41 may be allowed
to isomerise to the more stable isomer, such as in the case of 41a which was obtained in an
E:Z ratio of 96:4. This isomerisation can be suppressed by a substituent being present at the
1-position of the olefin (cf. 41b).
The reaction was shown to occur for aryl Grignard reagents possessing electron-
withdrawing or electron-donating groups, however ortho-substitution was shown to subdue
the reaction. The reaction also did not occur for alkyl or alkenyl Grignard reagents. A
variety of cyclic and acyclic olefins 40 with a 2-pyridyl directing group successfully
participated in the reaction. Yield also increased with the steric bulk of groups at the 1-
position of the olefin, however substituents at the 2-position hindered the reaction.
Interestingly unsaturated imines also took part in the reaction and, following hydrolysis,
could give the corresponding unsaturated ketones.
The exact catalytic cycle was not fully investigated, however a number of observations led
to a proposed mechanism (Scheme 20). Due to the necessary presence of a directing group
and the favourable effects of a 1-substituent, it was believed that the reaction involved a
five-membered metallacycle 42 resulting from C–H activation (vide infra, Section 3.1) and
that this then undergoes reductive elimination to give the Z-olefin.
Scheme 20 Proposed mechanism of direct C–H activation
33
Charette et al. have demonstrated the iron catalysed direct arylation of unactivated arenes
with aryl iodides, without the need for stoichiometric amounts of organometallic reagent or
a directing group (Scheme 21).42
It had previously been reported that reactions catalysed by iron may be positively affected
by trace amounts of other metals, particularly copper.43
The use of catalytic amounts of
copper as a co-catalyst were tested however it was found that the reaction was actually
adversely affected.
Various derivatives of 43 with a range of functionality underwent this reaction. However,
the use of aryl bromides gave much lower yields. Different arenes besides 44 were also
applied to afford the corresponding biaryl products in moderate to good yields; however
these arenes were used as the reaction solvent and thus were present in large excess. This
chemistry is also only applicable to symmetrical arenes due to poor regioselectivity.
Scheme 21 Fe-catalysed direct arylation of aryl iodides
The kinetic isotope effect (KIE) was determined to be 1.04, indicating that the C–H bond
breaking event was not rate determining. The reaction was also completely inhibited by the
addition of radical scavengers, such as TEMPO. Therefore, a radical-based pathway was
proposed (Scheme 22).
Scheme 22 Proposed mechanism for the iron-catalysed direct arylation of aryl iodides
34
Activation of the aryl-halogen bond occurs via single electron oxidation of the metal
centre, forming the initiating radical species and an oxidised metallo intermediate II.
Radical addition onto an arene gives radical species III and proximal abstraction of a
halogen from II forms the biaryl product and an equivalent of HI, as well as regenerating
the active form of the catalyst.
As is the case in metal-catalysed living radical polymerisation, the extremely high
efficiency and selectivity of the reaction relies on creating a dynamic equilibrium between
a low concentration of growing radicals and a large amount of dormant species, which
cannot propagate and/or self-terminate. This leads to side reactions being limited and the
efficient process of direct coupling.42
Initially it was believed that the t-BuOK base was simply required to quench HI to keep the
required pH of the system. However Shi later proposed a more prominent role in which it
interacts with benzene and promotes reactivity through π-π and ion-π stacking with the
phenanthroline ligand (Fig. 1).44
Figure 1 Activation of arene through interaction with t-BuOK and ligand
The same reaction was later carried out using a preformed Fe/phen catalyst system and
various aryl iodides and bromides. This procedure did not require inert atmospheres or
anhydrous solvents for successful reaction.45
It was also reported by Yu et al. that a Suzuki-Miyaura-type coupling between arylboronic
acids and benzene could be carried out using stoichiometric Fe2(SO4)3.46
Hayashi and
Shirakawa later reported a catalytic variant of this reaction using Fe(OTf)3, a substituted
bathophenanthroline ligand 47 and DTBP as oxidant (Scheme 23).47
Scheme 23 Iron-catalysed Suzuki-Miyaura-type C–H coupling
35
As was reported previously, substitution on the benzene aryl partner led to mixtures of
regioisomeric products. A mechanism consisting of a radical pathway was proposed
(Scheme 24). Interaction of the Lewis acidic Fe(OTf)3 with DTBP leads to C–O bond
cleavage and formation of a peroxoiron(III) species II, which undergoes homolysis to give
Fe(IV)-OH III and a t-BuO• radical IV. IV then oxidises the arylboronic acid to give an
aryl radical V (this was confirmed in a separate experiment), which then undergoes radical
substitution at the arene to give VI. Finally the Fe(IV) species III oxidises the resultant
radical to give the coupled product and regenerate Fe(III).
Scheme 24 Proposed catalytic cycle for Suzuki-Miyaura-type C–H coupling
1.3.2 Activation of sp3 C–H bonds
Recently the Cu-catalysed direct alkenylation of activated pyridines and quinolines has
been demonstrated as an efficient approach to alkenylated azaarenes; important structures
in many pharmaceutically active compounds. However, this process requires the use of
alkenyl iodides and ‘nitrogen-activating’ groups to proceed.48
Building upon the idea of forgoing the need for an activating group, Huang and co-workers
developed a novel iron-catalysed direct alkenylation of 2-substituted azaarenes 49 with
easily accessible N-sulfonyl aldimines 50 (Scheme 25).49
Notably the use of Cu catalysts in
this reaction resulted in relatively low yields.
36
Scheme 25 Fe-catalysed alkenylation of 2-substituted azaarenes
The reaction was not significantly influenced by functionality on the aromatic ring of 50
and also tolerated heterocycles and alkenyl groups being present. Replacement of the tosyl
group with a nosyl was also successful, yet Boc and Cbz protected aldimines gave very
low yields. A range of quinolines and quinoxalines was also successfully reacted, as well
as various 2-substituted pyridines, however these required the use of t-BuOK as a co-
catalyst.
The presence of radical scavengers did not affect the reaction, suggesting that a free radical
process was not occurring. A large KIE of 7.6 also indicated that C–H cleavage was rate
determining and, combined with the formation of solely E-alkene, it was proposed that a
concerted E2-elimination step was involved (Scheme 26). Formation of amine products via
either benzylic C–H activation or Lewis acid-catalysed deprotonation and subsequent
Mannich addition of the formed metal enamide was previously reported by this group.50,51
Performing the iron-catalysed reaction at lower temperatures resulted in formation of the
same amine products, suggesting that the reaction may proceed through intermediate 52.
The alkenylated product was also obtained by preparing the amine resulting from the
nucleophilic addition step and subjecting it to the reaction conditions, supporting its role as
an intermediate in the reaction.49
Scheme 26 Proposed intermediate in the direct-alkenylation reaction
Despite there being many examples of C–O bond formation via C–H activation, metal-
mediated C–N bond formation from C–H activation seems more difficult and was only
reported relatively recently. Many of these processes use nitrene derivatives as the primary
nitrogen source and PhI=NTs and its analogues have been widely used. However, such
37
hypervalent iodine reagents are not commercially available, can be unstable and produce
ArI as byproducts; leading to a number of practical limitations in their use. Thus the use of
amines and amides as nitrogen sources is an attractive prospect.
In 2008, Fu et al. reported an efficient, inexpensive and air-stable FeCl2/NBS
catalyst/oxidant system for the amidation of benzylic sp3 C–H bonds using carboxamides
and sulfonamides 54 (Scheme 27).52
There was no significant difference in the reactivity of
carboxamides and sulfonamides and various substitutions on the aryl ring were tolerated
and products 55 were obtained in moderate to good yields. The activity of 53 decreased in
the order: diphenylmethane > ethylbenzene > 4-bromoethylbenzene. The latter reagents
sometimes required further heating to 80 ⁰C to successfully react.
Scheme 27 Fe-catalysed amidation of C–H bonds
The presence of NBS and FeCl2 were integral to the reaction, which was unsuccessful if
either or both were not present. NBS acts as both an efficient oxidant and the free radical
initiator in the proposed mechanism (Scheme 28). It was proposed that NBS reacts with 54
to form N-bromocarboxamide/N-bromosulfonamide 56 to initiate the reaction. Pre-
preparing these species and adding the benzylic reagent and FeCl2 successfully provided
the amidation product, supporting their presence as intermediates. 56 then reacts with the
iron salt via ligand exchange, which leads to formation of an iron-nitrene complex III.53
This then undergoes the key C–H activation step with the benzylic substrate via transition
structure IV. Removal of the iron salt then provides the desired product 55 and restarts the
cycle.52
38
Scheme 28 Proposed mechanism for Fe-catalysed amidation of benzylic sp3 C–H bonds
1.4 Cross Dehydrogenative Coupling
In addition to the C–H activation reactions discussed in the previous section, the direct
coupling of two C–H bonds is the most efficient, environmentally benign and atom
economic method of constructing C–C bonds. Clearly this avoids the use of organohalides
or organometallic reagents and formally produces an equivalent of H2, reducing the waste
of the reaction. Early work carried out in this area, named cross-dehydrogenative coupling
(CDC), investigated the use of first row transition metals and copper salts were popular.
Later, iron-catalysed CDC reactions were reported and much research has been carried out
since.1
1.4.1 CDC of two sp3 C–H bonds
Li and co-workers have made significant contributions to this field and reported the first
iron-catalysed benzylic C–H bond activation in CDC with 1,3-dicarbonyl compounds, such
as 58 (Scheme 29).54
Scheme 29 Iron-catalysed CDC of benzylic C–H and 1,3-diketones
The main difficulty in this reaction was avoiding homocoupling of the starting materials.
FeCl2 was found to be the most effective catalyst, outperforming the previously used Cu
39
and Co. It was also found that the use of di-t-butylperoxide (DTBP) was better than t-
butylhydroperoxide (TBHP) as an oxidant and that the reaction proceeded efficiently for a
wider range of substrates at increased temperatures.
A range of different benzylic compounds besides 57, both cyclic and acyclic, and various
1,3-dicarbonyl compounds, including diketones, β-ketoesters and ketoamides, were
successfully coupled.
A radical pathway was proposed for the reaction (Scheme 30). DTBP initially oxidises
Fe(II) species I, producing Fe(III) species II and a t-butoxyl radical III. III can abstract the
benzylic H atom to form radical IV, while Fe(III) reacts with the 1,3-dicarbonyl to form an
iron(III) enolate V. The desired C–C coupled product is obtained following attack by the
electrophilic radical IV.
Scheme 30 Tentative mechanism for iron-catalysed CDC
Using the same approach, Li and co-workers have also shown that various cyclic alkanes
can be oxidised to react with 1,3-dicarbonyl compounds (Scheme 31).55
For these
examples high temperatures and an inert nitrogen atmosphere were required. The
tetrahydrate of FeCl2 also proved an equally useful catalyst. The alkylation of different ring
sizes and more complex structures, such as norbornane and adamantane, were also
reported, while the use of n-hexane led to two regioisomeric products due to reaction at the
C-2 and C-3 positions.
40
Scheme 31 Iron-catalysed CDC of cyclic alkanes and 1,3-dicarbonyl compounds
Li et al. have also reported a similar reaction using predominantly ethers 62 and 1,3-
dicarbonyl compounds 63 as the carbon nucleophile (Scheme 32).56
It was found that
various iron salts were efficient in this process, including FeCl2, FeBr2, Fe(OAc)2 and
Fe2(CO)9, and that DTBP was the best oxidant.
Using these conditions, a variety of cyclic and acyclic ethers were successfully reacted
with 63. It was also found that sulfide and amine substrates were suitable coupling
partners.
Scheme 32 Iron-catalysed CDC α- to heteroatoms
The C–H bonds α- to the heteroatoms can be readily abstracted via single electron transfer
pathways to yield the corresponding iminium, thionium or oxonium ions 64. These
intermediates can then further react with a nucleophile to form the C–C bond.1
1.4.2 CDC between sp2 and sp3 C–H bonds
Shi et al. have reported an iron-catalysed cross-dehydrogenative arylation (CDA) of a
benzylic C–H bond (Scheme 33).57
It was found that DDQ was the most efficient oxidant
for this reaction and its use more advantageous than peroxides for safety reasons. The use
of DCE as a cosolvent also greatly reduced the amount of diarylmethane required to obtain
good yields.
A large number of electron rich arenes 66 and diarylmethanes 67 were coupled in this
manner in good to excellent yields, with more electron rich arenes leading to double CDA.
Excellent regioselectivity was observed; controlled by the electronic properties of the
arenes (primarily an OMe or SMe group, demonstrated by formation of 68a and 68b
respectively).
41
Scheme 33 Iron-catalysed CDA of benzylic C–H bonds
A similar mechanism as previously proposed was invoked to explain this reaction (Scheme
34). The reaction is initiated by the iron-catalysed SET oxidation, forming the benzyl
radical III which can be further oxidised to the benzyl cation IV by Fe(III). This can then
be intercepted by the arene 66 in a Friedel-Crafts-type process to give V and subsequent
abstraction of hydrogen by the reduced hydroquinone VI yields the product and reforms
the catalyst.57
Scheme 34 Proposed mechanism for the CDA reaction
Subsequently, Shi attempted to develop a Heck-type reaction using diarylmethanes.
However this had an extremely limited scope, only tolerating unsubstituted styrene. Vinyl
acetates, such as 69, on the other hand, yield phenylketone products 70 in good to excellent
yields (Scheme 35).58
This reaction tolerated both electron-rich and electron-deficient
substitution patterns on 57 (also giving a moderate yield for simple toluene) and various
vinyl acetates.
42
Scheme 35 Iron-catalysed direct functionalisation of benzylic C–H bonds
1.4.3 CDC in Domino Processes
As demonstrated, iron is able to catalyse a number of different reactions and promote a
variety of processes. It has been shown that some of these roles can be combined in
domino processes.
Recently Hayashi et al. reported an iron-catalysed oxidative coupling of alkylamides 71
with arenes 72 (Scheme 36).59
The reaction involves two steps; oxidation of 71 to form 73,
followed by Friedel-Crafts alkylation. The combination of these two processes is not easy
as one catalyst must sequentially promote two mechanistically distinct reactions. It was
believed that this could be accomplished by iron as it is known to catalyse oxidation of sp3
C–H bonds and have strong Lewis acidity to promote SEAr.
This reaction had previously been reported using Zr(OTf)4 with O2 oxidant however the
scope was limited to γ-lactams and electron-rich heteroarenes. This was believed to be due
to the low catalytic activity of the zirconium complex towards oxidation.60
Scheme 36 Iron-catalysed oxidative coupling of alkylamides with arenes
During the investigation of this reaction, multiple metal salts, including Fe, Cu and Rh,
were tested for their ability to promote the individual reaction steps. It was found that only
iron (specifically FeCl3) showed high catalytic activity for both steps. Following this,
optimal conditions for the tandem procedure were successfully developed and a range of
electron-rich and electron-poor arenes 72 were reacted with different alkylamides 71 in
good to excellent yield. It was necessary to add a small amount of Fe(OTf)3 (3 mol%) to
the reactions of arenes with low nucleophilicities. Fe(OTf)3 is a better Lewis acid than
FeCl3 and so is more efficient in the SEAr step.59
43
Similar to the reaction by Huang reported earlier, Xu et al. reported the iron-catalysed
generation of 2-vinyl azaarenes 77 (Scheme 37).61
The reaction tolerated a range of
different heteroarene starting materials. It proceeded with both electron-donating and
electron-withdrawing aromatic rings at the C-3 position and the use of ortho-substituted
rings did not give any noticeable steric effects. However derivatives of 75 without any
substituents at the C-3 position failed to give the desired product.
Scheme 37 Vinylaromatic generation via iron-catalysed sp3 C–H functionalisation
This reaction employs a single electron transfer (SET) oxidation of amide 76 by Fe(III) to
give radical cation II, from which abstraction of an α-H leads to formation of iminium
species III. This then reacts with in situ generated enamine IV to provide V. Elimination
from this species ultimately yields the products 77 (Scheme 38).
Scheme 38 Proposed mechanism for generation of vinylaromatics
44
1.5 Summary
As mentioned previously, the many potential benefits iron possesses over classically used
metals for CH cross-coupling have resulted in an explosion of interest in this field in recent
years; as such the examples discussed here only scratch the surface of the iron literature.
Nevertheless they serve to show the range of transformations iron is capable of assisting in
and the real possibility of these systems replacing the use of precious metals in the future.
Despite the huge strides taken in this field, there remain a number of challenges that must
be overcome before Fe becomes a true successor to metals such as Pd. Most notable is the
lack of understanding in many catalytic cycles, with a range of different cycles often being
proposed. Elucidating the exact species present in these systems will aid in overcoming
limitations that may currently be present and allow the true potential of iron to be
unlocked.
45
2. Iron-mediated Coupling of Arylsulfides with Silanes
2.1 Introduction to Pummerer and Pummerer-Type Reactions
The Pummerer rearrangement was first discovered in 1909 and, since then, has received
attention in a variety of studies, including mechanistic and synthetic investigations. A large
amount of Pummerer-type reactions have been reported since its inception and this area
has been reviewed extensively.62
This section will introduce the classical Pummerer
rearrangement and briefly focus on the aromatic Pummerer-type reaction.
2.1.1 Classical Pummerer Rearrangement
The classical Pummerer rearrangement uses an aryl sulfoxide 78 as the substrate (Scheme
39). O-acetylation occurs upon addition of acetic anhydride to give 79; this serves to
activate the sulfoxide and elimination of the acyloxy group from 79 can occur on
abstraction of the α-proton by the acetate counter ion. This forms a thionium ion 80, which
can be attacked by a nucleophile, as it is highly electrophilic, to give 81a. If no external
nucleophile is present, the acetate counter ion can attack 80 to give an α-acetoxysulfide
81b, which can then be hydrolysed to a thioacetal and, ultimately, the corresponding
aldehyde 82.
Scheme 39 Classical Pummerer Rearrangment
A number of different nucleophiles, such as arenes, alkenes and amines, can be used in this
reaction.
Alternative methods of activation have been developed, such as the use of trifluoroacetic
anhydride (TFAA) or trifluoromethanesulfonic anhydride. This changes the leaving group
in the elimination step and can make this step more facile. However, the activating agent
must be compatible with the nucleophile.
It has also been shown that addition of Lewis acids, silyl chlorides and silyl triflates can be
beneficial to systems that exhibit low reactivity. This could be through further activation of
the acyloxysulfonium salt 79 or extension of the thionium ion’s lifetime by sequestering
the acetate counter ion. Furthermore, it has been shown that direct sulfide oxidation to the
46
desired thionium ion 80 is possible using reagents such as N-chlorosuccinimide or various
hypervalent iodine reagents such as PhI(OTFA)2.62
2.1.2 Aromatic Pummerer-Type Reactions
A number of reactions have been reported in aromatic systems that are related to the
Pummerer reaction. An example of this would be the 1,4-addition to p-sulfinylphenols 83
to give dihydroxybenzofurans 86 developed by Kita et al. (Scheme 40).63
The mechanism
involves activation of the sulfoxide 83 with TFAA and expulsion of the O-leaving group
by donation of the hydroxyl lone pair into the aromatic system to form a thio-quinonium
ion 84. 1,4-Addition of a styrene to 84 is then followed by a spontaneous cyclisation,
quenching the benzylic cation 85 and forming the dihydroxybenzofuran product 86 as a
single regio- and stereoisomer.
Scheme 40 1,4 addition to p-sulfinylphenols to give dihydroxybenzofurans
This reaction proceeded quickly at low temperature to give the product in moderate to high
yields and trans-products were observed with a high selectivity for a wide range of
substrates.
Inspired by the work of Kita, Procter et al. have reported the nucleophilic ortho-allylation
of aryl and heteroaryl sulfoxides 87 by reaction with triflic anhydride and
allyltrimethylsilanes (Scheme 41).64
This reaction complements the ability of sulfoxides to
direct ortho-metalation, followed by quenching with electrophiles. It has been shown to
have a wide substrate scope, with neutral and electron-rich systems being successfully
allylated in moderate to excellent yield; however halogenated substrates gave lower yields.
Both alkyl-aryl and biaryl sulfoxides could be reacted and substituted allyl and crotyl
silanes could also be used as substrates.
47
Scheme 41 Nucleophilic ortho-allylation of aryl sulfoxides
The reaction is proposed to occur through an interrupted Pummerer reaction (Scheme 42).
In this mechanism the activated sulfoxide reacts with the nucleophile directly at sulfur. The
resulting sulfonium salt 89 is proposed to undergo an in situ thio-Claisen rearrangement to
deliver the allyl group to the ortho-position of the aromatic ring. A number of observations
support this proposal, such as solely the ortho-substituted products 88 being obtained and
double-allylic inversion being observed for unsymmetrical allyl silanes (such as crotyl
TMS). Double-allylic inversion also suggests that attack of the nucleophile directly on the
ring is not occurring, as this would involve only one inversion step. The sulfonium ion 89
was also isolated and characterised by 1H NMR spectroscopy and the postulated
carbocation intermediate was intercepted using a sulfoxide with a heteroatom in the
ortho-position.64
Scheme 42 Mechanism of ortho-allylation of aryl sulfoxides
Further work by the Procter group has extended this reaction to use on heteroaryl
sulfoxides such as pyrroles and pyrazoles.65
This reaction can also be carried out using
propargyl silanes, to yield the corresponding ortho-propargyl arylsulfides via a similar
interrupted-Pummerer/thio-Claisen rearrangement.66,67
48
2.2 Results and Discussion
2.2.1 Proposed Project
As discussed in the preceding section, previous work within the Procter group has involved
the cross-coupling of organosilane nucleophiles with aromatic and heteroaromatic rings
that proceeds via an interrupted Pummerer reaction of aryl sulfoxides.64,67
This reaction
was efficient and had a wide substrate scope; however synthesis of the aryl sulfoxide
starting material usually required oxidation of the corresponding aryl sulfide, adding an
extra step to a target synthesis.
It was proposed that direct reaction of aryl sulfides 91 with nucleophiles and a SET oxidant
could produce similar products in a single step through an oxidative process described in
Scheme 43 with a phenyl sulfide and allyltrimethylsilane (allyl TMS).68
First, the sulfur
atom is oxidised to a radical cation III, which can then react with the allylsilane to produce
radical cation IV. Oxidation of IV and elimination of TMS will then give thionium ion V,
which can rearomatise to give the desired product 88. It was expected that this process
would give a mixture of ortho- and para-substituted products due to lack of selectivity in
the attack on the silane by radical cation III. It should be noted that another pathway may
be possible, involving oxidation of the nucleophile followed by reaction with the aryl
sulfide in a Friedel-Crafts-type mechanism.69
Scheme 43 Proposed oxidative process for nucleophilic cross-coupling with aryl sulfides
Previous work in other groups, such as Kamimura’s oxidative coupling of biaryl sulfide
91a (Scheme 44)68
and Li’s CDC reactions (Scheme 32),56
have used Fe sources as
oxidants for various sulfides. FeCl3 is also a commonly used reagent for oxidative biphenyl
49
couplings through oxidation of arenes to form similar intermediates to those shown in
Scheme 43.70
Hence it was thought that the use of iron(III) as the single electron oxidant
could achieve the desired products.
Scheme 44 Iron-catalysed oxidative coupling of biaryl sulfides
The products of this reaction could also be further functionalised using the organosulfanyl
group in a number of transformations, such as oxidation to sulfoxides and sulfones, which
can lead to sulfoxide-lithium exchange or nucleophilic aromatic substitution by
displacement of the sulfone.71
The Ni(II)-catalysed Kumada-Corriu cross-couplings of
organosulfanyl groups has also been carried out in previous investigations within the group
and would be a viable option for further functionalisation in this project (vide infra,
Section 4.6.1.1).72,73
2.2.2 Preliminary Reaction
Initial studies to investigate the feasibility of the proposed process used
(3,5-dimethoxy)(phenyl)sulfide 91b and allyl TMS (Scheme 45). These substrates were
chosen as it was thought that the use of an electron-rich aryl sulfide and the highly
nucleophilic allyl TMS would facilitate the oxidation step and addition to the radical cation
respectively.
Stoichiometric quantities of oxidant were initially used to determine whether the desired
reaction was possible. It was thought that once the reaction was better understood, an
investigation into the use of substoichiometric amounts could be carried out.
Pleasingly, the adopted reaction conditions gave the desired allylated product 88a in 8%
yield. Despite the hypothesised selectivity issues, only the ortho-allylated product was
isolated.
50
Scheme 45 Model reaction conditions
2.2.3 Synthesis of Biarylsulfide Starting Materials
Biaryl sulfides 91 can be easily synthesised via a number of methods. Previous methods
adopted in the Procter group include couplings of aryl bromides/iodides and thiophenols
catalysed by Pd(PPh3)4/CuI respectively (Scheme 46).74,75
A variety of sulfides can be
formed by altering the substitution on the arylhalide and thiophenol substrates.
Scheme 46 Pd- and Cu-catalysed formation of biaryl sulfides
2.2.4 Solvent Screen
A solvent screen was carried out to assess its effect on the yield of the desired product.
Commonly used solvents for FeCl3-mediated oxidative couplings were investigated (Table
1).70,3,4
Interestingly, changing the reaction solvent dramatically affected the amount of
products observed and, in some cases, led to the observation of both the para- and bis-
allylated products (96 and 97 respectively) in addition to 88a.
Aromatic solvents, such as toluene and benzene, did not improve the yield over MeCN and
the use of solvents such as THF and DMSO resulted in no reactivity (Entries 2-6). This is
likely due to coordination to the metal centre inhibiting the desired reactivity.
It appeared that chlorinated solvents, such as CH2Cl2 (Entry 7) and CHCl3 (Entry 8),
improved the observed yield, giving a combined yield of 30% and 22% respectively. As
expected statistically, 88a and 96 were usually obtained in an approximately 2:1 ratio.
The formation of the desired products was more favourable in nitromethane (Entry 9) and a
combined yield of 49% was obtained, but a large amount of bis-allylated product 97 was
also obtained in this solvent. Perhaps unsurprisingly, this suggested that 88a could further
51
react and may prove problematic during optimisation of the reaction. This issue of over-
reaction is commonly reported in the alkylation of arenes using directing groups.76
Interestingly very little of 96 was observed in this solvent, possibly indicating that the SPh
group directed the reaction to favour attack at the ortho-position. It could also indicate a
different mechanism is operating compared to that followed in CH2Cl2, leading to different
product ratios.77
Table 1 Solvent screen using FeCl3 oxidant
Entry Solvent 91b (%)a
88a (%)a
96 (%)a
97 (%)a
1 MeCN 68 8 - -
2 Toluene 73 7 3 -
3 Benzene 59 10 4 -
4 THF 92 - - -
5 DMSO 95 - - -
6 1,4-dioxane 93 - - -
7 CH2Cl2 65 20 8 2
8 CHCl3 48 15 6 1
9 MeNO2 30 35 3 11
a Determined by
1H NMR spectroscopy using MeNO2 standard (see Section 5.1)
It was decided that further experiments would be carried out in MeNO2, in the hope that
the amount of over-oxidation leading to 97 could be reduced. If this proved difficult, then
CH2Cl2 appeared a viable alternative, as a smaller amount of 97 was obtained in this
reaction. Interestingly, it was found that by submitting the crude reaction mixture obtained
in CH2Cl2 to the standard reaction conditions, 88a and 96 could be obtained in 45% and
25% respectively, with <5% 97 observed. These results rival those obtained using MeNO2,
however the lack of ortho-/para-selectivity made this option less attractive.
2.2.5 Oxidant Screen
An oxidant screen was carried out to determine whether alternative oxidants could yield
the desired products in a more efficient manner (Table 2).
52
Table 2 Oxidant screen carried out in MeNO2
Entry Oxidant 91b (%)a
88a (%)a
96 (%)a
97 (%)a
1 FeCl3 30 35 3 11
2 FeCl3b
26 39 3 13
3 FeBr3 45 23 2 5
4 Fe(acac)3 90 - - -
5 Cu(OAc)2 90 - - -
6 CuCl2 86 - - -
7 Cu(OTf)2 67 11 - -
8 MnO2 85 - - -
9 Mn(OAc)3
87 - - -
10 Mn(OAc)3c
89 - - -
a Determined by
1H NMR spectroscopy using MeNO2 standard
b >99.9% Fe
cAcOH solvent
FeCl3 was the best oxidant out of those tested in terms of overall yield of products (Entry
1). The reaction gave similar results when using a >99.9% Fe source, suggesting that the
observed reaction was not due to trace metal impurities (Entry 2).43
However, despite
giving a lower yield of 88a, FeBr3 also yielded a comparatively smaller amount of 97 and
thus had a better ratio of mono-:di-allylated products (Entry 3). If the overall reaction
could be improved upon then this could be a potential oxidant to attempt to decrease over-
oxidation. Other iron(III) salts (Fe(acac)3) proved unsuccessful in this oxidant screen,
merely returning starting material 91b (Entry 4).
Cu(II) and Mn(III) salts may also be used as single electron oxidants and so were also
tested in this screen to determine whether they could carry out the same chemistry. Neither
Cu(OAc)2 nor CuCl2 yielded any of the desired product (Entries 5 and 6), however a small
amount of 88a was observed using Cu(OTf)2 (Entry 7).78
Interestingly 96 and 97 were not
observed in this reaction. No reaction was observed upon use of either MnO2 or Mn(OAc)3
(Entries 8 and 9).79,80
53
2.2.6 Changing The Addition Rate of Allyl Silane
Following investigation into the solvent and oxidant, the reaction still suffered from a high
percentage of unreacted starting material being recovered. It was postulated that this could
be due to FeCl3 reacting competitively with allyl TMS and producing a polymeric by-
product instead of the desired product.81
In an attempt to combat this, slow addition of allyl
TMS to a mixture of 91b and FeCl3 was investigated (Table 3).
Table 3 Slow addition of allyl TMS to mixture of 91b and FeCl3
Entry Addition
Time (min.)
91b (%)a
88a (%)a
96 (%)a
97 (%)a
1 30 13 5 - 2
2 10 19 15 1 6
3b 10 18 20 2 3
4c 10 7 6 1 1
a Determined by
1H NMR spectroscopy using MeNO2 standard
b −25 ⁰C
c CH2Cl2 solvent
Adoption of a slow addition protocol of allyl TMS indeed reduced the amount of recovered
starting material; however this also resulted in a decrease in reaction efficiency (Entry 1).
Surprisingly no other noticeable peaks were observed in the 1H NMR spectrum to account
for this missing mass. It was thought that this could be due to FeCl3 quickly reacting with
91b before allyl TMS is available for reaction. This could lead to a side reaction that
results in material being lost in some way, possibly by formation of a polymer, degradation
of the radical intermediate/starting material or the formation of highly polar by-products
that were lost during workup.
The addition time of allyl TMS was reduced to 10 minutes to try to reduce these side
reactions (Entry 2). This seemed to be relatively successful and increased amounts of 88a
and 96 were observed following the reaction. Lowering the temperature to −25 ⁰C gave a
slightly greater amount of 88a (Entry 3), however the mass balance still remained low
(57% of starting material was unaccounted for). Therefore, it was decided that the original
54
addition procedure would be retained as it provided better mass balances (80% starting
material accounted for).
2.2.7 Changing Reagent Stoichiometry
The next set of experiments investigated the effect of changing the amounts of allyl TMS
and FeCl3 present in the reaction (Table 4). Decreasing the equivalents of allyl TMS with
respect to 91b from 10 to 5 led to a slightly lower yield (Entry 2). However the mass
balance also decreased from 79% to 64%, possibly due to the lower amount of allyl TMS
making decomposition pathways of the starting material more likely.
Although 5 equivalents gave similar yields, the use of 1 equivalent of allyl TMS only gave
a trace of 88a and poor mass balance (Entry 3). The yield could be increased slightly by
running the reaction at −25 ⁰C; however the most notable effect of this reduced
temperature was to increase the mass balance (Entry 4). This suggests that the deleterious
reactions responsible for a low mass balance are reduced at low temperature. Reducing the
amount of FeCl3 present also gave a correspondingly lower yield (Entry 5) and,
importantly, the absence of FeCl3 led to no observable product formation (Entry 6).
Table 4 Changing the stoichiometry of the reaction
Entry x
(eq.)
y
(eq.)
91b
(%)a
88a
(%)a
96
(%)a
97
(%)a
1 2.2 10 31 41 2 13
2 2.2 5 24 29 2 9
3 2.2 1 30 1 - -
4b 2.2 1 59 6 trace -
5 1 10 71 13 trace 4
6 - 10 98 - - -
a Determined by
1H NMR spectroscopy using MeNO2 standard
b −25 ⁰C
55
2.2.8 Other Biaryl Sulfides
Next, it was decided to use other biaryl sulfides in the currently optimal conditions to
determine the effect of this reaction partner. The use of a mono-substituted sulfide,
(4-methoxyphenyl)(phenyl)sulfide 91c, gave only a trace of allylation product 88b, but
predominantly returned starting material (Scheme 47). This could be due to the fact that
sulfur is less electron rich and thus less easily oxidised, favouring the side reaction of
FeCl3 with allyl TMS instead.
Scheme 47 Reaction of 91c under standard conditions
Scheme 48 Reaction of 91a under standard reaction conditions
It was thought that Kamimura’s unsymmetrical biaryl sulfide 91a would successfully give
allylated product since the required radical cation was suggested to be responsible for the
biaryl coupling observed in Scheme 44. Surprisingly, no allylated product was seen;
instead the reaction gave the same symmetrical dimer 92 that Kamimura obtained (Scheme
48).68
It is not known why this homocoupling is more favourable than the desired reaction
with allyl TMS. Kamimura suggested that reaction occurs exclusively at the para-position
(with respect to sulfur) due to steric effects; however previous results have shown that the
ortho-position is more favoured in the allylation reaction. Therefore, it is possible that the
desired o-allylation pathway is disfavoured due to these steric effects and this allows for
the biaryl coupling to occur. A similar dimer is not observed in the reaction of 91b, which
could be due to the fact that the arene is more hindered and any dimer would experience
severe steric clashes (Fig. 2).
56
Figure 2 Steric clash resulting from biaryl formation
2.2.9 Reaction with an unfunctionalised alkene
It was reasoned that the problems with conversion may be due to side reactions associated
with the reactivity of allyl TMS and FeCl3.81
The prevalence of over-oxidation using
MeNO2 was likely also due to the reactivity of allyl TMS under these conditions. Thus, the
use of less reactive alkene coupling partners was investigated. Surprisingly, reaction with
1-octene 98 (a simple, unfunctionalised alkene) cleanly gave 99a, which was chlorinated β
to the aryl ring (Scheme 49). Overall this can be viewed as a formal ‘chloroarylation’
across the double bond. Notably the mass balance of the reaction was again quite poor;
however only the linear product was observed, with no corresponding branched products
being formed.
Due to the potential interest of this reaction, work on the allylation was put aside and focus
was turned towards investigating the chloroarylation process. A literature search was
carried out to determine the novelty and standing of this reaction and will be discussed in
the following section.
Scheme 49 FeCl3-mediated chloroarylation of 1-octene
57
3. Metal-catalysed Reactions of Arenes and Alkenes
3.1 Oxidative Coupling of Arenes and Alkenes
As has been stated earlier, the desire for more green and sustainable chemistry has led to
increased interest in the direct reaction of two C–H bonds, without the need for pre-
functionalisation. This would lead to lower costs, due to fewer steps being required, and
less waste being produced compared to more standard metal-catalysed coupling
reactions.82
However this endeavour poses a number of issues when compared to
traditional cross-coupling; most notable are the need for a stoichiometric amount of
sacrificial oxidant and the difficulty of regioselective functionalisation of ubiquitous C–H
bonds.83
Olefins find many uses across organic synthesis and are present in a number of target
molecules. The idea of forming these motifs through an oxidative Heck-type process is an
attractive concept. Pioneering work in this area was carried out by Fujiwara and Moritani,
who in 1967 reported the coupling of arenes and olefins.84
The reaction required the use of
stoichiometric PdII-styrene complexes and a large excess of arene (which was used as the
solvent). AcOH co-solvent was also deemed vital for reactivity.85
Following further work, Pd(OAc)2 was found to be most effective for carrying out this
transformation and a range of simple arenes, such as toluene and anisole, could be coupled
to mono-, di- and tri-phenyl styrenes. Most interestingly, the authors found that the
reaction could be performed using catalytic amounts of Pd by using Cu(OAc)2 or AgOAc
and O2/air as stoichiometric oxidants (Scheme 50).86
Scheme 50 Catalytic Fujiwara-Moritani reaction
A mechanistic pathway was also proposed (Scheme 51). The cycle begins with
electrophilic metalation by Pd(II) complex I to give an aryl-Pd(II) species II, followed by
co-ordination and carbometalation of the alkene resulting in alkyl palladium IV.
Subsequent β-H elimination gives the coupled product and Pd(0) species V, which then
reacts with the stoichiometric oxidant to return Pd(II). This remains the currently accepted
mechanism for this reaction, which was later named the Fujiwara-Moritani reaction.87
58
Scheme 51 Mechanism for Fujiwara-Moritani reaction
While the Fujiwara-Moritani reaction was a seminal contribution to this field, it possessed
many limitations compared to the general Heck reaction (which was reported around the
same time). These include lower yields and the inability to control regioselective
functionalisation of the arene C–H bonds; product distribution was dependent upon the
electronics of the aromatic ring, with electron-donating substituents affording ortho- and
para-reactivity and electron-withdrawing substituents giving the meta-products.86
The identification of groups that can coordinate to the metal catalyst and direct reaction,
ostensibly to the ortho-position, dramatically increased the efficiency of this reaction and
led to a renewed interest in the field.88
Various directing groups have been reported and
some recent examples of directed oxidative-Heck reactions will be discussed herein.
3.1.1 Examples of Directing Groups
Stemming from earlier reports, Pd has been the most widely used metal in directed C–H
alkenylation reactions.89
In 2010 Yu and co-workers developed the reaction of
synthetically useful phenylacetic acids, such as 102, and acrylates using catalytic Pd(OAc)2
and benzoquinone (BQ), with O2 as the terminal oxidant (Scheme 52). The selectivity is
believed to arise from a weak interaction between the metal centre and the carbonyl of the
carboxylic acid.90
Scheme 52 Pd-catalysed ortho-alkenylation of phenylacetic acids
59
This reaction was tolerant of a range of functional groups on the aromatic ring, with
substrates containing fluoride, chloride, ketone and methoxy groups all proceeding in good
to excellent yields. Functionalisation of some drug molecules, such as ibuprofen and
naproxen, was also possible, demonstrating the utility of this reaction in late stage
manipulation of pharmaceutically relevant compounds. Substitution α to the carboxylic
acid moiety was also tolerated and higher substitution at this position led to increased
efficiency.
Remarkably, through extensive screening of ligands, it was found that the use of
N-protected amino acids allowed for increased reactivity in difficult substrates (Scheme
53a) and also control of regioselectivity between two ortho-positions on the ring (Scheme
53b).90
It was found that this olefination reaction could be carried out with as little as 0.2
mol% catalyst loading.91
Scheme 53 Use of amino acid ligands for increased A. reactivity and B. regioselectivity
It was also reported that use of these amino acid ligands allowed the formation of
dialkenylation products 109 in excellent yields. By carrying out sequential olefination
reactions, first without and then with amino acid ligand, it was also possible to form bis-
alkenyl products with different alkene substituents (Scheme 54).92
The reaction was
subsequently extended to allow for olefination of phenylethyl alcohols93
and ethers.94
60
Scheme 54 Sequential olefination with different alkene partners
In addition to Pd, efforts towards the use of Ru complexes for directed cross-
dehydrogenative alkenylations of arenes have recently been realised. The groups of
Ackermann and Jeganmohan have been particularly prevalent in this area and have
reported a range of directing groups, such as aldehydes,95
ketones,96
anilides and
benzamides.97
In 2012 both groups reported the use of weakly co-ordinating aryl esters as
directing groups for alkenylation with electron-deficient alkenes (Scheme 55).98,99
Scheme 55 Ester-directed alkenylation of arenes by A. Ackermann and B. Jeganmohan
Similar conditions were adopted by both groups, with the use of [RuCl2(p-cymene)]2 and
co-catalytic amounts of AgSbF6. The silver salt reacts to give a cationic complex, [Ru(p-
cymene)(OAc)][SbF6], which leads to a more facile C–H metalation step. Jeganmohan was
able to use catalytic amounts of a Cu salt with O2 as terminal oxidant; however
stoichiometric amounts of Cu were used by Ackermann. Despite slight differences, similar
yields and substrate scope were reported; the reaction generally required electron-rich
aromatics for efficient alkenylation and the use of electron-withdrawing groups, such as
nitro and trifluoromethyl, were incompatible with this system.98
61
Mechanistic studies suggest that the cycle involves a reversible, acetate-assisted
cycloruthenation by the cationic metal species to give a five-membered ruthenacycle II.
Migratory insertion then provides a seven-membered metallacycle III which undergoes
β-H elimination to yield the alkenylated product and, following oxidation by the Cu salt,
the starting metal species I (Scheme 56).99
Scheme 56 Proposed catalytic cycle for Ru-catalysed oxidative alkenylation
3.1.2 Sulfur Directing Groups in Oxidative Alkenylations
Despite a plethora of directing groups having been developed containing N or O atoms, the
use of sulfur to direct oxidative alkenylations is quite rare and has only recently been
established, with only a handful of examples demonstrated. Sulfur is known to bind
strongly to many transition metals and has classically been viewed as a poison in many
reactions by halting reactivity. However sulfur is an important motif in many natural and
industrially useful compounds and its use as a directing group would be beneficial for
product manipulation as it can be easily removed or used in further transformations.100,101
In 2012, Zhang and co-workers reported the first Pd-catalysed selective oxidative Heck
reaction of arenes and acrylates using a thioether directing group.100
A number of S-
containing groups were investigated (Scheme 57).
62
Scheme 57 Screen of S-containing directing groups
It was found that benzyl thioethers were the most efficient directing groups.
Benzyl(phenyl)sulfide 113d exhibited good reactivity, however a large amount of
dialkenylation product was observed (shown in parentheses); replacing this with
benzyl(methyl)sulfide 113e reduced the reactivity slightly but gave no diolefination. It was
established that the properties of the sulfur centre are integral to the reaction as the use of
sulfoxides 113a, sulfones 113b and thioesters 113c proved unsuccessful. Interestingly no
reaction was observed when sulfur was replaced by oxygen in 113f.
The alkenylation was shown to be tolerant of a range of functional groups; however
electron deficient arenes gave lower yields, which may suggest an electrophilic metalation
pathway (Scheme 58). The p-tolyl thioether group gave good yields of mono-olefinated
products for ortho- and meta-substituted arenes but, as was observed during screening, a
large amount of di-alkenylation was seen for para-substituted or unsubstituted rings. For
these examples the methyl thioether was the best directing group for mono-olefination,
obtaining the desired product in moderate yields.
Scheme 58 Pd-catalysed selective ortho-alkenylation with thioether directing groups
63
In the following year Shi et al. developed a variant of this reaction using a cationic Rh
complex.102
A screen of S-containing groups was also carried out for this reaction and
similar results as those observed previously by Zhang were reported. Interestingly it was
found that mono- and di-olefination could be controlled by carrying out the reaction in
either MeOH or t-BuOH (Scheme 59). This also led to a semi-one-pot dialkenylation
reaction with two different alkenes by performing a solvent swap following the first
coupling.
Scheme 59 Controlled Rh-catalysed olefination using thioether directing groups
Contrary to the Pd-catalysed reaction, electron-deficient arenes performed better in this
reaction. This suggested that the C–H activation may occur through a concerted metalation
deprotonation pathway rather than the electrophilic metalation process proposed for Pd.
Recently the same catalyst has been described by Satoh and Miura to carry out selective
olefination of 2-aryl-1,3-dithianes, such as 121, under mild conditions (Scheme 60).103
Scheme 60 Rh-catalysed selective alkenylation of 2-aryl-1,3-dithianes
The reaction mechanism is believed to occur similarly to that discussed earlier, in which
chelation of the dithiane moiety directs C–H bond cleavage at the ortho-position to form
five-membered rhodacycle II. Alkene insertion then occurs to give intermediate III, from
which β-H elimination provides the alkenylated product 122 and, following reoxidation,
the initial form of the catalyst I (Scheme 61).
64
Scheme 61 Proposed catalytic cycle for sulfur-directed oxidative C–H alkenylation
The products of this reaction can be easily converted to the corresponding aldehydes or
toluenes by using Dess-Martin periodinane or Raney Ni, respectively. This is beneficial as,
while the use of aldehydes as directing groups in this reaction is known, the scope is
limited to electron rich arenes.95
These research groups have also reported the use of
benzothioamides in a Rh-catalysed coupling with electron deficient alkenes and
styrenes.104
Sulfoxides have also been developed for use as directing groups in these reactions since the
original report by Zhang. Phenyl sulfoxides were shown to direct coupling with acrylates
to the ortho-position in combination with a Rh catalyst, however chelation was proposed to
occur through the O atom to provide a 5-membered rhodacycle following C–H
activation.105
Interestingly Zhang et al. have demonstrated that benzyl and phenylethyl sulfoxides 123
can promote selective olefination under Pd catalysis (Scheme 62).106
X-ray crystal
structures of the corresponding five- and six-membered palladacycles were obtained and
show that chelation occurs through sulfur. Impressively, phenylpropyl sulfoxides were also
found to be highly efficient remote directing groups. The binding mode of the sulfoxide in
this reaction is unknown.
65
Scheme 62 Use of sulfoxides as remote directing groups for arene C–H olefination
An interesting use of sulfoxides as both directing group and chiral auxiliary has also been
demonstrated by Colobert et al. for the atropodiastereoselective Pd-catalysed olefination of
biphenyls using enantiopure p-tolylsulfoxides.107
3.2 Hydroarylation of Alkenes
Another seminal piece of work in the field of C–H activation came in 1993 when Murai et
al. reported a directed activation of aryl C–H bonds and subsequent hydroarylation
catalysed by a low valent Ru complex (Scheme 63).108
Scheme 63 Ru-catalysed hydroarylation of olefins through direct C–H activation
This reaction was shown to be highly efficient, with excellent yields achieved in the
reported examples. However it proved limited to terminal, non-isomerisable alkenes and
issues with overalkylation were encountered in the absence of ortho-substituents. The
reaction mechanism involves chelation with the carbonyl as observed earlier with directed
alkenylations, however the C–H insertion pathway is believed to occur via oxidative
addition, resulting in a metal hydride species II being formed. Migratory insertion onto the
alkene then provides an alkyl metal IV which can undergo reductive elimination to form
the alkylated arene and the starting metal species I (Scheme 64). Notably no external
oxidant is required in this reaction.109
66
Scheme 64 Proposed mechanism for Ru-catalysed hydroarylation of olefins
Since the first reports of this reaction a number of investigations have been reported,
including other metals such as Re, Rh and Ir.110
While investigating the alkenylation of
fluoroarenes by Ni-catalysed hydroarylation of alkynes, Nakao and co-workers discovered
alkylation using vinyl naphthalene 129 and 1-phenyl-1,3-butadiene 131 was also possible
(Scheme 65).111
The reaction gave branched products 130 and 132 respectively, rather than
the linear ones shown earlier. It was postulated that the reaction required these alkenes as
the formation of benzylnickel and π-allyl intermediates, 133 and 134 respectively,
following insertion into the Ni-H bond may make this step more facile.
Scheme 65 Ni-catalysed hydroarylation of alkenes using electron-deficient arenes
More recently this reaction was further developed by Hartwig et al. and the Ni-catalysed,
linear-selective hydroarylation of olefins without directing groups was reported (Scheme
66).112
67
Scheme 66 Linear-selective hydroarylation of olefins with electron-deficient arenes
The procedure was limited to electron deficient arenes, such as 135, but a number of
olefins were successfully reacted. Due to the absence of a chelating group the reaction was
generally governed by sterics, with reaction at the least sterically hindered position being
most favourable, although mixtures of regioisomers were observed. In depth experimental
and computational studies suggested that the mechanism does not involve oxidative
addition to form a nickel hydride species but rather proton transfer from the σ-C–H bond of
the co-ordinated arene to the alkene (Scheme 67). This mechanism is similar to Ni-
catalysed hydroarylation of alkynes.113
This step is reversible and a lower barrier for the
subsequent rate determining reductive elimination gives rise to the observed high
selectivity for the linear products.
Scheme 67 Proposed mechanism for Ni-catalysed linear-selective hydroarylation
Interestingly the reaction could also be performed on internal alkenes and gave the same
products obtained from terminal olefins. Rather than a chain walking process involving
multiple proton transfers it is believed that the olefin isomerises through a mechanism
unrelated to the hydroarylation reaction. This isomerisation would lead to a range of
isomers being present from which Ni selectively co-ordinates to the terminal olefin. This
68
was supported by lack of D incorporation in the chain when deuterated arenes were reacted
with internal olefins. The exact details of this isomerisation mechanism were not disclosed.
3.3 Iron-mediated Functionalisation of Alkenes
Notably the previous section focused on hydroarylation of alkenes; however some
examples of iron-mediated difunctionalisations of olefins have recently been reported.
These occur via a radical pathway and the resultant radical species formed after the initial
addition can be quenched to form a range of compounds.
Scheme 68 Iron-mediated halo-nitration of alkenes
The iron-mediated radical chloro-nitration of alkenes, such as 137, was developed by
Taniguchi et al. using stoichiometric iron(III) nitrate nonahydrate and FeCl3 as chloride
source (Scheme 68).114
The heating of Fe(NO3)3.9H2O is known to produce NO2 gas (a
free radical). It was proposed that radical addition of NO2 onto the double bond gives a
radical intermediate 139 that can be trapped by the chlorine atom of FeCl3. It is notable
that this reaction gives linear addition of NO2 onto the alkene; this is expected of a radical
process due to the formation of the more stable secondary radical species.115
It was also
noted that the chlorinated product may arise from oxidation of the radical intermediate to a
carbocation, which is then quenched by Cl-.
Scheme 69 Iron(III)/NaBH4-mediated additions to unactivated alkenes
Interestingly, Boger et al. have reported reductive iron(III)/NaBH4-mediated additions to
unactivated alkenes, such as 140, with the use of several radical traps giving
anti-Markovnikov products (Scheme 69).116
A range of functionality could be introduced
by varying the trap used, for example TsCN gave the corresponding cyano product,
SELECTFLUOR® gave fluorine products and using O2 gave the alcohol in good yield.117
69
It is believed that this reaction occurs through an Fe(I)-H species which adds to the double
bond, resulting in the most stabilised radical which is then quenched.
A catalytic variant of this reaction was later utilised by Baran et al. to couple two olefins
by quenching the radical intermediate with an electron deficient alkene (Scheme 70).118,119
Scheme 70 Fe-catalysed reductive olefin coupling
The proposed reaction mechanism occurs via formation of Fe(III)-H species II from
PhSiH3 and the metal catalyst I. The more electron-rich alkene 142 can then abstract a
hydrogen atom from this species to give the more stable tertiary radical IV and Fe(II).
Notably this step may occur through hydrometalation of the olefin and subsequent
homolysis of the metal-carbon bond.120
The radical IV then undergoes conjugate addition
onto the electron deficient alkene 111 to give a second radical species V that is reduced by
the Fe(II) species III. The resultant carbanion VI then undergoes protonation to give the
observed products 143 (Scheme 71).
Scheme 71 Mechanism for reductive olefin coupling
70
3.4 Summary
Some examples of directed Fujiwara-Moritani reactions have been examined,
demonstrating the vast improvement this now well-established area has undergone since
those early reports. A large portion of this discipline is governed by Pd catalysis; however
the use of other metals, such as Rh and Ru, has increased in recent years. Despite the huge
array of reaction systems developed, the vast majority require the use of functionalised
alkenes, such as acrylates or styrenes. While some examples exist of simple, unactivated
olefins being used as coupling partners, these remain outliers in the field.121,122
Also, despite their synthetic utility, the use of sulfur-containing groups for oxidative Heck
reactions has been shown to be relatively underdeveloped. This was likely due to the belief
that they bind metal centres too strongly and suppress catalytic activity. However recent
reports of thioethers and sulfoxides partaking in successful couplings will hopefully lead to
this area being expanded in the future.
It has also been demonstrated that metals can carry out hydroarylation reactions by
performing C–H activation and addition into alkenes. Contrary to the oxidative
alkenylation reactions, a β-H elimination step is not involved in this mechanism, rather
reductive elimination occurs to give alkyl products.
The iron-mediated functionalisation of alkenes has also been developed. These occur
through a radical pathway and a range of different quenches can be utilised to give various
products. Notably many of these systems require stoichiometric amounts of metal;
however some examples of catalytic reductive systems have been reported.
71
4. Iron-mediated Chloroarylation of Alkenes
4.1 This Work
When compared with the transformations discussed in the preceding section, the current
Fe-mediated chloroarylation reaction poses some interest; it bears some similarity to both
the oxidative alkenylation (elimination of HCl would give the products of such a process)
and the hydroarylation (reductive elimination installing a chlorine rather than a hydrogen).
Notably this process makes use of a cheap metal, as opposed to the noble metals generally
required in the other procedures, the reaction works with 1-octene (a simple, unactivated
olefin) and it appears to be directed by the sulfur moiety. The complete regioselectivity
with respect to the olefin is also similar to the iron-mediated alkene functionalisations
shown, with complete selectivity for the linear product 99a.
The reaction appeared to represent a novel transformation and thus attempts to optimise it
were undertaken.
4.2 Optimisation Studies
4.2.1 Solvent Screen
As solvent effects appeared to have a large influence on the allylation reaction, a screen
was carried out for the reaction with 1-octene (Table 5). In contrast to the previously
investigated reaction, CH2Cl2 (Entry 2) proved a much better reaction solvent than MeNO2
(Entry 1). This could be due to a number of reasons, including solubility of the reagents
and solvent polarity. Interestingly, the reaction mixture was heterogeneous in the more
efficient CH2Cl2 system, while the use of MeNO2 led to a homogeneous system. The use of
a two-solvent system was consequently investigated to determine its effects (Entry 3).
Using a 1:1 mixture of CH2Cl2/MeNO2 gave a lower yield than just using CH2Cl2; however
the mass balance was slightly improved.
The higher boiling solvents 1,2-dichloroethane (DCE) and chlorobenzene gave comparable
results to CH2Cl2 (Entries 4 and 5). These solvents would allow higher temperatures to be
investigated during optimisation. As was observed in the previous allylation studies, the
use of more nucleophilic/coordinating solvents resulted in lower activity; MeCN showed
product formation in a low yield (Entry 6) and no reaction was observed using H2O, a
biphasic 1:1 CH2Cl2/H2O system, THF, toluene or dimethyl carbonate (Entries 7-11).
Intriguingly, running the reaction in a vast excess of 1-octene also led to a decrease in
72
product formation but high mass recovery, potentially suggesting 1-octene can inhibit the
reactivity of FeCl3 (Entry 12).
Table 5 Solvent screen for FeCl3-mediated reaction of 91b with 1-octene
Entry Solvent 91b (%)a
99a (%)a
1 MeNO2 40 14
2 CH2Cl2 9 36
3 CH2Cl2/MeNO2 29 31
4 DCE 10 34
5 C6H5Cl 9 34
6 MeCN 45 10
7 H2O 89 -
8 CH2Cl2/H2O 91 -
9 THF 89 -
10 Toluene 34 -
11 Dimethyl carbonate 94 -
12 98 (60 eq.) 52 15
a Determined by
1H NMR spectroscopy using MeNO2 standard
4.2.2 Oxidant Screen
An oxidant screen was carried out with a wide selection of available Fe(III) salts (Table 6).
This screen demonstrated that FeCl3 was the most effective oxidant tested (Entry 1) and
use of a >99.9% Fe sample made the reaction marginally better, suggesting that iron is
indeed responsible for the reaction, rather than the presence of an impurity (Entry 2).43
The
use of the hydrate of FeCl3 only gave a small amount of product (Entry 3). A similar,
brominated product 144 was observed using FeBr3, although it was isolated in lower yield
(Entry 4).
73
Table 6 Oxidant screen for Fe(III)-mediated reaction with octene
Entry Oxidant 91b (%)a
99 (%)a
1 FeCl3 9 36
2 FeCl3 (>99.9% Fe) 15 42
3 FeCl3.6H2O 87 4
4 FeBr3 36 22b
5 FeF3 95 -
6 Fe(acac)3 91 -
7 Fe(NO3)3.9H2O 99 -
8 Fe(OTf)3 1 -
9 FePO4.2H2O 88 -
10 Fe2(SO4)3.2H2O 97 -
11 Fe(ClO4)3.H2O 88 -
12 Fe2(C2O4)3.6H2O 90 -
13 Fe2O3 96 -
14 K3[Fe(CN)6] 99 -
15 Na2[Fe(CN)5NO] 99 -
16 Sodium Ferric EDTA 97 -
17 Tetraphenylporphyrin
Iron(III) chloride 98 -
18 Ferric Citrate 99 -
19 Ferrocenium BF4 98 -
20 Ammonium Ferric Chloride 99 -
21 Ammonium Ferric Sulfate 99 -
22 Fe(s) 90 -
23 Cu(OTf)2 95 -
a Using
1H NMR spectroscopy using MeNO2 standard
b X = Br
74
All other Fe(III) salts tested returned solely starting material (Entries 5-22), with the
exception of Fe(OTf)3 (Entry 8). Although there was very little starting material left in this
reaction, no other products were obtained. Fe(OTf)3 is known to be a strong Lewis acid
and so may have promoted side reactions leading to loss of material.123
This may indicate
that the poor mass balance observed in previous experiments could be due to a process
where FeCl3 is behaving as a Lewis acid. The problem may also have been due to the
acidity of the system; Fe(OTf)3 would lead to formation of triflic acid and thus a strongly
acidic medium. Interestingly, Cu(OTf)2, which gave some reaction with allyl TMS, failed
to give any of the desired product of cross-coupling (Entry 23).
4.2.3 Investigation of Bases and Additives
As it was hypothesised that the acidity of the reaction medium may play a role in the
amount of degradation observed, the addition of a base to the reaction was investigated
(Table 7). The use of KOH appeared to slow the reaction down slightly and gave a lower
yield of 99a (Entry 1). K2CO3 and Cs2CO3 did not especially affect the reaction and similar
yields as had been seen previously were observed (Entries 2 and 3). These reactions did
improve the mass balance however, supporting the concept that the acidity of the reaction
was important. It was also thought that addition of base to the reaction mixture may lead to
elimination of HCl from 99a to give an alkene in a Heck-like transformation; however no
alkene products were observed in these reactions.124
Interestingly, the use of organic bases,
such as Et3N and 3,5-di-t-butylpyridine, halted the reaction and led to 99a not being
observed (Entries 4 and 5). This is likely due to the bases interacting with iron, resulting in
the desired reaction being inhibited.
As shown in Section 1, ligands are commonly used in conjunction with iron to tune its
reactivity and selectivity.2 The addition of bases seemed to show that the reaction can be
affected by the presence of co-ordinating species and so some commonly used additives
were also screened (Entries 6-10). These included a range of nitrogen and phosphorus
ligands but unfortunately the formation of 99a was not observed.
75
Table 7 Addition of base to reaction mixture
Entry Additive 91b (%)a
99a (%)a
1 KOH 41 22
2 K2CO3 31 37
3 Cs2CO3 25 33
4 Et3N 82 -
5 DTBPy 83 -
6 TMEDA 93 -
7 1,10-phenanthroline 90 -
8 2,2’-bipyridine 92 -
9 PPh3 92 -
10 S-BINAP 90 -
a Determined by
1H NMR spectroscopy using MeNO2 standard
4.2.4 Further Optimisation Studies
The effects of reaction time, atmosphere, stoichiometry and concentration were
investigated (Table 8). When the reaction was run under an inert atmosphere, the process
appeared to improve slightly after an extended reaction time (Entry 2). Interestingly, the
coupling appeared to perform better under an oxygen atmosphere (Entry 3) and was just as
successful under air (Entry 4). Future experiments were thus performed open to air to
simplify the procedure. The results for entries 3 and 4 were similar to Entry 2, potentially
suggesting that running the reaction under air in some way increases the reaction rate (vide
infra).
The effects of differing amounts of octene and FeCl3 with respect to 91b were also
investigated. Decreasing the equivalents of alkene from 10 to 5 did not affect the reaction
greatly (Entry 5) and further decreases gave gradually lower yields (Entries 6-9). Leaving
the reaction for longer seemed to give lower yields and mass balance, suggesting in situ
degradation may occur (Entry 10). A larger amount of FeCl3 did not appear to increase the
yield greatly and merely led to less starting material being recovered (Entry 11). However,
decreasing the amount of FeCl3 present in the reaction led to noticeable decreases in yield
(Entries 12 and 13). It was previously thought that oxygen may be reoxidising iron,
76
resulting in more Fe(III) being available and thus the higher yields obtained in the presence
of O2. However this does not seem to be the case as running the reaction for longer with a
small amount of FeCl3 did not lead to a change in yield (Entry 14).
Table 8 Effect of changing various parameters on the reaction
Entry Reaction
Time (h)
Atmosphere 98
(eq.)
FeCl3
(eq.)
Conc.
(M)
T
(°C)
91b
(%)a
99a
(%)a
1 1.5 N2 10 2.2 0.1 rt 9 36
2 16 N2 10 2.2 0.1 rt 10 45
3 1.5 O2 10 2.2 0.1 rt 12 47
4 1.5 Air 10 2.2 0.1 rt 12 49
5 1.5 Air 5 2.2 0.1 rt 15 45
6 1.5 Air 4 2.2 0.1 rt 19 40
7 1.5 Air 3 2.2 0.1 rt 16 39
8 1.5 Air 2 2.2 0.1 rt 19 37
9 1.5 Air 1 2.2 0.1 rt 17 35
10 16 Air 1 2.2 0.1 rt 8 30
11 1.5 Air 10 4.4 0.1 rt 2 51
12 1.5 Air 10 1 0.1 rt 52 25
13 1.5 Air 10 0.1 0.1 rt 91 2
14 16 Air 10 0.1 0.1 rt 89 3
15 1.5 Air 10 2.2 0.01 rt 17 45
16 1.5 Air 10 2.2 1 rt 5 48
17 1.5 Air 10 2.2 0.1 60 11 50
18 1.5 Air 10 2.2 0.1 0 26 43
a Using
1H NMR spectroscopy using MeNO2 standard
b In DCE
77
It appeared that concentration did not have a dramatic effect on the reaction; increasing the
concentration to 1 M gave a similar yield to running the reaction at 0.1 M, however the
amount of starting material present following the reaction was lower (Entries 15 and 16).
Heating the reaction to 60 °C led to a similar yield as observed at ambient temperature
(Entry 17), while performing the reaction at 0 °C gave a slightly lower yield (Entry 18).
4.2.5 Controlled Addition of Reagents
As the reaction was suffering from poor mass recovery, it was hoped that changing the
addition rate of oxidant/starting material would rectify this issue (Table 9). It was thought
that slow addition of both FeCl3 and 91b to octene may prevent breakdown of the proposed
radical cation due to lack of a large excess of oxidant at any one time and the presence of
large amounts of alkene.125
As FeCl3 was not soluble in CH2Cl2, a solution of the oxidant
in MeNO2 was required to allow the slow addition to be carried out. As shown previously,
the two-solvent system should not greatly affect the potential yield (Section 4.2.1).
Pleasingly, this protocol indeed provided much improved mass recoveries (Entries 1 and
2). The use of 5 equivalents of octene, as well as quenching the reaction immediately
following addition, led to lower yields (Entries 3 and 4). Increasing the addition time to
1.5 h improved the reaction (Entry 5), yet an addition time of 3 h did not lead to further
enhancement (Entry 6).
It was predicted that addition of greater amounts of FeCl3 to the reaction mixture would
improve the yield, since a large amount of 91b now remained unreacted. This hypothesis
was proven true upon addition of 4 equivalents FeCl3 using the same procedure, which
gave an optimal yield of 70% by 1H NMR spectroscopy (Entry 8).
It appeared that addition of FeCl3 to a solution of both 91b and octene gave a slightly
decreased yield, but offered a much simpler reaction procedure (Entry 9). Increasing the
addition time using this protocol had no effect on the observed yield (Entry 10) and
performing the addition at 0 ⁰C did not change the yield to any significant degree (Entry
11). Additionally, slow mixing of two solutions, one containing FeCl3, the other containing
91b and 1-octene, gave a similar yield (Entry 12).
78
Table 9 Changing the addition rate of reagents
Entry Addition
Time
FeCl3 (h)
Addition
Time
91b (h)
Time
before
quench (h)
98
(eq.)
91b (%)a
99a (%)a
1 0.75 0.75 1 10 33 47
2 1 1 1 10 38 54
3 1 1 1 5 39 42
4 1 1 - 10 57 31
5 1.5 1.5 - 10 51 41
6 3 3 - 10 44 38
7 1 - 1 10 34 42
8b 1 1 1 10 6 70
9b 1 - 1 5 5 64
10b 2 - 1 5 2 65
11b, c 1 - 1 5 8 64
12b, d 1 1 1 5 8 61
a Determined by
1H NMR spectroscopy using MeNO2 standard
b 4 eq. FeCl3
c Addition at 0 ⁰C
d Octene in solution with 91b
4.3 Substrate Scope
4.3.1 Variation of Alkene Coupling Partners
With optimal conditions in hand, the substrate scope was investigated, beginning with the
variation of the terminal alkene coupling partner (Scheme 72). The reaction was shown to
proceed in the presence of a number of functional groups, such as Br, I, Cl, NO2 and aryl
moieties, with all products obtained in good to moderate yields. The reaction also appeared
to be largely affected by sterics, as reaction with 4-methyl-1-hexene gave a noticeably
reduced yield of 99d compared to the reaction with 1-hexene to give 99b (46% and 65%
respectively). Such a reduction in yield was somewhat surprising due to the methyl group
being far from the terminal position of the alkene, where coupling took place.
Unsurprisingly, this reaction also yielded a 1:1 mixture of diastereomers.
79
Scheme 72 Variation of the alkene coupling partner
Interestingly the reaction of 1,6-heptadiene 145a solely returned the linear product of
mono-coupling 99c, which itself contained a terminal alkene moiety. It was thought that
this product may further react, however no sign of this was observed. It was also
hypothesised that this reaction may give a cyclised product 146 through a 5-exo-trig
cyclisation of the proposed radical intermediate II (Scheme 73).126,127
The lack of cyclised
product suggested that oxidation of II was faster than 5-exo-trig cyclisation under the
reaction conditions (k = 2.3 × 105 s
-1).
128 Alternatively, the radical may be bound to iron,
thereby affecting the proposed cyclisation (vide infra).
80
Scheme 73 Proposed 5-exo-trig cyclisation of 1,6-heptadiene intermediate
In an attempt to make cyclisation in the above system more facile, heptadienes containing
a quaternary centre were synthesised and exposed to the reaction conditions (Scheme
74).129
Scheme 74 Reaction of more substituted dienes
Surprisingly the use of such alkenes led to neither the cyclised nor the linear, chlorinated
products and instead gave allylbenzene compounds 147a and 147b in low yields. Only
trace amounts of the expected chlorinated products were observed. It is uncertain how
these compounds were formed and whether this was due to elimination of HCl from the
chlorinated products 99 or an intermediate in the reaction pathway reacting in a different
manner due to the increased steric demand of the alkenes being used. The absence of the
conjugated alkene may suggest that elimination from the chlorinated compounds was not
occurring as it would need to selectively give the non-conjugated product (see Section 4.6
81
for the expected product distribution of elimination). It is possible that the allyl benzene
products 147 arise from a carbocation intermediate by loss of a proton, due to steric
blocking of the attack by chloride (vide infra).
Interestingly, similar products were reported by Yu et al. when 1-hexene was exposed to
the oxidative Heck conditions discussed in Section 3.1 (Scheme 53). This reaction
selectively returned the non-conjugated alkene, which was proposed to be due to the
intermediate being restricted from undergoing β-H elimination with the benzylic hydrogen
atoms due to its conformation.90
It is possible that the bulky substituents in the current iron
system enforce a conformation in which this elimination to form the non-conjugated alkene
is facile, encouraging formation of these products.
A more simple hindered alkene, 4,4-dimethyl-1-pentene 126, was reacted to determine
whether a similar product would be formed (Scheme 75). Indeed, the allylbenzene product
147c was isolated in comparable yields to those obtained in the previous reactions. This
further demonstrated the strong effect steric hindrance has upon the reaction.
Scheme 75 Reaction of 4,4-dimethyl-1-pentene
A number of other unsaturated compounds were tested under the reaction conditions, but
failed to undergo the desired coupling reaction (Fig. 3). Reaction of all of the alkenes listed
resulted in little sign of the desired products and merely returned varying amounts of
unreacted starting material. It was thought that the unprotected alcohol in 148 may be able
to co-ordinate to Fe and thus disrupt the reaction; however the TBS-protected alcohol 149
did not fare any better. Moreover, the use of a ketone 150 or an ester 151 also failed to
provide the coupled products.
Disubstituted alkenes 154 - 156 also did not react successfully, perhaps unsurprising due to
the marked steric effect observed in previous studies. Also, the lack of reactivity of styrene
108 may be due to FeCl3 reacting with the alkene partner, possibly leading to
polymerisation or other side reactions independent of the sulfide.130
Finally, other unsaturated systems, such as conjugated diene 158, allene 161 and terminal
and internal alkynes, 162 and 163 respectively, failed to show signs of cross-coupling.
82
Figure 3 Unsuccessful coupling partners
4.3.2 Variation of Arene Coupling Partners
The scope of the process with regard to the aryl sulfide partner 91 was then investigated
(Scheme 76). The reaction proved to be particularly sensitive to substitution in the aryl ring
participating in coupling, with successful reaction only being observed when a 3,5-OR
substitution was present (vide infra, Fig. 5). Despite this, a large amount of variation is
possible in the spectator ring and Me, Br, F, OMe, NO2 and CF3 groups were tolerated in
various ring positions (164a-h). It was also shown that variation of the methyl ether groups
was compatible with the cross-coupling (164i and 164j). All of these examples gave good
to moderate yields.
83
Scheme 76 Variation of arylsulfide in the cross-coupling
Sulfide 164f, containing 3,5-methoxy substitution in both arenes, showed a notable drop in
yield, this may indicate that the product is prone to further decomposition under the
reaction conditions. It was thought that this product could further react with an equivalent
of alkene as it contains a ring with the requisite substitution pattern; however the product
of over-reaction 165 was not observed. 164f was separately subjected to the alkene-
coupling conditions, however this only returned 70% unreacted material (by 1H NMR
spectroscopy) (Scheme 77). The loss in mass suggests that some reaction with FeCl3 may
be occurring, but the desired coupling was not observed.
84
Scheme 77 Attempted second chloroarylation reaction
Most interesting was the fact that the introduction of the electron-withdrawing groups NO2
and CF3 on the non-reacting ring resulted in higher yields of the desired products (164g
and 164h respectively). It was thought that these substrates would be more difficult to
oxidise, as the sulfur centre is less electron rich, meaning that the desired reaction may be
more difficult to carry out. To probe this, competition experiments were carried out
between the standard substrate 91b and the nitro-substituted sulfide 91d in the presence of
limiting FeCl3 (Scheme 78).
Scheme 78 Competition experiment between 91b and 91d
This competition experiment led to selective formation of 99a, with no 164g being
observed. This result illustrated that the rate of reaction of the more electron-deficient
sulfides was indeed slower as previously predicted. A competition study was also carried
out between 91b and the CF3-substituted sulfide 91e to determine whether an inductively
withdrawing group (CF3) performed differently to the mesomerically withdrawing NO2;
however the results were similar, suggesting the effect of these two groups on the reaction
were comparable (Scheme 79).
85
Scheme 79 Competition experiment between 91b and 91e
The increased yields from reacting these substrates under standard conditions may be
rationalised by the slow rate of substrate oxidation preventing the build-up of larger
concentrations of radical cation intermediate. This may disfavour destructive side reactions
that lead to decomposition of these intermediates and lower mass balances. This is
consistent with the previous observation that slow addition of FeCl3 to the aryl sulfide and
alkene gave higher yields and mass balances.
4.3.3 Use of Other Aryl Sulfides
A range of other aryl systems was tested under the reaction conditions (Fig. 5). As
mentioned previously, the reaction was particularly sensitive to substitution in the reacting
aryl ring and the use of sulfides containing a single methoxy group (91c, f and g) resulted
in no product formation. It was initially postulated that the absence of the second methoxy
group causes the compound to be less electron-rich and thus more difficult to oxidise,
however loss of material was still observed and low mass balances were obtained,
suggesting oxidation and decomposition were occurring. Switching to a 3,4-methoxy
substitution pattern (91h) did not lead to successful reaction, showing that substitution on
the meta positions was important, yet using a 3,4,5-trisubstitued system (91i) also failed to
give the desired products. This suggested that having a substituent para to sulfur
interrupted the standard reaction pathway and led to the formation of undesired
products/decomposition of intermediates. This was also demonstrated by introducing a
para-electron-donating group (OMe 91j and SMe 91k) on the spectator ring, while still
maintaining the 3,5-methoxy pattern on the reacting ring. Note that previously the use of
electron-withdrawing substituents in this position increased the yield of the reaction
(Section 4.3.2). Intriguingly, the use of these donating groups had the opposite effect and
no products were observed. A possible explanation for this effect is that the corresponding
radical cation intermediate can be considered a quinone-type species (Fig. 4).131
This
86
species is thus stabilised and likely unable to carry out the anticipated reaction and may
decompose in situ or be hydrolysed upon workup. No evidence of by-products from such
species was observed in these reactions, with only starting material being observed.
.
Figure 4 Proposed thioquinone-type radical cation intermediate
As it was thought that the electronics of the sulfur centre may be responsible for the lack of
reactivity of the mono-methoxy compounds, bis(3-methoxyphenyl)sulfide (91l) was
synthesised. Nevertheless, this sulfide also showed no reactivity under our standard Fe(III)
conditions. Thus, in keeping the 3,5-substitution pattern, the use of other groups in these
positions was investigated, however it appeared that changing even one of the methoxy
groups to Me (91o) resulted in an unsuccessful reaction. It is possible that the presence of
methyl groups provides new pathways for decomposition of the radical cation
intermediate. Notably, a methyl group was present in 164a (Section 4.3.2) and gave the
desired cross-coupled product (albeit in slightly lower yield than the compound without
Me). Using a naphthyl (91p) or thiophene group (91u) as the reacting ring was also
unsuccessful.
Introducing other substituents onto the ring whilst maintaining the 3,5-methoxy pattern,
such as NO2 (91q-r) and Me (91s), also hindered the reaction; as did the use of other sulfur
groups such as t-BuS (91t) or a sulfone (166).
Finally, the use of other heteroatoms was investigated to determine whether the presence of
SPh is in fact pivotal for the reaction.132
Trimethoxybenzene 167 was subjected to the
reaction conditions, but no reaction was observed. The oxygen and nitrogen analogues of
the model sulfide 168-170 were also synthesised and exposed to the standard reaction
conditions, however they also failed to give the corresponding products. This appears to
indicate that sulfur is indeed vital to the cross-coupling reaction. The attempted reactions
of all of these compounds (except for 169, which contains a free NH) showed poor mass
balances, suggesting that oxidation may be occurring. This may further indicate that sulfur
87
plays an important part in the actual coupling step and may support its role as a directing
group for Fe.100
Figure 5 Aromatic substrates that failed to undergo cross-coupling
4.4 Mechanistic Studies
4.4.1 Proposed Mechanism
The proposed reaction mechanism is similar to that shown earlier for the allylation reaction
using allyl TMS as the nucleophile (Scheme 80). The reaction is initiated by single
electron oxidation of the aryl sulfide by Fe(III) to a radical cation species I, which can then
be intercepted by the terminal alkene to give another radical cation II. Following
rearomatisation, this then provides a radical III that can be further oxidised to a cationic
species IV by another equivalent of Fe(III). Quenching of IV with Cl− then leads to the
desired product 99. It is possible that conversion of the radical species to the chloride may
88
occur in a concerted manner, through direct quenching with FeCl3, rather than being
stepwise.114
Scheme 80 Proposed mechanism for coupling of biaryl sulfides and terminal olefins
This mechanism may pose a simplified version of the species present. For example, it is
possible that sulfur acts as a chelating group, delivering the observed ortho-selectivity with
respect to the sulfur centre (Fig. 6). As hypothesised previously (Section 4.3.1), the lack of
radical cyclisation in the reaction of 1,6-heptadiene may be due to metal-bound species,
such as 172, rather than discrete free radicals being present.
Figure 6 Alternative intermediate species in chloroarylation reaction
Oxidative C–H couplings via an SET process have been reported previously, such as the
Cu(II)-catalysed functionalisation of aryl C–H bonds reported by Yu et al. (Scheme 81).133
Scheme 81 Cu(II)-catalysed functionalisation directed by pyridyl group
This process is believed to occur by coordination of the pyridyl group to Cu(II), followed
by single electron oxidation of the attached aryl ring. The ortho-selectivity is proposed to
be due to an intramolecular anion transfer from the resultant cuprate complex II. A second
SET followed by rearomatisation then yields the desired product (Scheme 82).133,134
89
Scheme 82 Proposed mechanism for Cu-catalysed functionalisation of C–H bonds
An iron-catalysed oxidative radical cross-coupling/cyclisation between phenols and
styrenes was recently reported by Lei et al. (Scheme 83).135
This transformation appears to
bear some similarity to the current chloroarylation process and a SET process is also
proposed.
Scheme 83 Iron-catalysed oxidative coupling/cyclisation between phenols and styrenes
It is proposed that DDQ is the single electron oxidant used to make phenoxy radical II.
Acting as a Lewis acid, FeCl3 is then proposed to form C-centred radical III, which
undergoes addition/cyclisation onto the styrene. A second oxidation of the resultant radical
species IV followed by rearomatisation then yields the observed product V (Scheme 84). It
is important to note that the Lewis acid is believed to be key to this reaction. Electron
paramagnetic resonance (EPR) studies could be used to track the formation/reaction of the
HDDQ radical VI and found that, whilst it was formed upon reaction of the phenol and
DDQ, subsequent reaction only occurred upon addition of a Lewis acid. Catalytic amounts
of other Lewis Acids besides FeCl3 also yielded the same product.
Scheme 84 Proposed mechanism of cross-coupling/cyclisation
Under similar conditions, a more recent publication by the same group described a related
coupling using electron-rich arenes, such as trimethoxybenzene, and diarylethylenes.136
90
4.4.2 Cyclic Voltammetry
Cyclic voltammetry (CV) was used to measure the oxidation potentials of (3,5-
dimethoxyphenyl)(phenyl)sulfide 91b and (3-methoxyphenyl)(phenyl)sulfide 91g and so
establish the feasibility of their oxidation using FeCl3 (Fig. 7).
Figure 7 Voltammogram for sulfides vs reference electrode
These studies determined that the oxidation potential of 91b [+1.71 V (vs SHE) in MeCN]
is compatible with the previously proposed mechanism. FeCl3 is a very strong oxidant in
non-aqueous media [~+2.00 V (vs SHE) in MeCN]137
and so has the ability to oxidise 91b
to the radical cation. This also indicates why FeCl3.6H2O [~+1.50 V (vs SHE) in MeCN]137
is unable to carry out the reaction (see Table 6). Notably, the oxidation potential of simple
terminal alkenes is generally much greater than +2.00 V, meaning oxidation of this partner
to the radical cation is unlikely.138
Interestingly, the oxidation potential of 91g [+1.72 (vs SHE) in MeCN] was found to be
similar to that of 91b. It was previously thought that the failure of this substrate to undergo
the desired reaction may be due to the decreased electron density resulting in a higher
oxidation potential, thus making it unreactive (Section 4.3.3). However, the similar
oxidation potential does not support this theory. Notably, a low mass balance was obtained
upon attempts to react this substrate, suggesting that FeCl3 was indeed oxidising the aryl
sulfide, yet the issue may have been the coupling step itself. Therefore, the oxidation
potential does not appear to be the key to understanding the scope of this reaction. It is
possible that the radical cation formed from 91g is significantly more reactive than that
derived from the standard substrate 91b and the rate of decomposition is higher than that of
91
coupling. The 3,5-dimethoxy pattern currently required may be stabilising this intermediate
by both steric and electronic effects, thus slowing the rate of decomposition and allowing
the coupling step to occur.
4.4.3 Solvent Investigations
As the reaction appeared to give higher yields in chlorinated solvents, studies were carried
out to determine whether the chlorine in the product came from FeCl3 or the solvent
itself.139
The coupling reaction was carried out in CH2Br2 to determine whether halogen
exchange is possible, however this reaction gave a similar yield of chlorinated product 99a
compared to standard conditions when using CH2Cl2 solvent (Scheme 85). Also, upon
using FeBr3 as the oxidant with CH2Cl2, only the brominated product 144 was observed
(Table 6). Thus the ligand on the Fe centre is incorporated into the observed products,
suggesting a redox process may be occurring and also possibly indicating a close
interaction between iron and the carbon centre that is halogenated.
Scheme 85 Use of brominated solvent to investigate halide incorporation
4.4.4 Use of Other Oxidants
The proposed mechanism was also indirectly supported when it was found that the
analogous reaction can be carried out using ceric ammonium nitrate (CAN), another
commonly used powerful single electron oxidant (Scheme 86). As expected from previous
results, this reaction gave the nitrated product 178a in good yield. CAN commonly
undergoes SET processes and so formation of a similar product to that observed with FeCl3
suggests a similar process may be in action for the chlorination also.140
Indeed, CAN has
also been shown to oxidise biaryl sulfides to their corresponding sulfoxides through the
same radical cation intermediate proposed in the current investigation.141
Scheme 86 Reaction of biaryl sulfide and octene with CAN
92
After the discovery of this CAN-mediated reaction a brief investigation was carried out to
determine whether the yield could be improved (Table 10). Interestingly, no product was
observed when using CH2Cl2 as a solvent (Entry 1). A reduced yield was observed with
MeNO2 (Entry 2) and no product was formed in H2O (Entry 3).142
Intriguingly, the reaction
worked well in EtOH (a commonly used solvent in CAN-mediated reactions)143
to give the
nitrated product 178a in good yield (Entry 4). It may be expected that the nucleophilic
solvent could intercept some of the proposed intermediates, however no other products
were observed.116
This may indicate that the reaction does not proceed through the
proposed carbocation. Alternatively, it may suggest that an inner sphere electron transfer is
occurring, with the ligand being transferred from the metal during the oxidation step and
resulting in the observed products.144,145
Increasing the reaction time in EtOH or MeCN did
not improve the reaction greatly (Entries 5 and 7 respectively).
Similar to the FeCl3-mediated reaction, decreasing the amount of oxidant lowers the yield
accordingly (Entries 8 and 9). Interestingly, the reaction proceeded to the same degree
under an N2 atmosphere as it did in air (Entry 10), in contrast to results observed for the
chloroarylation reaction (Section 4.2.4), and decreasing the concentration greatly lowered
the observed yield (Entry 11). The mass balance of this reaction was almost quantitative,
possibly indicating that the coupling was very favourable, the rate of sulfide oxidation was
decreased or that the radical cation was less reactive and the SET reversible under these
conditions. The discrepancy in concentration effects may be due to this system being
homogeneous, whilst the FeCl3 mixture in CH2Cl2/MeNO2 is heterogeneous. Therefore, the
actual concentration of dissolved oxidant may not vary much in the FeCl3 system, leading
to the consistent results obtained during those screening studies (Section 4.2.4).
Unfortunately, slow addition of CAN over 1 h to the reaction mixture had little effect on
the yield (Entry 12).
Other Ce(IV) reagents were tested to determine if the SO4 moiety would be installed at the
homobenzylic position to give 178b, however no reaction was observed using
(NH4)4.Ce(SO4)4 or Ce(SO4)2 (Entries 13 and 14). The oxidation potential of ceric
ammonium sulfate (CAS) is reported to be lower than CAN [CAS Eo +1.44 V (vs NHE) in
1 N H2SO4 vs CAN Eo +1.61 V (vs NHE) in 1 N HNO3] and so appears unable to oxidise
the arene partner.146
Of course these potential values are in aqueous systems and so the
exact values will be different in MeCN solution. This result further supports the proposal
that a SET process is occurring as powerful oxidising agents are required for the reaction
to proceed.
93
Table 10 Screen of Ce(IV) reagents/conditions for an analogous cross-coupling
Entry Solvent x
(eq.)
Time
(h)
Atmosphere Conc.
(M)
Oxidant 91b
(%)a
178
(%)a
1 CH2Cl2 2.2 2 Air 0.1 CAN 99 -
2 MeNO2 2.2 2 Air 0.1 CAN 6 25
3 H2O 2.2 2 Air 0.1 CAN 99 -
4 EtOH 2.2 2 Air 0.1 CAN 21 50
5 EtOH 2.2 16 Air 0.1 CAN 25 55
6 MeCN 2.2 2 Air 0.1 CAN 10 62
7 MeCN 2.2 5 Air 0.1 CAN 8 64
8 MeCN 1 2 Air 0.1 CAN 61 35
9 MeCN 0.1 2 Air 0.1 CAN 96 -
10 MeCN 2.2 2 N2 0.1 CAN 10 60
11 MeCN 2.2 2 Air 0.01 CAN 70 27
12b MeCN 2.2 2 Air 0.1 CAN 8 66
13 MeCN 2.2 2 Air 0.1 CAS 99 -
14 MeCN 2.2 2 Air 0.1 Ce(SO4)2 99 -
a Yield by
1H NMR spectroscopy using MeNO2 standard
b Solution of CAN in MeCN charged over 1 h
4.4.5 Electron Paramagnetic Resonance
EPR studies were found to be useful in probing the mechanism of Lei’s reaction (Section
4.4.1).135
It was thus thought that similar studies could be carried out on the current system
to determine if the proposed radical species could be observed. When carrying out these
studies, a broad signal was observed, however this appeared to originate from Fe(III) and
not an organic radical. Therefore, EPR studies were inconclusive, as this signal would
block observation of the desired radical. Attempts to reduce the amount of Fe(III) present
to minimise this signal would also reduce the amount of radical that may be formed.
Further investigations would be required to determine whether any of these limitations can
be overcome.
Another possibility would be to study the CAN reaction system, as the same mechanism is
believed to be occurring. Ce3+
is paramagnetic and so can be observed using EPR;
94
observation of these signals would suggest a redox process is occurring and support the
hypothesis of a SET mechanism.147
4.4.6 Alternative Mechanisms
FeCl3 is a commonly used Lewis acid and so an alternate mechanistic proposal may invoke
iron adopting this role. The initial reason for the proposal of a radical mechanism came
from the observed regioselectivity of the alkene coupling, in that solely the linear (Anti-
Markovnikov) product was observed, with no sign of the corresponding branched
product.115
The Markovnikov product would be expected if a more standard Lewis acidic
mechanism was occurring, as demonstrated by Beller et al. for the Fe-catalysed
hydroarylation of styrenes to selectively give the corresponding 1,1-diarylmethanes 180
(Scheme 87).148
Scheme 87 Fe-catalysed hydroarylation of styrenes
This reaction was proposed to occur via an electrophilic aromatic substitution pathway, in
which FeCl3 is behaving as a Lewis acid to activate the double bond for attack by the
aromatic partner. Notably, in this literature example the same product was observed upon
use of other Lewis acids, such as Sc(OTf)3. To ensure that this pathway was not playing a
role in the current reaction, FeCl3 was replaced by other commonly used Lewis acids
(Table 11). The results from this investigation are consistent with FeCl3 playing a different
role in the current reaction as there was no evidence of the desired coupling occurring.
95
Table 11 Screen of Lewis acids
Lewis Acid 91b (%)a
99 (%)a
InCl3 96 -
Sc(OTf)3 98 -
BF3·Et2O 98 -
In(OTf3) 97 -
CeCl3 99 -
a Determined by
1H NMR spectroscopy using MeNO2 standard
An alternative approach to viewing the coupling may involve electrophilic metalation of
the aryl sulfide, followed by carbometalation of the alkene (Scheme 88).149
Scheme 88 Alternative electrophilic metalation/carbometalation reaction
The selectivity of the electrophilic metalation could be explained by Fe-S coordination
leading to directed attack ortho to sulfur, which would also justify the requirement of a
strongly electron rich compound. The use of a hindered aryl sulfide may account for the
regioselectivity of the addition to the double bond, with the hindered aryl adding to the
terminal position. Finally, the transfer of the metal-centred ligand into the product would
also be explained by the reductive elimination in the final step.
It is difficult to account for the poor mass balance obtained in the chloroarylation reactions
by invoking this mechanism. Potentially, the aryl sulfide may remain bound to the iron
centre and be lost upon workup. However, 2,2’-bipyridine is added as part of the workup
procedure, which should displace any Fe-bound product that may be present; performing a
96
workup without 2,2’-bipyridine has little effect on the mass recovery, suggesting this may
not be the problem.
If this mechanism were in operation, only 1 equivalent of FeCl3 should be needed;
however an excess is currently required. It may also suggest a catalytic reaction would be
feasible if the formed Fe(I) can be reoxidised following reaction.
It should be noted that this mechanism can be viewed as an extreme of the SET process
suggested earlier; rather than the free radical species previously proposed, this mechanism
suggests the presence of formal C–M bonds (vide supra).
4.5 Towards a Catalytic Process
4.5.1 Iron Catalysis
The adoption of a slow addition process seemed key to the optimisation of the Fe-mediated
reaction by reducing the concentration of reactive intermediates. A similar effect may be
observed if a catalytic protocol could be developed, as it would also lead to a slow
generation of radicals if successful. Thus, preliminary investigations were conducted to
determine whether the reaction could be carried out with substoichiometric amounts of iron
(Table 12). Standard oxidants utilised in the literature were tested (see Section 1); however
it was found that the desired product 99a was not obtained in any notable yield.150
The
oxidants of particular interest were DCE and 1,2-dichloroisobutane, as these could play a
dual role as oxidant and chlorine source; unfortunately their use does not appear to aid a
catalytic process (Entries 1-3).
A reduction in the amount of starting material was observed using TBHP (Entry 5). It was
thought the small amount of 99a observed may be due to lack of Cl− following the first
cycle. However, repeating the reaction with an external chloride source did not increase the
amount of product (Entry 6).
It has also been demonstrated that NaNO2 can be used to turnover an Fe-TEMPO species;
however no products were observed using catalytic amounts of FeCl3/TEMPO/NaNO2
(Entries 16 and 17).151
As TEMPO can be used as a radical trap, a control was carried out
with stoichiometric iron and showed that no reaction occurred with this additive in the
reaction system, forgoing the possibility of a catalytic system with these reagents
(Entry 18).
97
Table 12 Attempts to perform the reaction with catalytic amounts of FeCl3
Entry x (mol %) Oxidant 91b (%)a
99a (%)a
1 10 DCE 85 4
2b 10 DCE 84 3
3 10 1,2-dichloroisobutane 85 4
4 10 O2 87 2
5 10 TBHP 59 2
6c 10 TBHP 42 1
7b 10 TBHP 10 -
8 10 DTBP 94 -
9 - DDQ 90 -
10 10 DDQ 92 -
11b 10 DDQ 85 -
12b, c 10 DDQ 89 -
13 - K2S2O8 93 -
14 10 K2S2O8 85 -
15b 10 K2S2O8 84 -
16 10 NaNO2/TEMPO 95 -
17 10 NaNO2 96 -
18 220 TEMPO 82 -
a Determined by
1H NMR spectroscopy using MeNO2 standard
b Reflux in DCE
c With 2.2 eq. LiCl
4.5.2 Photoredox Catalysis
Photoredox catalysis is a powerful tool that can give access to reactive organic radical
species and has garnered much attention recently.152
Accordingly, it was proposed that the
desired radical cation species could be accessed using this methodology.
Standard oxidative and reductive quenching cycles are shown in Scheme 89. The cycle
begins by photoexcitation of the photocatalyst (PC) using visible light to give an excited
state (PC*). The excited state is a stronger oxidant and/or reductant than the ground state
and so can either lose or accept an electron from another compound present (common
quenchers are shown in Scheme 89). The oxidised/reduced forms of the catalyst (PC+ and
PC− respectively) are generally powerful reductants/oxidants themselves and so a further
98
SET returns the ground state catalyst, which can again undergo photoexcitation and repeat
the cycle.153
Scheme 89 Standard photoredox catalysis cycle
A photocatalytic cycle to perform a similar reaction to that previously investigated would
require one of two scenarios:
1. The excited state of the photocatalyst (PC*) is strong enough to oxidise the arene
partner to the radical cation species (i.e. the arene is a reductive quencher). This
would then require an oxidant to return the reduced form of the catalyst back to the
ground state.
2. An oxidative quencher is required to give the oxidised form of the photocatalyst
(PC+). This is then strong enough to oxidise the arene partner to give the radical
cation and ground state catalyst.
An initial screen of a range of common photoredox catalysts was carried out to probe the
feasibility of this process (Table 13). These reactions were carried out in air, with O2
viewed as the oxidant for the photocatalyst; however only unreacted starting material was
obtained.154
99
Table 13 Initial photocatalyst screen
Entry Catalyst 91b (%)a
99 (%)a
1 Ru(bpy)3Cl2 88 -
2 Ru(bpz)3(PF6)2 99 -
3 [Ir(dtbbpy)(py)2]PF6 89 -
4 [Co(bpy)3](PF6)2 94 -
5 Fe(bpy)3Cl2 97 -
6 Ir(ppy)3 91 -
7 [Ir{dF(CF3)ppy}2(dtbbpy)]PF6 94 -
8 Cu(dap)2Cl 91 -
9 9-mesityl-10-
methylacridinium perchlorate 93 -
10 Eosin Y 94 -
11 Rose Bengal 89 -
12 Fluorescin 91 -
13 Methylene Blue Hydrate 89 -
a Yield by
1H NMR spectroscopy using MeNO2 standard
Ru(bpy)3Cl2 is the most commonly used photoredox catalyst and so a solvent screen was
carried out to see if this allowed for any reactivity to be observed (Table 14).152
Unfortunately, the desired reaction did not occur in any of the solvents tested.
100
Table 14 Solvent screen with Ru(bpy)3Cl2
Entry Solvent 91b (%)a
99 (%)a
1 CH2Cl2 97 -
2 MeCN 88 -
3 EtOAc 99 -
4 DMF 98 -
5 MeNO2 88 -
a Yield by
1H NMR spectroscopy using MeNO2 standard
As it appeared that no reaction occurred using O2 as oxidant, reactions were carried out
with common oxidative quenchers in an attempt to access the oxidised photocatalysts
(Table 15).153
These reactions were carried out under N2 and the solvent sparged to remove
O2 from the system.
Fe(III) and Co(III) are common quenchers in oxidative processes but no coupling was
observed in these reactions. Viologens are also well-known electron acceptors but did not
promote reaction.153
Notably octyl viologen was not soluble in MeCN and so a different
solvent was utilised.155
A closer look at electron potentials suggests that many of the photoredox catalysts tested
are simply not strong enough oxidants to produce the desired radical cations. E1/2 (IrIV
/IrIII
)
for [Ir{dF(CF3)ppy}2(dtbbpy)]PF6 is reported as +1.69 V, which is similar to the biaryl
sulfide tested previously (+1.71 V). This may suggest that reaction is possible under the
right conditions, however further screening and quenching studies would be required to
investigate this.152
Another potential candidate for the photoredox process would be Ru(bpz)3(PF6)2 as this
also has a high E1/2 (RuIII
/RuII) of +1.89 V.
152 This system should therefore be strong
enough to carry out the desired oxidation; however attempts to use this catalyst bore no
success, which may be due to a failure to access the oxidised form of the catalyst. The
excited state is also very oxidising (E1/2 (RuII*/Ru
I) = +1.42 V) and so reduction of the
catalyst is a favourable side reaction that may hinder the desired reactivity.152
101
Table 15 Investigation of oxidative quenchers towards a photocatalytic process
Entry Catalyst Solvent Quencher 91b
(%)a
99 (%)a
1 Ru(bpy)3Cl2 MeCN - 92 -
2 Ru(bpy)3Cl2 MeCN Fe(acac)3 91 -
3 Ru(bpy)3Cl2 MeCN Co(acac)3 85 -
4 Ru(bpy)3Cl2 MeCN Methyl viologen 93 -
5 Ru(bpy)3Cl2 EtOAc Octyl viologen 89 -
6 Ru(bpy)3Cl2 EtOAc/H2O Octyl viologen 94 -
7 Ru(bpz)3(PF
6)
2 MeCN - 99 -
8 Ru(bpz)3(PF
6)
2 MeCN Fe(acac)
3 98 -
9 Ru(bpz)3(PF6)2 MeCN Co(acac)3 99 -
10 Ir(ppy)3 MeCN - 95 -
11 Ir(ppy)3 MeCN Fe(acac)3 93 -
12 Ir(ppy)3 MeCN Co(acac)3 86 -
13 [Ir{dF(CF3)ppy}2(dtbbpy)]PF6 MeCN - 97 -
14 [Ir{dF(CF3)ppy}2(dtbpby)]PF6 MeCN Fe(acac)3 98 -
a Yield by
1H NMR spectroscopy using MeNO2 standard
From these initial screens, it appears that a photocatalytic route to the desired cross-
coupled products is not feasible, however further investigations may be required before
coming to a definitive conclusion.
4.6 Product Manipulation
The chlorinated products of the Fe(III)-mediated reaction are of synthetic interest, as there
are a range of functionalities present that can be utilised as handles for subsequent
manipulation. Further reactions of the products were thus investigated.
The organosulfanyl group can be exploited in a variety of reactions via access to different
oxidation levels.71
It was demonstrated that the corresponding sulfone 181 could be easily
synthesised in excellent yield through meta-chloroperoxybenzoic acid (mCPBA) oxidation
of 99a (Scheme 90).156
102
Scheme 90 mCPBA oxidation to the sulfone
Desulfurisation could also be carried out using excess Raney nickel (Scheme 91).157
Notably this also led to formation of the additionally dechlorinated product 183. This
reaction was carried out by Miles Aukland.
Scheme 91 Desulfurisation of products using Raney Ni
As the Fe-mediated reaction is currently limited to sulfides with a 3,5-dioxygenation
pattern, reactions that could take advantage of such structures were investigated.
Pleasingly, ortho-directed metalation was found to be highly efficient and allowed
selective functionalisation para to sulfur by varying the electrophilic quench to give
184a-c (Scheme 92).158
Scheme 92 ortho-Directed metalation using various quenches
It was thought that the β-chlorine may pose issues in this reaction, as lateral metalation
may occur to give the benzylic lithium species, which can eliminate Cl−, giving the
corresponding styrene.159
Fortunately no sign of elimination was observed, showing that
lateral metalation is not facile. Since the elimination products would formally be the
outcome of an oxidative Heck reaction (see section 3.1), they were deemed of interest.
103
Therefore, the use of other bases to promote elimination was investigated; DBU, LDA and
KOt-Bu all returned starting material. Pleasingly, it was found that refluxing the compound
in EtOH with NaOEt successfully led to elimination to give the corresponding styrene as
the major product 185 (Scheme 93).124
Scheme 93 Elimination to give conjugated and non-conjugated alkenes
It was thought that elimination from the benzylic position should give the most
thermodynamically stable product 185; therefore formation of the non-conjugated isomer
186 was surprising.124
This may be due to the benzylic position being more sterically
hindered, which may make deprotonation more difficult. Steric bulk may also mean that
styrene 185 is twisted from the plane of the aromatic ring, decreasing conjugation in the
molecule as π-π delocalisation between the alkene and arene orbitals is not possible.
Further manipulations of the halogen were then investigated (Scheme 94). Displacement of
chloride via SN2 reaction was possible using NaN3 to give the corresponding azide 187 in
88% yield based on recovered starting material (brsm) (Scheme 94a).160
Strangely, a
Finkelstein reaction to give iodide 188, which should occur via a similar mechanism, was
unsuccessful and only returned unreacted starting material. This reaction is usually
favourable due to formation of NaCl by-product, which is insoluble in the acetone solvent.
A range of standard reaction conditions were attempted but yielded no success (Scheme
94b).161
It was also found that formation and subsequent quenching of a radical using
Bu3SnH/AIBN was possible to give the dechlorinated product 189 (Scheme 94c).162
Potentially, other radical traps may be utilised to install alternate functionalities in this
position.116
104
Scheme 94 Manipulation of alkyl chloride moiety in cross-coupled products
4.6.1 Formation of Dihydrobenzofuran Motifs
It was hypothesised that formation of important dihydrobenzofuran species may be
possible by using the oxygen moieties to cyclise and displace chloride (Scheme 95). This
work was carried out in collaboration with fellow PhD student Miles Aukland.
Scheme 95 Proposed cyclisation of coupling products to form dihydrobenzofuran
105
The simplest method of carrying out this reaction would be to form a phenol via
demethylation and, if cyclisation does not occur in situ, promoting the cyclisation of 190.
However, attempts to demethylate 99a using BBr3 proved unsuccessful and led to
decomposition of starting material to give an inseparable mixture of products.163
It was
thought that the harsh conditions generally required for demethylation may be the cause
and access to the desired compound using a more mild method was investigated.
Scheme 96 Deallylation/cyclisation sequence to form dihydrobenzofuran
It was decided that deallylation would be an attractive prospect as a range of procedures
are available that utilise fairly mild conditions.164
Pleasingly, exposure of 164j to
Pd(PPh3)4/K2CO3 successfully triggered a deallylation/cyclisation sequence to give a
moderate yield of the desired dihydrobenzofuran 191a (Scheme 96).165
Scheme 97 Pd-catalysed deallylation
Morpholine is commonly used in deallylation reactions as an efficient allyl scavenger, thus
acting as a good nucleophile to turn over the Pd-allyl species IV (Scheme 97).165
After
screening a range of conditions it was found that the use of morpholine and either NaH or
NaBH4 as additives allowed for high conversion to dihydrobenzofurans (Table 16).166
106
Table 16 Improved conditions for deallylation/cyclisation cascade
Entry Additive Temperature
(°C)
Time
(h)
191b
(%)a
192
(%)a
1 NaH rt 18 - 89
2 NaH 60 18 90 -
3 NaBH4 rt 18 85 -
4 NaBH4 60 5 84 -
a Isolated yield
By using NaH at ambient temperature, it was found that selective formation of mono-
deprotected 192 occurred (Entry 1). This was somewhat surprising and suggested
deallylation of the less hindered O-allyl is not as facile. This could be due to a buttressing
effect from the presence of the alkyl chain forcing a conformation leading to an n-π or n-σ*
interaction from the lone pair of oxygen with the phenyl ring or C–Cl bond respectively
(Fig. 8).167
This may serve to weaken the O-allyl bond and make Pd-insertion easier for
this group.
Figure 8 Possible n-σ* interaction
It is also possible that deallylation is reversible under these conditions and, as cyclisation is
only possible with one oxygen atom, this drives the reaction towards 192. However, if this
was the case, it would be expected that a mixture of 191b and 192 would be obtained.
Nevertheless, simply heating the reaction mixture to 60 °C for 18 h allows complete
deprotection to occur to give 191b (Entry 2).
107
NaBH4 is also a common additive in Pd-catalysed deallylation reactions as it aids reduction
of the Pd-allyl intermediate formed in the reaction (Scheme 97).165
Upon using these
stronger deallylation conditions at room temperature, it was found that complete
deprotection occurred in 18 h to give 191b (Entry 3). The reaction time was reduced to 5 h
with a comparable yield of product isolated when the reaction was heated to 60 °C
(Entry 4).
It was found that these conditions tolerated further functionality on the alkyl chain, with
the reaction proceeding in excellent yields with NO2, Br and Ph groups present
(Scheme 98).
Scheme 98 Substrate scope for dihydrobenzofuran formation
4.6.1.1 Manipulation of Dihydrobenzofurans
Pleasingly, the triflation of 191b was successfully carried out in high yield, opening a path
for further functionalisation (Scheme 99a). Pd-catalysed sp2-couplings of the resultant
triflate 193 could be carried out using standard Suzuki conditions (Scheme 99b).168
These
couplings proceeded in excellent yields to give 194a-c and allowed introduction of both
electron-rich and electron-deficient aromatic groups into the molecule.
Copper-free Sonogashira conditions with phenylacetylene also allowed for introduction of
a sp-C to give 195 in excellent yield (Scheme 99c).168
These reactions demonstrate that
through the use of well-known cross-coupling methods, a range of interesting structures
can be accessed from the products of Fe-mediated C–H coupling.
108
Scheme 99 Triflation and Pd-catalysed couplings of dihydrobenzofuran
Standard desulfurisations of the dihydrobenzofurans using Raney Ni were also carried out
to show the ease with which the sulfanyl group can be removed from these compounds
(Scheme 100).
Scheme 100 Desulfurisation of dihydrobenzofurans using Raney Ni
The organosulfanyl moiety can also be used for Ni-catalysed Kumada-Corriu cross-
couplings (Scheme 101).72,64
These coupings all proceeded in good to excellent yields and
could be carried out with a range of Grignard reagents. As Ni(0) can insert into either of
the two S–Ar bonds present in the molecule, an excess of the Grignard reagent was
109
required to bypass any regioselectivity issues and give high yields of the desired
compounds.169
Scheme 101 Ni-catalysed Kumada-Corriu cross-coupling
4.7 Summary
A sulfur-directed Fe(III)-mediated ortho C–H coupling of arenes with unactivated terminal
alkenes has been developed. The cross-coupling proceeds in moderate to good yield for a
range of alkenes and biaryl sulfides, with the latter currently requiring a 3,5-oxygenation
pattern with respect to the sulfur. The products of the reaction have shown a range of
reactivities and a number of transformations have been carried out to demonstrate various
avenues that can further be explored for their exploitation in target synthesis. Most notable
was the use of the essential ether groups and the installed chlorine moiety towards an
expedient synthesis of decorated dihydrobenzofuran motifs, also utilising classical Pd- and
Ni-catalysed cross-coupling chemistry.
While so far this reaction has required use of stoichiometric amounts of metal and attempts
towards a catalytic system have proven unfruitful, the transformation represents a novel
entry in the iron literature and so comparison with the work of others to aid in further
optimisation has been difficult. Additional investigations will undoubtedly shine more light
on the intricacies of this reaction system and allow for limitations to be addressed.
110
4.8 Future Work
4.8.1 Iron-mediated Chloroarylation of Alkenes
Most useful in moving this project forward would be to carry out further mechanistic
inquiries to elucidate the role of the metal and the integral part sulfur has to play. A
number of techniques have been utilised in probing the mechanism of various Fe-catalysed
reactions, such as Mossbauer spectroscopy and magnetic circular dichroism.170
These
specialised techniques may provide some insights into the current reactivity.
Based on observed results, such as the selectivity for linear products and investigation into
relative oxidation potentials, a novel SET activation method has been proposed (see
Section 4.4.1). Definitive evidence for this hypothesis has not yet been obtained and other
mechanisms are possible. A common experiment in probing whether a radical mechanism
is occurring would be to utilise radical clock studies. This was attempted using 1,6-dienes,
which may undergo radical 5-exo-trig cyclisations; however no cyclised products were
observed, posited to be due to fast radical oxidation/trapping. Another possible trapping
experiment would be the use of vinyl cyclopropane 199, with ring-opened products 200
being indicative of a radical process (Scheme 102). The ring-opening reaction
(k = 8.0 × 107 s
-1)171
should be faster than the 5-exo-trig cyclisation (k = 2.3 × 105 s
-1)128
previously investigated.
Scheme 102 Use of vinylcyclopropane in radical clock studies
Literature conditions describe the preparation of vinyl cyclopropane 199 via methylenation
of cyclopropylcarboxaldehyde 201 (Scheme 103).172
Vinyl cyclopropane was observed in
the crude 1H NMR spectrum when this reaction was carried out, however attempts to
111
isolate the product by the described distillation method (with the product boiling at 40 °C)
proved unsuccessful and an azeotropic mixture with DMSO was obtained.
Scheme 103 Preparation of vinyl cyclopropane via Wittig reaction
A further review of the literature demonstrated that vinyl cyclopropane is notoriously
difficult to isolate due to its tendency to azeotrope with most solvents.173
Other methods
were followed using toluene and mesitylene, but pure product was not obtained and
attempts were eventually ceased. To carry out the radical clock experiment, successful
isolation of this compound would be necessary. Alternatively, synthesis of substituted
vinyl cyclopropanes that may be easier to isolate could be carried out.174
Despite a number of further manipulations being performed, there exist other possibilities
that can be investigated. For example, the dibenzothiepine motif 202 is present in a number
of drug molecules and it may be possible to access these structures using the products of
the chloroarylation reaction (Scheme 104).175
This reaction would require displacement of
chlorine by the second arene ring and so a Friedel-Crafts or radical process may be
possible.
Scheme 104 Proposed conversion of chloroarylation products to dibenzothiepines
It has also recently been discovered in the Procter group that addition of AgOTf to
chloroarylation product 99a leads to formation of sulfonium salt 203 in high yield (Scheme
105). These compounds may show interesting reactivity patterns and so further
investigations will be carried out.
112
Scheme 105 Silver-mediated dehalogenation to form sulfonium salts
4.8.2 Manipulation of Allylation Products – The Truce-Smiles Rearrangement
Rather than its removal, a repurposing of the sulfanyl group required for the iron-mediated
cross-coupling was suggested. It was proposed that ortho-allylphenylsulfides, the products
of the Procter group’s sulfoxide-directed C–H alkylation process and also the iron-
mediated allylation of sulfides previously discussed, could be used in a Truce-Smiles
rearrangement after oxidation to the corresponding sulfones (Scheme 106).176
This reaction
would give rise to interesting vinyl-substituted diarylmethane compounds. Diarylmethanes
are useful in many industries, such as their presence in a number of dyes.177
Some
preliminary work was carried out to investigate the feasibility of this proposal.
Scheme 106 Proposed Truce-Smiles rearrangement of allylphenylsulfones
As the iron-mediated allylation of sulfides was not optimised, the most efficient route to
the required sulfides was via the C–H allylation of aryl sulfoxides.64
Following this
procedure successfully led to formation of 88c in 80% yield (Scheme 107).
Scheme 107 ortho-C–H Allylation of diphenylsulfoxide
113
Oxidation to the corresponding sulfone 204 was attempted using mCPBA, which had
proven successful in earlier manipulations of the chloroarylation products (Section 4.6).
However, the presence of the allyl group led to a complex mixture of products which
proved difficult to purify. Thus, a method for the selective oxidation of sulfur that would
tolerate the presence of a terminal olefin was sought. A procedure utilising
(NH4)2MoO4/H2O2 in MeOH was assessed, yet this gave a low yield of the desired product
204.178
After a short optimisation, it was found that carrying out this protocol in MeCN
successfully gave 204 in 58% yield (Scheme 108). This step will likely require further
optimisation in the future.
Scheme 108 Selective oxidation to the allylated sulfone
With 204 in hand, the Truce-Smiles rearrangement was attempted using n-BuLi as base
(Scheme 109).179
The sought-after rearrangement appeared to be successful, though the
corresponding sulfinic acid proved difficult to isolate and was prone to decomposition; as
such, only 23% of 205 was obtained.
Scheme 109 Preliminary studies on the Truce-Smiles rearrangement
It was found that the intermediate metal sulfinates 206 formed following rearrangement
can be easily intercepted using a range of electrophiles to give the corresponding
sulfones.180
The use of MeI was examined and, following a short investigation of
conditions, methyl sulfone 207 could be obtained in 70% after the two steps (Scheme 110).
114
Scheme 110 Use of MeI as quench for intermediary metal sulfinate
A number of other bases were inspected, such as LDA and KOt-Bu, however these failed
to give the rearranged product.181
The triad of n-BuLi/KOt-Bu/TMP is reported to
efficiently carry out benzylic metalation, but these conditions proved incompatible with
this system and decomposition of the starting material was observed without any
concomitant rearrangement occurring.159
Interestingly, the use of NaNH2 led to
isomerisation of the allyl unit to the internal alkene 208 in high yield (Scheme 111).182
This
may be due to reversible deprotonation, which leads to formation of the thermodynamic
alkene and the observed lack of rearrangement.
Scheme 111 Isomerisation of the allyl unit using NaNH2
Additional work is required to further optimise the Truce-Smiles reaction system and to
determine its scope. A number of possibilities can be explored in the future, as the metal
sulfinate intermediates are versatile reagents that can be used to access a variety of
compounds.183
Some interesting examples are demonstrated in Scheme 112.
115
Scheme 112 Potential further manipulations of metal sulfinate intermediates
The use of diphenyl iodonium salts to synthesise arylsulfones from sulfinates has
previously been reported (Pathway A).184
The products 209 may undergo another Truce-
Smiles rearrangement to form vinyl triarylmethanes 210. The formation of arylsulfoxides
from sulfinates is also known (Pathway B); these arylsulfoxides 211 can then carry out
another ortho-allylation/oxidation/Truce-Smiles procedure to give structures such as
212.185
This protocol can be repeated using the new metal sulfinate species as an iterative
approach towards extended or polymeric structures.
A number of other prospects, such as an asymmetric variant of the Truce-Smiles
rearrangement,186
metathesis reactions involving the vinyl moieties187
or the use of
sulfinate intermediates in Pd-catalysed reactions,188
can be further explored using this
chemistry and there are clearly many avenues to investigate.
116
5. Experimental
5.1 General Experimental
All experiments were performed under an atmosphere of nitrogen unless stated otherwise.
THF was distilled from sodium/benzophenone and CH2Cl2 was distilled from CaH2. All
other solvents and reagents were purchased from commercial sources and used as supplied.
Following reaction workup, the crude reaction mixtures were dissolved in a solution of
MeNO2 in CDCl3 of known concentration and crude yields were determined by 1H NMR
spectroscopy. 1H NMR spectra were obtained at room temperature on a 300, 400 or 500
MHz Bruker spectrometer, 13
C NMR spectra were recorded on a 75, 100 or 125 MHz
Bruker spectrometer. All chemical shift values are reported in parts per million (ppm)
relative to the solvent signal and were determined in CDCl3, with coupling constant (J)
values reported in Hz. The notation of signals is: Proton: δ chemical shift in ppm (number
of protons, multiplicity, J value(s), proton assignment). Carbon: δ chemical shift in ppm
(carbon assignment). If assignment is ambiguous, for example in the case of overlapping
signal, a range of shifts is reported.
Column chromatography was carried out using 35 – 70 μm, 60 Å silica gel. Routine TLC
analysis was carried out on silica gel 60 Å F254 coated aluminium sheets of 0.2 mm
thickness. Plates were viewed using a 254 nm ultraviolet lamp and dipped in aqueous
potassium permanganate, p-anisaldehyde or phosphomolybdic acid solutions.
Low resolution and high resolution mass spectra were obtained using either positive and/or
negative electrospray ionisation (ES), electron impact ionisation (EI), chemical ionisation
(CI) and photoionisation (PI) techniques.
IR spectra were recorded on a FTIR spectrometer as evaporated films (from CHCl3) using
sodium chloride windows or using neat samples.
5.2 Cyclic Voltammetry
All voltammetry was performed in a 5 mL water jacketed glass cell at 25 °C under Ar,
following purging with Ar (MeCN saturated with Ar for MeCN solutions), using CH
Instruments CHI600B Electrochemical Analyser with 3 mm diameter glassy carbon
working electrode and platinum wire counter electrode . Reference electrodes used were
Ag/AgCl 3 M KCl(aq) and a pseudo-reference electrode consisting of Ag wire coated in
AgCl (Ag wire dipped in concentrated HCl for a few minutes) in 0.1 M
117
tetrabutylammonium hexafluorophosphate (TBAHFP) separated from the analyte solution
via a glass frit.
The condition of the Ag/AgCl 3 M KCl(aq) reference electrode was tested by measuring
the formal potential of 1 mM K4Fe(CN)6.3H2O in 0.1 M KCl at pH 7. The pseudo-
reference electrode was calibrated by measuring the formal potential of 1 mM ferrocene in
0.1 M TBAHFP MeCN vs. Ag/AgCl 3 M KCl(aq) then measuring the formal potential of 1
mM ferrocene in 0.1 M TBAHFP in MeCN vs. the pseudo-reference electrode. The
stability of the pseudo-reference electrode was checked by repeating the ferrocene formal
potential measurement after measurement of analyte solutions had been completed.
Potassium ferrocyanide and ferrocene formal potentials were calculated by taking the value
at the mid-point between reduction and oxidation peaks. The formal potentials of (3,5-
dimethoxyphenyl)(phenyl)sulfide and (3-methoxyphenyl)(phenyl)sulfide were calculated
by fitting an EC mechanism model to the experimental data and finding the best fit over all
scan rates investigated (using 'sensible' values for the EC model parameters).
5.3 Sulfide Synthesis
General Procedure A: Pd-catalysed sulfide formation74
Tetrakis(triphenylphosphine)palladium(0) (58.0 mg, 0.05 mol), (S)-BINAP (62 mg, 0.10
mmol), potassium hydroxide (1.12 g, 20.0 mmol), the corresponding arylbromide (10.0
mmol), 2-propanol (10.3 mL) and the corresponding thiol (10.0 mmol) were charged to a
metal-capped, oven-dried test tube with Teflon-lined septum, pre-flushed with N2 at room
temperature. The mixture was heated to 80 ⁰C and stirred for 24 h. The reaction mixture
was then allowed to cool to room temperature before the addition of H2O (5 mL) and
dilution with EtOAc (5 mL). The organic layer was separated and washed twice more with
H2O (2 × 5 mL). The combined aqueous extracts were then further extracted with EtOAc
(2 × 10 mL) and the combined organic layers washed with brine (5 mL), dried over
Na2SO4 and concentrated in vacuo. The crude product was purified by column
chromatography on silica gel.
General Procedure B: Cu-catalysed sulfide formation75
Cu(I) iodide (19.0 mg, 0.10 mmol), potassium carbonate (553 mg, 4.00 mmol) and the
corresponding aryl iodide (2.00 mmol) were charged to a metal-capped, oven-dried test
tube with Teflon-lined septum. The tube was then evacuated and backfilled with argon
three times. 2-Propanol (2 mL), ethylene glycol (220 μL, 4.00 mmol) and the
118
corresponding thiol (1.00 mmol) were added and the mixture heated to 80 °C for 24 h with
stirring. The mixture was then cooled, passed through a plug of Celite® 545 with EtOAc
eluent and concentrated in vacuo. The crude product was purified by column
chromatography.
(2,5-Dimethoxyphenyl)(phenyl)sulfide68 91a
Thiophenol (2.16 mL, 20.0 mmol) was charged to a stirred solution of p-benzoquinone
(2.16 g, 20.0 mmol) in MeOH (50 mL). The mixture was stirred for 10 min., followed by
removal of solvent in vacuo to give a yellow solid; δH (400 MHz, CDCl3) 6.12 (1 H, br. S,
OH), 6.85 - 7.04 (3 H, m, aryl H), 7.09 - 7.21 (3 H, m, aryl H), 7.22 - 7.30 (2 H, m,
aryl H).189
The solid was dissolved in THF (50 mL) and added dropwise to a stirred
mixture of NaH (60% in oil, 2.40 g, 60 mmol) in 150 mL THF. MeI (4.98 mL, 80.0 mmol)
was added dropwise to this mixture and left to stir at room temperature for 24 h. The
mixture was then quenched with H2O (100 mL) and extracted with EtOH (3 × 100 mL).
The combined organic residues were washed with brine (50 mL), dried over Na2SO4,
filtered and the solvent was removed in vacuo. The crude product was purified using
column chromatography (50:1 petroleum ether:EtOAc) to give 91a (4.63 g, 18.8 mmol,
94% yield) as a colourless oil; δH (400 MHz, CDCl3) 3.58 (3 H, s, OCH3), 3.76 (3 H, s,
OCH3), 6.52 (1 H, d, J 3.0 Hz, aryl H), 6.66 (1 H, dd, J 8.8, 3.0 Hz, aryl H), 6.75 (1 H, d, J
8.8 Hz, aryl H), 7.16 - 7.28 (3 H, m, aryl H), 7.29 - 7.34 (2 H, m, aryl H).
(3,5-Dimethoxyphenyl)(phenyl)sulfide190 91b
As described in general procedure A, 1-bromo-3,5-dimethoxybenzene (2.19 g, 10.0 mmol)
and thiophenol (1.08 mL, 10.0 mmol), after purification by column chromatography (50:1
hexanes:EtOAc) gave 91b (2.21 g, 8.97 mmol, 90% yield) as a colourless oil; δH (400
MHz, CDCl3) 3.74 (6 H, s, OCH3), 6.34 (1 H, t, J 2.3 Hz, aryl H), 6.47 (2 H, d, J 2.3 Hz,
119
aryl H), 7.25 - 7.36 (3 H, m, aryl H), 7.38 - 7.43 (2 H, m, aryl H); δC (100 MHz, CDCl3)
55.8 (OCH3), 99.6 (aryl C-H), 108.4 (aryl C-H), 127.6 (aryl C-H), 129.4 (aryl C-H), 122.1
(aryl C-H), 135.3 (aryl Cq), 138.3 (aryl Cq), 161.4 (aryl Cq).
(4-Methoxyphenyl)(phenyl)sulfide191 91c
As described in general procedure A, 4-bromoanisole (1.25 mL, 10.0 mmol) and
thiophenol (1.08 mL, 10.0 mmol), after purification by column chromatography (50:1
hexanes:EtOAc) gave 91c (1.87 g, 8.65 mmol, 87% yield) as a colourless oil; δH (400
MHz, CDCl3) 3.65 (3 H, s, OCH3), 6.73 (2 H, d, J 9.1 Hz, aryl H), 6.93 - 7.10 (5 H, m, aryl
H), 7.24 (2 H, d, J 9.1 Hz, aryl H); δC (100 MHz, CDCl3) 55.6 (OCH3), 115.1 (aryl C-H),
124.7 (aryl Cq), 126.2 (aryl C-H), 128.3 (aryl C-H), 129.4 (aryl C-H), 135.7 (aryl C-H),
140.0 (aryl Cq), 160.3 (aryl Cq).
(3,5-Dimethoxyphenyl)(4-nitrophenyl)sulfide192
91d
As described in general procedure B, 1-iodo-4-nitrobenzene (498 mg, 2.00 mmol) and 3,5-
dimethoxybenzenethiol (340 mg, 2.00 mmol), after purification by column
chromatography (10% EtOAc in hexanes) gave 91d (542 mg, 1.86 mmol, 93%) as a
yellow solid; δH (400 MHz, CDCl3) 3.80 (6 H, s, OCH3), 6.53 (1 H, t, J 2.3 Hz, aryl H),
6.68 (2 H, d, J 2.3 Hz, aryl H), 7.24 (2 H, d, J 8.8 Hz, aryl H), 8.09 (2 H, d, J 8.8 Hz, aryl
H); δC (100 MHz, CDCl3) 55.6 (OCH3), 101.9 (aryl C-H), 112.0 (aryl C-H), 124.0 (aryl C-
H), 127.0 (aryl C-H), 132.0 (aryl Cq), 145.4 (aryl Cq), 148.0 (aryl Cq), 161.6 (aryl Cq).
120
(3,5-Dimethoxyphenyl)(4-(trifluoromethyl)phenyl)sulfide 91e
As described in general procedure B, 4-iodobenzotrifluoride (295 μL, 2.00 mmol) and 3,5-
dimethoxybenzenethiol (340 mg, 2.00 mmol), after purification by column
chromatography (50:1 hexanes:EtOAc) gave 91e (465 mg, 1.48 mmol, 68%) as a
colourless oil; δH (500 MHz, CDCl3) 3.78 (6 H, m, OCH3), 6.47 (1 H, t, J 2.4 Hz, aryl H),
6.62 (2 H, d, J 2.4 Hz, aryl H), 7.34 (2 H, d, J 8.2 Hz, aryl H), 7.51 (2 H, d, J 8.2 Hz, aryl
H); δC (125 MHz, CDCl3) 55.5 (OCH3), 100.9 (aryl C-H), 110.7 (aryl C-H), 124.1 (q, J
271.6 Hz, CF3), 125.8 (q, J 4.5 Hz, aryl C-H), 128.5 (q, J 32.7 Hz, aryl Cq), 128.8 (aryl C-
H), 134.4 (aryl Cq), 142.2 (aryl Cq), 161.3 (aryl Cq); νmax (thin film/cm-1
) 1013 (s), 1043
(s), 1061 (s), 1061 (s), 1088 (s), 1119 (s), 1154 (s), 1205 (m), 1321 (s), 1419 (w), 1581 (s),
2940 (w); MS (ES+) m/z 315 [(M+H)
+]; HRMS C15H14F3O2S [(M+H)
+] Expected
315.0667, Found 315.0671.
(2-Methoxy)(phenyl)sulfide190 91f
As described in general procedure A, 2-bromoanisole (1.25 mL, 10.0 mmol) and
thiophenol (1.08 mL, 10.0 mmol) after purification by column chromatography (50:1
hexanes:EtOAc) gave 91f (1.29 g, 5.96 mmol, 60% yield) as a colourless oil; (400
MHz, CDCl3) 3.89 (3 H, s, OCH3), 6.86 - 6.94 (2 H, m, aryl H), 7.09 (1 H, dd, J 7.7, 1.6
Hz, aryl H), 7.22 - 7.39 (6 H, m, aryl H); δC (100 MHz, CDCl3) 55.9 (OCH3), 110.9 (aryl
C-H), 121.2 (aryl C-H), 124.1 (aryl Cq), 127.1 (aryl C-H), 128.3 (aryl C-H), 129.2 (aryl C-
H), 131.5 (aryl C-H), 131.6 (aryl C-H), 134.5 (aryl Cq), 157.3 (aryl Cq).
121
(3-Methoxy)(phenyl)sulfide193 91g
As described in general procedure A, 3-bromoanisole (1.27 mL, 10.0 mmol) and
thiophenol (1.08 mL, 10.0 mmol), after purification by column chromatography (50:1
hexanes:EtOAc) gave 91g (1.98 g, 9.15 mmol, 92% yield) as a colourless oil; (400
MHz, CDCl3) 3.77 (3 H, s, OCH3), 6.79 (1 H, ddd, J 8.3, 2.5, 0.9 Hz, aryl H), 6.87 - 6.89
(1 H, m, aryl H), 6.90 – 6.94 (1 H, m, aryl H), 7.19 - 7.35 (4 H, m, aryl H), 7.36 – 7.41 (2
H, m, aryl H); δC (100 MHz, CDCl3) 55.3 (OCH3), 112.8 (aryl C-H), 115.9 (aryl C-H),
123.0 (aryl C-H), 127.3 (aryl C-H), 129.2 (aryl C-H), 130.0 (aryl C-H), 131.4 (aryl C-H),
135.3 (aryl Cq), 137.2 (aryl Cq), 160.0 (aryl Cq).
(3,4-Dimethoxyphenyl)(phenyl)sulfide 91h
As described in general procedure A, 4-bromoveratrole (1.44 mL, 10.0 mmol) and
thiophenol (1.08 mL, 10.0 mmol), after column chromatography (50:1 hexanes:EtOAc)
gave 91h (2.05 g, 8.32 mmol, 83%) as a white solid; m.p. 41.4-42.8 °C; (400 MHz,
CDCl3) 3.85 (3 H, s, OCH3), 3.91 (3 H, s, OCH3), 6.87 (1 H, d, J 8.3 Hz, aryl H), 7.00 (1
H, d, J 2.1 Hz, aryl H), 7.09 (1 H, dd, J 8.3, 2.1 Hz, aryl H), 7.13 - 7.22 (3 H, m, aryl H),
7.23 - 7.29 (2 H, m, aryl H); δC (100 MHz, CDCl3) 55.9 (OCH3), 56.0 (OCH3), 111.8 (aryl
C-H), 116.6 (aryl C-H), 124.6 (aryl Cq), 125.9 (aryl C-H), 126.7 (aryl C-H), 128.2 (aryl C-
H), 129.0 (aryl C-H), 138.4 (aryl Cq), 149.4 (aryl Cq), 149.5 (aryl Cq); νmax (thin film/cm-1
);
1024 (s), 1136 (m), 1230 (s), 1253 (vs), 1439 (m), 1503 (vs), 1583 (m), 2836 (w), 2905
(w), 2952 (w), 3000 (w), 3056 (w); MS (GCMS) m/z 246 (M+); HRMS (PI) C14H15O2S
[(M+H)+] Expected 247.0787, Found 247.0786.
122
(3,4,5-Trimethoxyphenyl)(phenyl)sulfide 91i
As described in general procedure A, 5-bromo-1,2,3-trimethoxybenzene (2.47 g, 10.0
mmol) and thiophenol (1.08 mL, 10.0 mmol), after purification by column chromatography
(10% EtOAc in hexanes) gave 91i (1.80 g, 6.51 mmol, 65%) as a white solid; m.p 51.0-
53.1 °C; (400 MHz, CDCl3) 3.80 (6 H, s, OCH3), 3.86 (3 H, s, OCH3), 6.66 (2 H, s, aryl
H), 7.19 - 7.26 (1 H, m, aryl H), 7.28 – 7.32 (4 H, m, aryl H); δC (100 MHz, CDCl3) 56.1
(OCH3), 60.9 (OCH3), 109.4 (aryl C-H), 126.6 (aryl C-H), 129.1 (aryl C-H), 129.3 (aryl
Cq), 129.6 (aryl C-H), 136.7 (aryl Cq), 137.8 (aryl Cq), 153.6 (aryl Cq); νmax (thin film/cm-1
)
1005 (m), 1125 (vs), 1231 (s), 1307 (m), 1403 (s), 1578 (s), 2829 (w), 2935 (w), 2999 (w),
3056 (w); MS (ES+) m/z 277 [(M+H)
+]; HRMS C15H17O3S [(M+H)
+] Expected 277.0893,
Found 277.0891.
(3,5-Dimethoxyphenyl)(4-methoxyphenyl)sulfide 91j
As described in general procedure A, 1-bromo-3,5-dimethoxybenzene (2.19 g, 10.0 mmol)
and 4-methoxythiophenol (1.23 mL, 10.0 mmol), after purification by column
chromatography (50:1 hexanes:EtOAc) gave 91j (1.77 g, 6.40 mmol, 64% yield) as a white
solid; m.p. 61.2-63.8 °C; (400 MHz, CDCl3) 3.72 (6 H, s, OCH3), 3.84 (3 H, s, OCH3),
6.25 (1 H, t, J 2.3 Hz, aryl H), 6.30 (2 H, d, J 2.3 Hz, aryl H), 6.89 - 6.95 (2 H, m, aryl H),
7.43 - 7.48 (2 H, m, aryl H); δC (100 MHz, CDCl3) 55.3 (OCH3), 55.4 (OCH3), 98.0 (aryl
C-H), 105.6 (aryl C-H), 115.0 (aryl C-H), 123.3 (aryl Cq), 135.9 (aryl C-H), 141.1 (aryl
Cq), 160.1 (aryl Cq), 161.0 (aryl Cq); νmax (thin film/cm-1
) 1030 (m), 1043 (m), 1153 (vs),
1203 (s), 1244 (s), 1282 (m), 1418 (m), 1453 (m), 1492 (s), 1582 (vs), 2834 (w), 2937 (w),
2958 (w), 3000 (w); MS (ES+) m/z 277 [(M+H)
+]; HRMS C15H17O3S [(M+H)
+] Expected
277.0893, Found 277.0884.
123
(3,5-Dimethoxyphenyl)[4-(methylsulfanyl)phenyl]sulfide 91k
As described in general procedure A, 1-bromo-3,5-dimethoxybenzene (2.19 g, 10.0 mmol)
and 4-(methylsulfanyl)-thiophenol (1.56 g, 10.0 mmol), after purification by column
chromatography (50:1 hexanes:EtOAc) gave 91k (2.61 g, 8.93 mmol, 89% yield) as a
colourless oil; (400 MHz, CDCl3) 2.49 (3 H, s, SCH3), 3.74 (6 H, s, OCH3), 6.31 (1 H,
t, J 2.3 Hz, aryl H), 6.41 (2 H, d, J 2.3 Hz, aryl H), 7.19 - 7.24 (2 H, m, aryl H), 7.33 - 7.37
(2 H, m, aryl H); δC (100 MHz, CDCl3) 15.6 (SCH3), 55.4 (OCH3), 98.9 (aryl C-H), 107.4
(aryl C-H), 127.1 (aryl C-H), 130.3 (aryl Cq), 133.0 (aryl C-H), 138.7 (aryl Cq), 138.9 (aryl
Cq), 161.0 (aryl Cq); νmax (thin film/cm-1
) 1044 (m), 1063 (m), 1154 (vs), 1204 (s), 1419
(m), 1453 (m), 1476 (m), 1583 (vs), 2832 (w), 2936 (w), 2958 (w), 3000 (w); MS (ES+)
m/z 293 [(M+H)+]; HRMS C15H17O2S2 [(M+H)
+] Expected 293.0664, Found 293.0655.
bis(3-Methoxyphenyl)sulfide194 91l
As described in general procedure A, 3-bromoanisole (1.27 mL, 10.0 mmol) and 3-
methoxythiophenol (1.24 mL, 10.0 mmol), after purification by column chromatography
(50:1 hexanes:EtOAc) gave 91l (2.05 g, 8.32 mmol, 83%) as a colourless oil; (400
MHz, CDCl3) 3.78 (6 H, s, OCH3), 6.80 (2 H, ddd, J 8.3, 2.5, 0.9 Hz, aryl H), 6.89 - 6.92
(2 H, m, aryl H), 6.93 - 6.97 (2 H, m, aryl H), 7.23 (2 H, t, J 8.0 Hz, aryl H); δC (100 MHz,
CDCl3) 55.3 (OCH3), 113.0 (aryl C-H), 116.3 (aryl C-H), 123.4 (aryl C-H), 130.0 (aryl C-
H), 136.7 (aryl Cq), 160.1 (aryl Cq).
bis(4-Methoxyphenyl)sulfide191 91m
As described in general procedure A, 4-bromoanisole (1.25 mL, 10.0 mmol) and 4-
methoxythiophenol (1.23 mL, 10.0 mmol), after purification by column chromatography
(50:1 hexanes:EtOAc) gave 91m (2.04 g, 83% yield) as a white solid; (400 MHz,
124
CDCl3) 3.80 (6 H, s, OCH3), 6.82 – 6.88 (4 H, m, aryl H), 7.26 – 7.31 (4 H, m, aryl H); δC
(100 MHz, CDCl3) 55.3 (OCH3), 114.7 (aryl C-H), 127.4 (aryl Cq), 132.7 (aryl C-H), 158.9
(aryl Cq).
(3,5-Dimethylphenyl)(phenyl)sulfide195 91n
As described in general procedure A, 1-bromo-3,5-dimethylbenzene (1.85 g, 10.0 mmol)
and thiophenol (1.08 mL, 10.0 mmol), after purification by column chromatography (50:1
hexanes:EtOAc) gave 91n (1.96 g, 9.14 mmol, 91%) as a colourless oil; (400 MHz,
CDCl3) 2.29 (6 H, s, ArCH3), 6.89 - 6.92 (1 H, m, aryl H), 7.00 - 7.03 (2 H, m, aryl H),
7.20 - 7.26 (1 H, m, aryl H), 7.27 - 7.35 (4 H, m, aryl H); δC (100 MHz, CDCl3) 21.2
(ArCH3), 126.7 (aryl C-H), 129.0 (aryl C-H), 129.1 (aryl C-H), 130.5 (aryl C-H), 134.7
(aryl Cq), 136.3 (aryl Cq), 138.9 (aryl Cq).
(3-Methoxy-5-methylphenyl)(phenyl)sulfide 91o
As described in general procedure A, 3-bromo-5-methoxytoluene (2.01 g, 10.0 mmol) and
thiophenol (1.08 mL, 10.0 mmol), after purification by column chromatography (50:1
hexanes:EtOAc) gave 91o (1.61 g, 6.99 mmol, 70%) as a colourless oil; ; (400 MHz,
CDCl3) 2.29 (3 H, s, CH3), 3.75 (3 H, s, OCH3), 6.60 – 6.63 (1 H, m, aryl H), 6.69 (1 H, t,
J 1.5 Hz, aryl H), 6.78 (1 H, td, J 1.5, 0.8 Hz, aryl H), 7.22 - 7.29 (1 H, m, aryl H), 7.29 -
7.35 (2 H, m, aryl H), 7.35 - 7.39 (2 H, m, aryl H); δC (100 MHz, CDCl3) 21.4 (ArCH3),
55.2 (OCH3), 113.2 (aryl C-H), 113.9 (aryl C-H), 123.9 (aryl C-H), 127.1 (aryl C-H),
129.2 (aryl C-H), 131.1 (aryl C-H), 135.6 (aryl Cq), 136.5 (aryl Cq), 140.2 (aryl Cq), 160.0
(aryl Cq); νmax (thin film/cm-1
) 1058 (s), 1152 (s), 1165 (m), 1274 (s), 1415 (m), 1438 (m),
1463 (m), 1575 (s), 2833 (w), 2937 (w), 3001 (w), 3058 (w); MS (ES+) m/z 231 [(M+H)
+];
HRMS C14H15OS [(M+H)+] Expected 231.0838, Found 231.0838.
125
Naphthalen-2-yl(phenyl)sulfide196 91p
As described in general procedure A, 2-bromonaphthalene (2.07 g, 10.0 mmol) and
thiophenol (1.08 mL, 10.0 mmol), after purification by column chromatography (50:1
hexanes:EtOAc) gave 91p (1.90 g, 8.04 mmol, 80%) as a white solid; (400 MHz,
CDCl3) 7.19 - 7.30 (3 H, m, aryl H), 7.31 - 7.39 (3 H, m, aryl H), 7.39 - 7.47 (2 H, m, aryl
H), 7.67 - 7.82 (4 H, m, aryl H); δC (100 MHz, CDCl3) 126.2 (aryl C-H), 126.6 (aryl C-H),
127.1 (aryl C-H), 127.4 (aryl C-H), 127.7 (aryl C-H), 128.7 (aryl C-H), 128.8 (aryl C-H),
129.2 (aryl C-H), 129.9 (aryl C-H), 130.9 (aryl C-H), 132.3 (aryl Cq), 133.0 (aryl Cq),
133.8 (aryl Cq), 135.8 (aryl Cq).
(3,5-Dimethoxy-2-nitrophenyl)(phenyl)sulfide 91q and (3,5-dimethoxy-4-
nitrophenyl)(phenyl)sulfide 91r
Fe(NO3)3.9H2O (1.21 g, 3.00 mmol) was charged to a solution of 91b (500 mg, 2.03
mmol) in MeCN (30 mL). The mixture was heated to reflux and stirred for 2 h, before
cooling to room temperature. The solvent was then removed in vacuo and the crude
dissolved in EtOAc (20 mL). The mixture was extracted with H2O (3 × 20 mL) and the
aqueous extracts washed with EtOAc (3 × 20 mL). The combined organic extracts were
dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by
column chromatography (50% CHCl3 in hexanes) to give 91q (273 mg, 0.937 mmol, 47%)
as a yellow solid and 91r (128 mg, 0.439 mmol, 22%) as an orange solid; For 91q, m.p
75.5-76.2 °C; δH (400 MHz, CDCl3) 3.65 (3 H, s, OCH3), 3.89 (3 H, s, OCH3), 6.12 (1 H,
d, J 2.5 Hz, aryl H), 6.35 (1 H, d, J 2.5 Hz, aryl H), 7.35 - 7.43 (3 H, m, aryl H), 7.45 - 7.53
(2 H, m, aryl H); δC (100 MHz, CDCl3) 55.6 (OCH3), 56.6 (OCH3), 97.6 (aryl C-H), 106.4
(aryl C-H), 129.0 (aryl C-H), 129.6 (aryl C-H), 132.3 (aryl Cq), 133.9 (aryl C-H), 135.3
(aryl Cq), 153.8 (aryl Cq), 161.4 (aryl Cq); νmax (thin film/cm-1
) 1039 (s), 1166 (m), 1222
(m), 1292 (s, N-O sym), 1319 (m), 1520 (s), 1579 (vs, N-O asym), 2841 (vw), 2942 (vw),
2973 (vw), 3010 (vw); MS (ES+) m/z 292 [(M+H)
+]; HRMS C14H14NO4S [(M+H)
+]
126
Expected 292.0638, Found 292.0628; For 91r, m.p 71.4-72.2 °C; δH (400 MHz, CDCl3)
3.76 (6 H, s, OCH3), 6.44 (2 H, s, aryl H), 7.36 - 7.45 (3 H, m, aryl H), 7.45 - 7.52 (2 H, m,
aryl H); δC (100 MHz, CDCl3) 56.4 (OCH3), 104.5 (aryl C-H), 128.8 (aryl C-H), 129.7
(aryl C-H), 132.3 (aryl Cq), 133.4 (aryl C-H), 142.5 (aryl Cq), 152.0 (aryl Cq); νmax (thin
film/cm-1
) 880 (s, para aryl), 1131 (vs), 1234 (s), 1373 (s, N-O sym), 1404 (m), 1526 (vs,
N-O asym), 1577 (s), 2839 (vw), 2943 (vw), 3013 (vw); MS (ES+) m/z 292 [(M+H)
+];
HRMS C14H14NO4S [(M+H)+] Expected 292.0638, Found 292.0626.
(3,5-Dimethoxy-4-methylphenyl)(phenyl)sulfide 91s
91b (400 mg, 1.60 mmol) was dissolved in THF (16 mL) and cooled to −78 °C. A solution
of n-butyllithium (1.60 M in hexanes, 1.22 mL, 1.95 mmol) was then added and the
mixture was warmed to room temperature and MeI (896 µL, 14.4 mmol) added dropwise.
The solution was left to stir for 10 min. and sat. aq. NH4Cl (2 mL) and EtOAc (2 mL) were
then added. The organic layer was then washed twice more with sat. aq. NH4Cl (2 ml). The
aqueous layer was extracted with EtOAc (2 × 2 mL) and the combined organic extracts
were dried with Na2SO4, filtered and solvent removed in vacuo. The crude product was
purified by column chromatography (30% CHCl3 in hexanes) to give 91s (352 mg, 1.35
mmol, 84%) as a colourless oil; δH (400 MHz, CDCl3) 2.09 (3 H, s, ArCH3), 3.77 (6 H, s,
OCH3), 6.62 (2 H, s, aryl H), 7.18 - 7.24 (1 H, m, aryl H), 7.27 - 7.32 (4 H, m, aryl H); δC
(100 MHz, CDCl3) 8.2 (ArCH3), 55.8 (OCH3), 107.8 (aryl C-H), 114.5 (aryl Cq), 126.4
(aryl C-H), 129.0 (aryl C-H), 129.5 (aryl C-H), 131.8 (aryl Cq), 137.0 (aryl Cq), 158.6 (aryl
Cq); νmax (thin film/cm-1
) 1136 (vs), 1231 (m), 1288 (w), 1398 (s), 1439 (m), 1449 (m),
1477 (m), 1578 (s), 2831 (w), 2937 (w), 3000 (w); MS (ES+) m/z 261 [(M+H)
+]; HRMS
C15H17O2S [(M+H)+] Expected 261.0944, Found 261.0936.
127
t-Butyl(3,5-dimethoxyphenyl)sulfide 197 91t
1-Bromo-3,5-dimethoxybenzene (450 mg, 2.00 mmol), Pd(PPh3)4 (23.1 mg, 20.0 µmol),
NaOt-Bu (392 mg, 4.00 mmol), n-BuOH (20 mL) and t-BuSH (225 µL, 2.00 mmol) were
added to a metal-capped, oven-dried test tube with Teflon-lined septum, pre-flushed with
N2 at room temperature. The mixture was heated to 120 °C and stirred for 18 h. The
reaction mixture was then allowed to cool to room temperature before the addition of H2O
(20 mL) and dilution with EtOAc (20 mL). The organic layer was separated and washed
twice more with H2O (2 × 20 mL). The combined aqueous extracts were then further
extracted with EtOAc (2 × 20 mL) and the combined organic layers washed with brine (20
mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was
purified by column chromatography on silica gel (5% EtOAc in hexanes) to give 91t (427
mg, 1.89 mmol, 94%) as a colourless oil; δH (400 MHz, CDCl3) 1.33 (9 H, s, C(CH3)3),
3.80 (6 H, s, OCH3), 6.48 (1 H, t, J 2.5 Hz, aryl H), 6.71 (2 H, d, J 2.5 Hz, aryl H); δC (100
MHz, CDCl3) 31.1 (C(CH3)3), 46.1 (C(CH3)3), 55.4 (OCH3), 101.3 (aryl C-H), 115.0 (aryl
C-H), 134.3 (aryl Cq), 160.2 (aryl Cq); νmax (thin film/cm-1
) 1046 (m), 1062 (m), 1152 (vs),
1204 (s), 1276 (m), 1363 (w), 1416 (m), 1455 (m), 1582 (vs), 2833 (w), 2861 (w), 2939
(w), 2959 (w), 3000 (w); MS (APCI) m/z 227 [(M+H)+]; HRMS C12H19O2S [(M+H)
+]
Expected 227.1100, Found 227.1095.
(3,5-Dimethoxyphenyl)(p-tolyl)sulfide 91v
As described in general procedure A, 1-bromo-3,5-dimethoxybenzene (2.19 g, 10.0 mmol)
and p-thiocresol (1.24 g, 10.0 mmol), after purification by column chromatography (50:1
hexanes:EtOAc) gave 91v (2.37 g, 9.10 mmol, 91%) as a white solid; m.p. 64.7-67.4 ⁰C;
δH (400 MHz, CDCl3) 2.37 (3 H, s, ArCH3), 3.74 (6 H, s, OCH3), 6.30 (1 H, t, J 2.3 Hz,
128
aryl H), 6.40 (2 H, d, J 2.3 Hz, aryl H), 7.17 (2 H, d, J 7.8 Hz, aryl H), 7.36 (2 H, d, J 7.8
Hz, aryl H); δC (100 MHz, CDCl3) 21.1 (ArCH3), 55.3 (OCH3), 98.6 (aryl C-H), 107.0
(aryl C-H), 130.0 (aryl C-H), 130.2 (aryl Cq), 132.9 (aryl C-H), 138.0 (aryl Cq), 139.5 (aryl
Cq), 161.0 (aryl Cq); νmax (thin film/cm-1
) 1044 (s), 1103 (s), 1203 (s), 1280.2 (w), 1418
(m), 1581 (s), 2833 (w), 2936 (s); MS (ES+) m/z 261 [(M+H)
+]; HRMS C15H17O2S
[(M+H)+] Expected 261.0949, Found 261.0945.
3,5-Dimethoxybenzenethiol163
94a
Dimethylthiocarbamoyl chloride (7.90 g, 64.0 mmol) in DMF (10 mL) was added slowly
to a mixture of 3,5-dimethoxyphenol (5.00 g, 32.0 mmol) and 1,4-
diazabicylclo[2.2.2]octane (7.18 g, 64.0 mmol) in DMF (30 mL). The mixture was stirred
at room temperature overnight and 10% aq. LiCl (40 mL) and ether (150 mL) were added.
The organic layer was separated and washed with 10% aq. LiCl (3 × 40 mL) and brine (20
mL). The combined organic layers were dried with Na2SO4, filtered and concentrated in
vacuo. The crude product was purified by column chromatography on silica gel (4:1
hexanes:EtOAc) to give O-3,5-dimethoxyphenyl dimethylthiocarbamate (7.54 g, 31.2
mmol, 98%) as a white solid; δH (500 MHz, CDCl3) 3.33 (3 H, s, C(O)N(CH3)2), 3.46 (3 H,
s, C(O)N(CH3)2), 3.79 (6 H, s, OCH3), 6.26 (2 H, d, J 2.5 Hz, aryl H), 6.37 (1 H, t, J 2.2
Hz, aryl H). The solid was heated to 260 °C for 3 h under nitrogen to give a brown oil after
cooling, which was dissolved in MeOH (100 mL). KOH (11.60 g, 200 mmol) was added
and the mixture was refluxed for 2 h with stirring. After cooling, the mixture was
concentrated and EtOAc (150 mL) and 1N HCl (30 mL) were added. The organic layer
was washed with brine (3 × 40 mL), dried with Na2SO4, filtered and concentrated in vacuo.
The crude product was purified by column chromatography on silica gel (10% EtOAc in
hexanes) to give 94a (3.48 g, 20.4 mmol, 64% (3 steps)) as a colourless oil; δH (400 MHz,
CDCl3) 3.47 (1 H, s, SH), 3.77 (6 H, s, OCH3), 6.27 (1 H, t, J 2.3 Hz, aryl H), 6.43 (2 H, d,
J 2.3 Hz, aryl H).
129
(4-Bromophenyl)(3,5-dimethoxyphenyl)sulfide 91w
As described in general procedure B, 1-bromo-4-iodobenzene (566 mg, 2.00 mmol) and
94a (340 mg, 2.00 mmol), after purification by column chromatography (50:1
hexanes:EtOAc) gave 91w (534 mg, 1.64 mmol, 80%) as a white solid; m.p. 54.2-56.2 ⁰C;
δH (400 MHz, CDCl3) 3.76 (6 H, s, OCH3), 6.37 (1 H, t, J 2.1 Hz, aryl H), 6.48 (2 H, d, J
2.1 Hz, aryl H), 7.23 (2 H, d, J 8.5 Hz, aryl H), 7.43 (2 H, d, J 8.5 Hz, aryl H); δC (100
MHz, CDCl3) 55.4 (OCH3), 99.7 (aryl C-H), 108.7 (aryl C-H), 121.3 (aryl Cq), 132.3 (aryl
C-H), 132.7 (aryl C-H), 134.5 (aryl Cq), 137.0 (aryl Cq), 161.1 (aryl Cq); νmax (thin film/cm-
1) 1044 (m), 1154 (s), 1204 (m), 1281 (w), 1418 (m), 1581 (s), 2833 (w), 2936 (w), 3001
(w); MS (ES+) m/z 326
79Br, 328
81Br [(M+H)
+]; HRMS C14H14BrO2S [(M+H)
+] Expected
325.9878, Found 325.9886.
(3,5-Dimethoxyphenyl)(4-fluorophenyl)sulfide 91x
As described in general procedure B, 1-bromo-3,5-dimethoxybenzene (2.19 g, 10.0 mmol)
and 4-fluorobenzenethiol (1.10 mL, 10.0 mmol), after purification by column
chromatography (50:1 hexanes:EtOAc) gave 91x(1.40 g, 5.30 mmol, 53%) as a colourless
oil; δH (400 MHz, CDCl3) 3.74 (6 H, s, OCH3), 6.31 (1 H, t, J 2.3 Hz, aryl H), 6.38 (2 H, d,
J 2.3 Hz, aryl H), 7.06 (2 H, t, J 8.8 Hz, aryl H), 7.44 (2 H, dd, J 8.8, 5.3 Hz, aryl H); δC
(100 MHz, CDCl3) 55.3 (OCH3), 98.8 (aryl C-H), 107.1 (aryl C-H), 116.4 (d, J 22.1 Hz,
aryl C-H), 129.2 (d, J 3.7 Hz, aryl Cq), 134.8 (d, J 8.1 Hz, aryl C-H), 139.0 (aryl Cq), 161.1
(aryl Cq), 163.0 (d, J 248.4 Hz, aryl C-F); νmax (thin film/cm-1
) 1043 (m), 1152 (s), 1203
130
(s), 1281 (w), 1418 (m), 1453 (m), 1488 (s), 1581 (s), 2834 (w), 2938 (w); MS (ES+) m/z
265 [(M+H)+]; HRMS C14H14FO2S [(M+H)
+] Expected 265.0699, Found 265.0711.
(3,5-Dimethoxyphenyl)(2-fluorophenyl)sulfide 91y
As described in general procedure A, 1-bromo-3,5-dimethoxybenzene (2.19 g, 10.0 mmol)
and 2-fluorothiophenol (1.49 mL, 10.0 mmol), after purification by column
chromatography (50:1 hexanes:EtOAc) gave 91y (1.53 g, 5.79 mmol, 58% yield) as a
colourless oil; δH (500 MHz, CDCl3) 3.78 (6 H, s, OCH3), 6.40 (1 H, t, J 2.2 Hz, aryl H),
6.51 (2 H, d, J 2.2 Hz, aryl H), 7.10 - 7.19 (2 H, m, aryl H), 7.28 - 7.42 (2 H, m, aryl H); δC
(125 MHz, CDCl3) 55.3 (OCH3), 99.4 (aryl C-H), 108.0 (aryl C-H), 115.9 (d, J 22.7 Hz,
aryl C-H), 121.7 (d, J 18.2 Hz, aryl Cq), 124.7 (d, J 3.6 Hz, aryl C-H), 129.7 (d, J 8.2 Hz,
aryl C-H), 134.0 (aryl C-H), 136.3 (aryl Cq), 161.0 (aryl Cq), 161.2 (d, J 247 Hz, aryl C-F);
νmax (thin film/cm-1
) 1042 (m), 1153 (s), 1203 (s), 1281 (w), 1418 (m), 1454 (m), 1471 (s),
1581 (s), 2834 (w), 2938 (w); MS (ES+) m/z 265 [(M+H)
+]; HRMS C14H14FO2S [(M+H)
+]
Expected 265.0699, Found 265.0705.
(3,5-Dimethoxyphenyl)(3-methoxyphenyl)sulfide 91z
As described in general procedure A, 1-bromo-3,5-dimethoxybenzene (2.19 g, 10.0 mmol)
and 3-methoxythiophenol (1.20 mL, 10.0 mmol), after purification by column
chromatography (50:1 hexanes:EtOAc) gave 91z (2.39 g, 8.64 mmol, 86% yield) as a
colourless oil; δH (500 MHz, CDCl3) 3.75 (6 H, s, OCH3), 3.78 (3 H, s, OCH3), 6.35 (1 H,
t, J 2.2 Hz, aryl H), 6.50 (2 H, d, J 2.2 Hz, aryl H), 6.81 (1 H, dt, J 7.9, 1.9 Hz, aryl H),
6.94 (1 H, t, J 1.9 Hz, aryl H), 6.98 (1 H, dt, J 7.9, 1.9 Hz, aryl H), 7.24 (1 H, t, J 7.9 Hz,
131
aryl H); δC (125 MHz, CDCl3) 55.3 (OCH3), 55.4 (OCH3), 99.6 (aryl C-H), 108.5 (aryl
C-H), 113.2 (aryl C-H), 116.6 (aryl C-H), 123.7 (aryl C-H), 130.0 (aryl C-H), 136.2 (aryl
Cq), 138.7 (aryl Cq), 160.0 (aryl Cq), 161.1 (aryl Cq); νmax (thin film/cm-1
) 1039 (s), 1152
(s), 1203 (m), 1281 (m), 1417 (m), 1574 (s), 2832 (w), 2936 (w), 3000 (w); MS (ES+) m/z
277 [(M+H)+]; HRMS C15H17O3S [(M+H)
+] Expected 277.0898, Found 277.0903.
bis(3,5-Dimethoxyphenyl)sulfide192
91aa
As described in general procedure A, 1-bromo-3,5-dimethoxybenzene (2.19 g, 10.0 mmol)
and 94a (1.70 g, 10.0 mmol), after purification by column chromatography (50:1
hexanes:EtOAc) gave 91aa (2.25 g, 7.34 mmol, 73%) as a white solid; δH (400 MHz,
CDCl3) 3.76 (12 H, s, OCH3), 6.36 (2 H, t, J 2.3 Hz, aryl H), 6.53 (4 H, d, J 2.3 Hz, aryl
H); δC (100 MHz, CDCl3) 55.4 (OCH3), 99.7 (aryl C-H), 108.8 (aryl C-H), 137.0 (aryl Cq),
161.0 (aryl Cq).
1-Bromo-3,5-diisopropoxybenzene163
93a
A solution of 1-bromo-3,5-dimethoxybenzene (2.50 g, 12.0 mmol) in CH2Cl2 (7 ml) was
cooled to 0 ⁰C and a 1 M BBr3 solution in CH2Cl2 (25 mL) was added dropwise. The ice
bath was removed and the reaction was stirred at room temperature for 18 h. The reaction
was quenched with MeOH and concentrated in vacuo. The residue was dissolved in EtOAc
(100 mL) and washed with H2O (50 mL). The organic layer was separated, dried over
Na2SO4 and concentrated to give 5-bromobenzene-1,3-diol as an orange oil; δH (400 MHz,
CDCl3) 5.10 (2 H, br s, OH), 6.30 (1 H, t, J 2.1 Hz, aryl H), 6.60 (2 H, d, J 2.3 Hz, aryl H).
5-bromobenzene-1,3-diol (2.09 g) was dissolved in DMF (40 mL) and K2CO3 (6.08 g, 44.0
mmol) was added at room temperature, followed by 2-bromopropane (4.13 mL, 44.0 mol).
132
The mixture was heated to 60 ⁰C and stirred for 18 h. The reaction was cooled to room
temperature, quenched with water (120 mL) and extracted with EtOAc (3 × 50 mL). The
organic layer was separated, dried with Na2SO4 and concentrated in vacuo. The crude
product was purified by column chromatography on silica gel (10:1 hexanes:EtOAc) to
give 93a (2.48 g, 9.08 mmol, 76%) as a colourless oil; δH (500 MHz, CDCl3) 1.25 (12 H,
d, J 6.0 Hz), 4.40 (2 H, sept, J 6.0 Hz), 6.27 (1 H, t, J 2.2 Hz), 6.54 (2 H, d, J 2.2 Hz).
(3,5-Diisopropoxyphenyl)(phenyl)sulfide 91ab
As described in general procedure A, 93a (2.19 g, 8.00 mmol) and thiophenol (0.80 mL,
8.00 mmol), after purification by column chromatography (50:1 hexanes:EtOAc) gave
91ab (1.84 g, 6.08 mmol, 76% yield), as a colourless oil; δH (500 MHz, CDCl3) 1.31 (12
H, d, J 6.0 Hz, (OCH(CH3)2), 4.46 (2 H, sept, J 6.0 Hz, OCH(CH3)2)), 6.33 (1 H, t, J 2.2
Hz, aryl H), 6.46 (2 H, d, J 2.2 Hz, aryl H), 7.25 - 7.29 (1 H, m, aryl H), 7.31 - 7.36 (2 H,
m, aryl H), 7.39 - 7.43 (2 H, m, aryl H); δC (125 MHz, CDCl3) 22.0 (OCH(CH3)2), 70.0
(OCH(CH3)2), 102.8 (aryl C-H), 109.9 (aryl C-H), 127.2 (aryl C-H), 129.1 (aryl C-H),
131.5 (aryl C-H), 135.2 (aryl Cq), 137.6 (aryl Cq), 159.3 (aryl Cq); νmax (thin film/cm-1
)
1033 (m), 1112 (s), 1151 (s), 1182 (m), 1277 (w), 1428 (w), 1575 (s), 2931 (w), 2975 (w);
MS (ES+) m/z 303 [(M+H)
+]; HRMS C18H23O2S [(M+H)
+] Expected 303.1419, Found
303.1425.
5-(Phenylsulfanyl)benzene-1,3-diol 91ac
A 1 M BBr3 solution in CH2Cl2 (10 mL, 10.0 mmol) was added dropwise to a solution of
91b (0.62 g, 2.50 mmol) in CH2Cl2 (6 mL) at 0 °C under N2. When addition was complete,
the mixture was warmed to room temperature and stirred for 2 h. The reaction was then
quenched with MeOH (4 mL) and concentrated in vacuo. The residue was dissolved in
EtOAc (5 mL) and extracted with H2O (2 × 5 mL). The combined organic layers were then
133
washed with brine (5 mL), dried over Na2SO4 and concentrated in vacuo. The crude
product was purified by column chromatography on silica gel (30% EtOAc in hexanes) to
give 91ac (0.45 g, 2.06 mmol, 82%) as an off-white crystalline solid; m.p. 136.0 – 140.0
°C (from CHCl3); δH (400 MHz, CDCl3) 4.68 (2 H, s, OH), 6.20 (1 H, t, J 2.2 Hz, aryl H),
6.32 (2 H, d, J 2.2 Hz, aryl H), 7.29 - 7.38 (3 H, m, aryl H), 7.42 - 7.46 (2 H, m, aryl H); δC
(100 MHz, CDCl3) 101.2 (aryl C-H), 108.9 (aryl C-H), 127.9 (aryl C-H), 129.4 (aryl C-H),
132.7 (aryl C-H), 133.9 (aryl Cq), 139.3 (aryl Cq), 156.9 (aryl Cq); νmax (thin film/cm-1
) 996
(s), 1066 (w), 1155 (s), 1200 (w), 1265 (w), 1300 (w), 1328 (w), 1344 (w), 1439 (w), 1471
(s), 1587 (s), 1620 (s), 2853 (w), 2923 (w), 2956 (w), 3055 (w), 3233 (w, br); MS (ES-) m/z
217 [(M−H)−]; HRMS C12H9O2S [(M−H
−)] Expected 217.0323, Found 217.0324.
[3,5-bis(Allyloxy)phenyl] (phenyl)sulfide 91ad
Allyl bromide (0.700 mL, 8.00 mmol) was added to a solution of 91ac (426 mg, 2.00
mmol) and K2CO3 (0.832 g, 6.0 mmol) in acetone (2 mL) at room temperature under N2.
The resulting mixture was stirred for 48 h, before adding H2O until the disappearance of
the precipitate. The crude product was then extracted with Et2O (3 × 5 mL). The combined
organic extracts were washed with H2O (2 × 5 mL) and brine (5 mL), dried over MgSO4
and concentrated in vacuo. The crude product was purified by column chromatography on
silica gel (25% CH2Cl2 in hexanes) to give 91ad (0.32 g, 1.07 mmol, 54%) as a colourless
oil; δH (500 MHz, CDCl3) 4.45 (4 H, dt, J 5.4, 1.5 Hz, OCH2), 5.27 (2 H, dq, J 10.5, 1.5
Hz, CH=CH2), 5.37 (2 H, dq, J 17.3, 1.5 Hz, CH=CH2), 6.00 (2 H, ddt, J 17.3, 10.5, 5.4
Hz, CH=CH2), 6.37 (1 H, t, J 2.2 Hz, aryl H), 6.47 (2 H, d, J 2.2 Hz, aryl H), 7.28 - 7.36 (3
H, m, aryl H), 7.38 - 7.42 (2 H, m, aryl H); δC (100 MHz, CDCl3) 68.9 (CH2), 100.7
(CH=CH2), 108.9 (aryl C-H), 118.1 (C=CH2), 127.5 (aryl C-H), 129.3 (aryl C-H), 131.9
(aryl C-H), 132.9 (aryl C-H), 134.6 (aryl Cq), 138.1 (aryl Cq), 159.9 (aryl Cq); νmax (thin
film/cm-1
) 924 (w), 997 (w), 1023 (w), 1084 (w), 1149 (s), 1278 (w), 1419 (w), 1439 (s),
1578 (s), 2862 (w), 2918 (w), 2983 (w), 3019 (w), 3076 (w); MS (ES+) m/z 299 [(M+H)
+];
HRMS C18H18O2SNa [(M+Na)+] Expected 321.0925, Found 321.0921.
134
5.4 Synthesis of Other Arenes
1,3-Dimethoxy-5-(phenylsulfonyl)benzene 166
m-CPBA (≤77%, 0.672 g, 3.00 mmol) was added to a solution of 91b (246 mg, 1 mmol) in
CH2Cl2 (10 mL). The mixture was stirred at ambient temperature for 18 h and then
quenched with aq. NaHCO3 (2 mL). The aqueous layer was washed with CH2Cl2 (3 × 2
mL) and the combined organic extracts were dried with MgSO4, filtered and the solvent
removed in vacuo. The crude product was purified by column chromatography (20%
EtOAc in hexanes) to give 166 (233 mg, 0.837 mmol, 84%) as a white solid; m.p. 81.7-
82.8 °C; δH (400 MHz, CDCl3) 3.82 (6 H, s, OCH3), 6.60 (1 H, t, J 2.5 Hz, aryl H), 7.07 (2
H, d, J 2.5 Hz, aryl H), 7.47 - 7.54 (2 H, m, aryl H), 7.55 - 7.61 (1 H, m, aryl H), 7.91 -
7.98 (2 H, m, aryl H); δC (100 MHz, CDCl3) 55.8 (OCH3), 105.4 (aryl C-H), 105.5 (aryl C-
H), 127.6 (aryl C-H), 129.2 (aryl C-H), 133.2 (aryl C-H), 141.4 (aryl Cq), 143.3 (aryl Cq),
161.2 (aryl Cq); νmax (thin film/cm-1
) 1040 (m), 1067 (m), 1099 (m), 1151 (vs, S=O sym),
1206 (s), 1289 (s), 1306 (s, S=O asym), 1426 (m), 1460 (m), 1600 (s), 2837 (w), 2942 (m),
3006 (m), 3088 (m); MS (ES+) m/z 279 [(M+H)
+]; HRMS C14H14O4NaS [(M+Na)
+]
Expected 301.0505, Found 301.0495.
1,3-Dimethoxy-5-phenoxybenzene198 168
Bromobenzene (0.52 mL, 4.90 mmol), 3,5-dimethoxyphenol (500 mg, 3.20 mmol), CuI
(6.10 mg, 32.0 µmol), Fe(acac)3 (22.6 mg, 64.0 µmol), K2CO3 (885 mg, 6.40 mmol) and
DMF (5 mL) were added to a metal-capped, oven-dried test tube with Teflon-lined septum,
pre-flushed with N2 at room temperature. The mixture was heated to 135 °C and stirred for
18 h. The mixture was then cooled to room temperature, filtered on Celite® 545 using
Et2O and the filtrate washed with 10% aq. LiCl (2 × 10 mL). The organic layer was dried
over MgSO4, filtered and solvent removed in vacuo. The crude reaction mixture was then
purified by column chromatography on silica gel (5% EtOAc in hexanes) to give 168 (94.4
135
mg, 0.410 mmol, 13%) as a colourless oil; δH (400 MHz, CDCl3) 3.76 (6 H, s, OCH3), 6.18
(2 H, d, J 2.3 Hz, aryl H), 6.23 (1 H, t, J 2.3 Hz, aryl H), 7.02 - 7.07 (2 H, m, aryl H), 7.09
- 7.15 (1 H, m, aryl H), 7.31 - 7.38 (2 H, m, aryl H); δC (100 MHz, CDCl3) 55.4 (OCH3),
95.4 (aryl C-H), 97.2 (aryl C-H), 119.2 (aryl C-H), 123.5 (aryl C-H), 129.7 (aryl C-H),
156.7 (aryl Cq), 159.2 (aryl Cq), 161.6 (aryl Cq); νmax (thin film/cm-1
) 1053 (m), 1063 (m),
1130 (s), 1204 (s), 1427 (m), 1472 (m), 1489 (m), 1584 (s), 2837 (w), 2941 (w), 2959 (w),
3002 (w); MS (ES+) m/z 231 [(M+H)
+]; HRMS C14H15O3 [(M+H)
+] Expected 231.1016,
Found 231.1007.
3,5-Dimethoxy-N-phenylaniline199 169
Bromobenzene (290 µL, 2.70 mmol), 3,5-dimethoxyaniline (500 mg, 3.30 mmol),
Pd2(dba)3 (7.50 mg, 8.00 µmol), BINAP (13.4 mg, 2.20 µmol), NaOt-Bu (366 mg, 3.80
mmol) and toluene (5 mL) were added to a metal-capped, oven-dried test tube with Teflon-
lined septum, pre-flushed with N2 at room temperature. The mixture was heated to 100 °C
and stirred for 24 h, before being cooled to room temperature. Sat. aq. NH4Cl (10 mL) was
added and the aqueous layer extracted with CH2Cl2 (3 × 10 mL). The combined organic
extracts were washed with brine (10 mL), dried over MgSO4, filtered and solvent removed
in vacuo. The crude product was purified by column chromatography on silica gel (15%
EtOAc in hexanes) and recrystallised from hexane to give 169 (562 mg, 2.45 mmol, 90%)
as white crystals; δH (400 MHz, CDCl3) 3.77 (6 H, s, OCH3), 5.70 (1 H, br s, NH), 6.08 (1
H, t, J 2.1 Hz, aryl H), 6.25 (2 H, d, J 2.1 Hz, aryl H), 6.96 (1 H, tt, J 7.3, 1.2 Hz, aryl H),
7.09 – 7.14 (2 H, m, aryl H), 7.25 - 7.32 (2 H, m, aryl H); δC (100 MHz, CDCl3) 55.3
(OCH3), 93.0 (aryl C-H), 95.8 (aryl C-H), 118.8 (aryl C-H), 121.5 (aryl C-H), 129.3 (aryl
C-H), 142.6 (aryl Cq), 145.3 (aryl Cq), 161.6 (aryl Cq).
136
3,5-Dimethoxy-N,N-diphenylaniline200 170
Bromobenzene (1.05 mL, 9.80 mmol), 3,5-dimethoxyaniline (500 mg, 3.30 mmol),
Pd2(dba)3 (59.7 mg, 70.0 µmol), JohnPhos (77.8 mg, 260 µmol), NaOt-Bu (783 mg, 8.20
mmol) and toluene (15 mL) were charged to a metal-capped, oven-dried test tube with
Teflon-lined septum, pre-flushed with N2 at room temperature. The mixture was heated to
100 °C and stirred for 24 h, before being cooled to room temperature. The mixture was
filtered on Celite® 545 using CH2Cl2 and then dried over MgSO4, filtered and solvent
removed in vacuo. The crude product was purified by column chromatography on silica gel
(5% EtOAc in hexanes) and recrystallised from Et2O to give 170 (787 mg, 2.58 mmol,
79%) as a white solid; δH (400 MHz, CDCl3) 3.73 (6 H, s, OCH3), 6.19 (1 H, t, J 2.3 Hz,
aryl H), 6.26 (2 H, d, J 2.3 Hz, aryl H), 7.06 (2 H, tt, J 7.3, 1.0 Hz, aryl H), 7.12 - 7.17 (4
H, m, aryl H), 7.26 - 7.32 (4 H, m, aryl H); δC (100 MHz, CDCl3) 55.3 (OCH3), 94.7 (aryl
C-H), 102.2 (aryl C-H), 123.0 (aryl C-H), 124.6 (aryl C-H), 129.2 (aryl C-H), 147.6 (aryl
Cq), 149.7 (aryl Cq), 161.2 (aryl Cq).
5.5 Synthesis of Alkenes 5-Nitro-1-pentene
201 213a
5-Bromo-1-pentene (2.53 g, 17.0 mmol) was added to a solution of NaNO2 (1.29 g, 18.7
mmol) in DMF (35 mL) and stirred at room temperature for 2 h. The reaction was
quenched with H2O (30 mL) and extracted with Et2O (3 × 30 mL). The combined organic
extracts were washed with 10% aq. LiCl (2 × 30 mL), dried with MgSO4, filtered and
solvent removed in vacuo. The crude product was purified by column chromatography on
silica gel (10% CHCl3 in hexanes) to give 213a (510 mg, 4.43 mmol, 26%) as a yellow oil;
δH (400 MHz, CDCl3) 2.07 - 2.22 (4 H, m, CH2), 4.40 (2 H, t, J 6.5 Hz, CH2NO2), 5.04 -
5.13 (2 H, m, CH=CH2), 5.77 (1 H, ddt, J 17.0, 10.4, 6.5 Hz, CH=CH2); δC (125 MHz,
CDCl3) 26.3 (CH2), 30.1 (CH2CH=CH2), 74.7 (CH2NO2), 116.8 (CH=CH2), 135.7
(CH=CH2).
137
8-Nitro-1-octene202 213b
8-Bromo-1-octene (1.68 mL, 10.0 mmol) was added dropwise to a solution of NaNO2 (759
mg, 11.0 mmol) in DMF (20 mL). The mixture was stirred at room temperature for 4 h and
then quenched with 10% aq. LiCl (30 mL) and diluted with Et2O (30 mL). The organic
layer was washed with H2O (2 × 20 mL), dried over MgSO4, filtered and solvent removed
in vacuo. The crude product was purified by column chromatography on silica gel (5%
Et2O in hexanes) to give 213b (738 mg, 4.69 mmol, 47%) as a yellow oil; δH (500 MHz,
CDCl3) 1.33 - 1.48 (6 H, m, CH2), 1.97 - 2.12 (4 H, m, CH2), 4.40 (2 H, t, J 6.6 Hz,
CH2NO2), 4.97 (1 H, ddt, J 10.2, 1.8, 1.1 Hz, CH=CH2), 5.03 (1 H, dq, J 17.0, 1.8 Hz,
CH=CH2), 5.82 (1 H, ddt, J 17.0, 10.2, 6.6 Hz, CH=CH2); δC (125 MHz, CDCl3) 26.3
(CH2), 26.8 (CH2), 28.7 (CH2), 29.2 (CH2), 30.1 (CH2CH=CH2), 74.7 (CH2NO2), 116.8
(CH=CH2), 135.7 (CH=CH2).
9-Phenyl-1-nonene203 214
Benzylmagnesium bromide (5.00 mL, 2.00 M in THF, 10.0 mmol) was added to a
suspension of CuCl2 (33.6 mg, 250 µmol) in Et2O (5 mL) at −78 °C. 8-Bromo-1-octene
(956 mg, 5.00 mmol) was then added and the mixture warmed to room temperature and
stirred for 4 h. The mixture was then cooled to 0 °C and quenched with 1 M HCl (30 mL)
and the aqueous layer extracted with EtOAc (3 × 30 mL). The organic layer was dried with
MgSO4, filtered and solvent removed in vacuo. The crude product was purified by column
chromatography on silica gel (hexanes) to give 214 (637 mg, 3.15 mmol, 68%) as a
colourless oil; δH (500 MHz, CDCl3) 1.23 - 1.43 (8 H, m, CH2), 1.62 (2 H, quin, J 7.4 Hz,
ArCH2CH2), 2.05 (2 H, q, J 7.0 Hz, CH2CH=CH2), 2.61 (2 H, t, J 7.4 Hz, ArCH2), 4.94 (1
H, d, J 10.2 Hz, CH=CH2), 5.00 (1 H, d, J 17.0 Hz, CH=CH2), 5.82 (1 H, ddt, J 17.0, 10.2,
7.0 Hz, CH=CH2), 7.15 - 7.21 (3 H, m, aryl H), 7.25 - 7.31 (2 H, m, aryl H); δC (125 MHz,
CDCl3) 28.9 (CH2), 29.1 (CH2), 29.3 (CH2), 29.4 (CH2), 31.5 (CH2CH=CH2), 33.8
(ArCH2CH2), 36.0 (ArCH2), 114.1 (CH=CH2), 125.5 (aryl C-H), 128.2 (aryl C-H), 128.4
(aryl C-H), 139.2 (CH=CH2), 142.9 (ArCH2).
138
4,4-Dimethylhepta-1,6-diene204 145b
In a dried, nitrogen-filled flask fitted with stirrer and addition funnel, a solution of allyl
bromide (12.1 g, 100 mmol) in anhydrous THF (50 mL), was added dropwise to zinc (6.54
g, 100 mmol) at 20 °C. The resulting solution was stirred at room temperature for 1 h.
Propynylmagnesium bromide (75.0 mL, 0.5 M in THF, 37.5 mmol) was then added
dropwise to the mixture and the solution was stirred at 60 °C for 2 h. The mixture was then
cooled to 0 °C and quenched with 1 M HCl (20 mL). The mixture was diluted with Et2O
and the aqueous layer further extracted with Et2O (3 × 20 mL). The combined organic
phases were washed with brine (3 × 10 mL), dried over MgSO4, filtered and solvent
removed in vacuo. The crude product was distilled to give 145b (1.86 g, 15.0 mmol, 40%)
as a colourless oil; δH (400 MHz, CDCl3) 0.87 (6 H, s, (CH3)2), 1.96 (4 H, d, J 7.5 Hz,
CH2CH=CH2), 4.96 - 5.07 (4 H, m, CH=CH2), 5.83 (2 H, ddt, J 16.9, 10.3, 7.5 Hz,
CH=CH2); δC (100 MHz, CDCl3) 26.7 (CH3), 33.4 (CH2CH=CH2), 46.3 alkyl Cq), 116.8
(CH=CH2), 135.6 (CH=CH2).
1,1-Diallylcyclohexane205 145c
A mixture of catechol (4.40 g, 40.0 mmol), cyclohexanone (1.96 g, 20.0 mmol) and p-
toluenesulfonic acid (462 mg, 2.00 mmol) in toluene was heated under reflux for 24 h.
Water was removed by azeotropic distillation using a Dean-Stark trap. The reaction
mixture was allowed to cool and the solvent removed in vacuo. The residue was purified
by column chromatography on silica gel (petroleum ether 60-80) to give
spiro[benzo(d)(1,3)dioxole-2,1'-cyclohexane] (3.24 g, 16.8 mmol, 84%) as a colourless oil;
δH (400 MHz, CDCl3) 1.46 - 1.57 (2 H, m), 1.70- 1.79 (4 H, m), 1.87 - 1.97 (4 H, m), 6.72
- 6.80 (4 H, m).206
A flask equipped with a thermometer, a magnetic stirring bar and argon
outlet was charged with anhydrous CH2Cl2 (70 mL) and anhydrous MeNO2 (4.33 mL, 80
mmol). The solution was cooled to −78 °C and TiCl4 was added (4.39 mL, 40.0 mmol),
followed by the dioxole (16.8 mmol) in CH2Cl2 (10 mL) and then allyl TMS (6.85 g, 60.0
mmol) in CH2Cl2 (20 mL). The reaction was followed by TLC and, upon completion, the
solution was warmed to room temperature and poured into sat. aq. NH4Cl solution (50
139
mL). The aqueous layer was extracted with CH2Cl2 (2 × 30 mL) and the combined extracts
washed until neutrality. The solution was dried over MgSO4, filtered and concentrated in
vacuo. The residue was purified by chromatography on silica gel (5% Et2O in pentane) to
give 145c (1.18 g, 7.18 mmol, 42%) as a colourless oil; δH (400 MHz, CDCl3) 1.21 - 1.52
(10 H, m, CH2), 2.03 (4 H, dt, J 7.5, 1.0 Hz, CH2CH=CH2), 4.99 - 5.07 (4 H, m, CH=CH2),
5.82 (2 H, ddt, J 16.7, 10.4, 7.5 Hz, CH=CH2); δC (100 MHz, CDCl3) 21.8 (CH2), 26.4
(CH2), 35.4 (CH2CH=CH2), 35.9 (CH2), 42.0 (alkyl Cq), 117.1 (CH=CH2), 135.2
(CH=CH2).
5.6 Iron-mediated Allylation of Arylsulfides
General Procedure C
FeCl3 (0.1-2.2 eq.) was added to a solution of the corresponding sulfide (0.20 mmol,
0.1 M) and allyl TMS (1-10 eq.) and the mixture was stirred for 1.5 h under N2. The
solution was then quenched with H2O (2 ml), diluted with EtOAc (2 mL) and the organic
layer washed with H2O (2 × 2 ml). The aqueous layer was extracted with EtOAc (3 × 2
mL) and the combined organic extracts were dried with Na2SO4, filtered and solvent
removed in vacuo.
(2-Allyl-3,5-dimethoxyphenyl)(phenyl)sulfide 88a and (2,6-Diallyl-3,5-
dimethoxyphenyl)(phenyl)sulfide 97
As described in general procedure C, 91b (50.0 mg, 0.203 mmol), allyl TMS (320 μl, 2.00
mmol) and FeCl3 (72.4 mg, 0.450 mmol) with MeNO2 solvent, after purification by
column chromatography (20% CHCl3 in hexanes) gave 88a (20.2 mg, 70.5 µmol, 35%)
and 97 (7.31 mg, 22.4 µmol, 11%) as colourless oils; For 88a, δH (500 MHz, CDCl3) 3.56
(2 H, dt, J 6.1, 1.5 Hz, ArCH2CH=CH2), 3.68 (3 H, s, OCH3), 3.82 (3 H, s, OCH3), 4.92 -
4.98 (2 H, m, CH2CH=CH2), 5.91 (1 H, ddt, J 17.7, 9.5, 6.1 Hz, CH2CH=CH2), 6.42 (1 H,
d, J 2.5 Hz, aryl H), 6.43 (1 H, d, J 2.5 Hz, aryl H), 7.19 - 7.25 (1 H, m, aryl H), 7.25 - 7.31
140
(4 H, m, aryl H); δC (125 MHz, CDCl3) 31.2 (ArCH2), 55.3 (OCH3), 55.8 (OCH3), 98.4
(aryl C-H), 108.6 (aryl C-H), 114.6 (CH=CH2), 122.6 (aryl Cq), 126.6 (aryl C-H), 129.0
(aryl C-H), 130.3 (aryl C-H), 135.8 (aryl Cq), 136.3 (CH=CH2), 136.4 (aryl Cq), 158.8 (aryl
Cq), 158.9 (aryl Cq); νmax (thin film/cm-1
): 1047 (s), 1146 (s), 1247 (s), 1296 (s), 1437 (s),
1140 (s), 1477 (s), 1572 (s), 1596 (s), 2956 (w), 3002 (w), 3074 (w); MS (ES+) m/z 287
[(M+H)+]; HRMS C17H19O2S [(M+H)
+] Expected 287.1100, Found 287.1108; For 97, δH
(400 MHz, CDCl3) 3.58 (4 H, dt, J 6.1, 1.5 Hz, ArCH2CH=CH2), 3.88 (6 H, s, OCH3), 4.81
- 4.88 (4 H, m, CH2CH=CH2), 5.84 (2 H, ddt, J 18.2, 9.1, 6.1 Hz, CH2CH=CH2), 6.62 (1
H, s, aryl H), 6.90 - 6.95 (2 H, m, aryl H), 7.04 (1 H, tt, J 7.3, 1.3 Hz, aryl H), 7.13 - 7.19
(2 H, m, aryl H); δC (100 MHz, CDCl3) 32.6 (ArCH2), 55.9 (OCH3), 97.5 (aryl C-H), 114.4
(CH=CH2), 124.5 (aryl C-H), 125.7 (aryl C-H), 125.8 (aryl Cq), 128.7 (aryl C-H), 132.1
(aryl Cq), 137.1 (CH=CH2), 139.0 (aryl Cq), 157.3 (aryl Cq); νmax (thin film/cm-1
) 734, 910
(w), 1047 (w), 1125 (s), 1196 (s), 1297 (s), 1436 (s), 1458 (s), 1478 (s), 1583 (s), 1636 (w),
2936 (w), 3002 (w), 3074 (w); MS (ES+) 327 [(M+H)
+]; HRMS C20H23O2S [(M+H)
+]
Expected 327.1413, Found 327.1403.
(4-Allyl-3,5-dimethoxyphenyl)(phenyl)sulfide 96
As described in general procedure C, 91b (50.0 mg, 0.203 mmol), allyl TMS (320 μl, 2.00
mmol) and FeCl3 (72.4 mg, 0.450 mmol) with CH2Cl2 solvent, after purification by column
chromatography (20% CHCl3 in hexanes) gave 96 (4.6 mg, 16.1 µmol, 8%) as a colourless
oil; δH (500 MHz, CDCl3) 3.39 (2 H, dt, J 6.2, 1.5 Hz, ArCH2CH=CH2), 3.76 (6 H, s,
OCH3), 4.95 (1 H, dd, J 10.1, 1.5 Hz, CH2CH=CH2), 4.99 (1 H, dd, J 17.0, 1.5 Hz,
CH2CH=CH2), 5.94 (1 H, ddt, J 17.0, 10.1, 6.2 Hz, CH2CH=CH2), 6.61 (2 H, s, aryl H),
7.20 - 7.25 (1 H, m, aryl H), 7.28 - 7.35 (4 H, m, aryl H); δC (125 MHz, CDCl3) 27.1
(ArCH2), 55.9 (OCH3), 107.6 (aryl C-H), 114.2 (CH=CH2), 116.2 (aryl Cq), 126.6 (aryl C-
H), 129.1 (aryl C-H), 130.0 (aryl C-H), 133.3 (aryl Cq), 136.4 (CH=CH2), 136.5 (aryl Cq),
158.5 (aryl Cq); νmax (thin film/cm-1
) 1121 (s), 1136 (s), 1237 (w), 1292 (w), 1400 (s), 1439
(w), 1478 (w), 1578 (s), 1577 (s), 2832 (w), 2937 (w), 3074 (w); MS (ES+) 287 [(M+H)
+];
HRMS C17H19O2S [(M+H)+] Expected 287.1100, Found 287.1105.
141
[2,2',5,5'-Tetramethoxy-(1,1'-biphenyl)-4,4'-diyl]bis(phenylsulfide)68 92
As described in general procedure C, 91a (50.0 mg, 0.203 mmol), allyl TMS (320 μl, 2.00
mmol) and FeCl3 (72.4 mg, 0.450 mmol) with MeNO2 solvent, after purification by
column chromatography (50:1 hexanes:EtOAc) gave 92 (64.8 mg, 0.132 mmol, 65%) as a
yellow solid; δH (400 MHz, CDCl3) 3.50 (6 H, s, OCH3), 3.76 (6 H, s, OCH3), 6.65 (2 H, s,
aryl H), 6.78 (2 H, s, aryl H), 7.21 (2 H, dt, J 7.3, 1.5 Hz, aryl H), 7.27 (4 H, t, J 7.3 Hz,
aryl H), 7.31 – 7.38 (4 H, m, aryl H); δC (100 MHz, CDCl3) 56.4 (OCH3), 56.6 (OCH3),
114.6 (aryl C-H), 115.1 (aryl C-H), 123.9 (aryl Cq), 126.7 (aryl Cq), 127.3 (aryl C-H),
129.2 (aryl C-H), 131.6 (aryl C-H), 134.4 (aryl Cq), 151.1 (aryl Cq), 151.2 (aryl Cq).
5.7 Iron-mediated C-H Coupling of Arylsulfides and Terminal Alkenes
General Procedure D
A solution of FeCl3 (0.800 mmol) in MeNO2 (1 mL) was added dropwise over 1 h to a
stirred solution of the corresponding sulfide (0.200 mmol) and alkene (1.00 mmol) in
CH2Cl2 (1 mL). The mixture was then left to stir for 1 h. The reaction mixture was then
quenched with H2O (2 ml), diluted with CH2Cl2 (2 mL), 2,2’-bipyridine (127 mg, 0.800
mmol) added and stirred for 15 min. at room temperature. The organic layer was then
washed with H2O (2 × 2 ml) and the combined aqueous layers were extracted with CH2Cl2
(3 × 2 mL). The combined organic extracts were dried with MgSO4, filtered and solvent
removed in vacuo. The crude mixture was then passed through a silica plug with CHCl3
eluent.
142
[2-(2-Chlorooctyl)-3,5-dimethoxyphenyl] (phenyl)sulfide 99a
As described in general procedure D, 91b (50.0 mg, 0.203 mmol), 1-octene (160 μl, 1
mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography
(30% CHCl3 in hexanes) gave 99a (51.2 mg, 0.130 mmol, 64%) as a colourless oil; δH
(500 MHz, CDCl3) 0.79 (3 H, t, J 6.9, CH2CH3), 1.11 - 1.34 (7 H, m, CH2), 1.44 - 1.56 (1
H, m, CH2), 1.60 - 1.68 (2 H, m, CH2), 3.14 (1 H, dd, J 13.6, 6.9 Hz, ArCH2CHCl), 3.24 (1
H, dd, J 13.6, 7.6 Hz, ArCH2CHCl), 3.59 (3 H, s, OCH3), 3.74 (3 H, s, OCH3), 4.18 (1 H,
dt, J 12.9, 7.3 Hz, CHCl), 6.32 (1 H, d, J 2.5 Hz, aryl H), 6.35 (1 H, d, J 2.5 Hz, aryl H),
7.09 - 7.22 (5 H, m, aryl H); δC (125 MHz, CDCl3) 14.1 (CH3), 22.6 (CH2), 26.7 (CH2),
28.8 (CH2), 31.7 (CH2), 36.3 (ArCH2CHCl), 37.7 (CH2), 55.3 (OCH3), 55.6 (OCH3), 63.4
(CHCl), 98.3 (aryl C-H), 108.8 (aryl C-H), 121.3 (aryl Cq), 126.6 (aryl C-H), 129.1 (aryl
C-H), 130.0 (aryl C-H), 136.4 (aryl Cq), 136.6 (aryl Cq), 159.1 (aryl Cq), 159.3 (aryl Cq);
νmax (thin film/cm-1
) 1046 (s), 1163 (s), 1198, 1459 (w), 1570 (s), 1596 (s), 2856 (w), 2929
(w), 2954 (w); MS (ES+) m/z 393
35Cl, 395
37Cl [(M+H)
+]; HRMS C22H30O2ClS [(M+H)
+]
Expected 393.1650, Found 393.1651.
[2-(2-Chlorohexyl)-3,5-dimethoxyphenyl] (phenyl)sulfide 99b
As described in general procedure D, 91b (50.0 mg, 0.203 mmol), 1-hexene (127 μl, 1.02
mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography
(30% CHCl3 in hexanes) gave 99b (46.0 mg, 0.126 mmol, 62%) as a colourless oil; δH
(500 MHz, CDCl3) 0.90 (3 H, t, J 7.3 Hz, CH2CH3), 1.23 - 1.43 (3 H, m, CH2), 1.54 - 1.65
(1 H, m, CH2), 1.71 - 1.78 (2 H, m, CH2), 3.24 (1 H, dd, J 13.6, 7.3 Hz, ArCH2CHCl), 3.34
(1 H, dd, J 13.6, 7.6 Hz, ArCH2CHCl), 3.69 (3 H, s, OCH3), 3.84 (3 H, m, OCH3), 4.28 (1
143
H, m, CHCl), 6.42 (1 H, d, J 2.2 Hz, aryl H), 6.45 (1 H, d, J 2.2 Hz, aryl H), 7.20 - 7.32 (5
H, m, aryl H); δC (125 MHz, CDCl3) 14.0 (CH3), 22.2 (CH2), 28.9 (CH2), 36.3
(ArCH2CHCl), 37.5 (CH2), 55.3 (OCH3), 55.6 (OCH3), 63.3 (CHCl), 98.3 (aryl C-H),
108.9 (aryl C-H), 121.3 (aryl Cq), 126.6 (aryl C-H), 129.1 (aryl C-H), 130.1 (aryl C-H),
136.4 (aryl Cq), 136.7 (aryl Cq), 159.2 (aryl Cq), 159.3 (aryl Cq); νmax (thin film/cm-1
) 1048
(s), 1156 (s), 1198, 1459 (w), 1581 (s), 1598 (s), 2856 (w), 2935 (w); MS (ES+) m/z 365
35Cl, 367
37Cl [(M+H)
+]; HRMS C20H26O2ClS [(M+H)
+] Expected 365.1337, Found
365.1334.
[2-(2-Chlorohept-6-en-1-yl)-3,5-dimethoxyphenyl] (phenyl)sulfide 99c
As described in general procedure D, 91b (50.0 mg, 0.203 mmol), 1,6-heptadiene (138 μl,
1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column
chromatography (30% CHCl3 in hexanes) gave 99c (42.2 mg, 0.112 mmol, 55%) as a
colourless oil; δH (500 MHz, CDCl3) 1.43 - 1.54 (1 H, m, CH2), 1.67 - 1.80 (3 H, m, CH2),
1.96 - 2.12 (2 H, m. CH2CH2CH=CH2), 3.24 (1 H, dd, J 13.6, 7.3 Hz, ArCH2CHCl), 3.34
(1 H, dd, J 13.6, 7.6 Hz, ArCH2CHCl), 3.69 (3 H, s, OCH3), 3.84 (3 H, s, OCH3), 4.29 (1
H, m, CHCl), 4.95 (1 H, dq, J 10.1, 1.3 Hz, CH=CH2), 5.00 (1 H, dq, J 17.1, 1.8 Hz,
CH=CH2), 5.79 (1 H, ddt, J 17.1, 10.1, 6.6 Hz, CH2CH=CH2), 6.42 (1 H, d, J 2.2 Hz, aryl
H), 6.44 (1 H, d, J 2.2 Hz, aryl H), 7.21 - 7.32 (5 H, m, aryl H); δC (125 MHz, CDCl3) 25.9
(CH2), 33.2 (CH2CH2CH=CH2), 36.3 (ArCH2CHCl), 37.1 (CH2), 55.3 (OCH3), 55.6
(OCH3), 63.0 (CHCl), 98.3 (aryl C-H), 108.9 (aryl C-H), 114.7 (CH=CH2), 121.2 (aryl Cq),
126.6 (aryl C-H), 129.1 (aryl C-H), 130.1 (aryl C-H), 136.3 (aryl Cq), 136.7 (aryl Cq),
138.5 (CH=CH2), 159.1 (aryl Cq), 159.3 (aryl Cq); νmax (thin film/cm-1
) 1047 (s), 1144 (s),
1198 (s), 1295 (w), 1460 (m), 1571 (s), 1597 (s), 2835 (w), 2936 (w); MS (ES+) m/z 377
35Cl, 379
37Cl [(M+H)
+]; HRMS C21H26O2ClS [(M+H)
+] Expected 377.1337, Found
377.1339.
144
[2-(2-Chloro-4-methylpentyl)-3,5-dimethoxyphenyl] (phenyl)sulfide 99d
As described in general procedure D, 91b (50.0 mg, 0.203 mmol), 4-methyl-1-hexene
(142 μL, 1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column
chromatography (30% CHCl3 in hexanes) gave 99d (35.7 mg, 94.2 µmol, 46% as a 1:1
mixture of diastereoisomers) as a colourless oil; δH (400 MHz, CDCl3) 0.75 - 0.93 (6 H, m,
CH3), 0.98 - 1.58 (3 H, m, CH2), 1.60 - 1.88 (2 H, m, CH2), 3.17 - 3.40 (2 H, m,
ArCH2CHCl), 3.69 (3 H, s, OCH3), 3.83 (3 H, s, OCH3), 4.31 - 4.44 (1 H, m, CHCl), 6.42
(1 H, app. s, aryl H), 6.45 (1 H, app. s, aryl H), 7.17 - 7.32 (5 H, m, aryl H); δC (100 MHz,
CDCl3) 10.7 + 11.4 (CH3), 18.0 + 19.4 (CH3), 27.9, 30.0, 31.5, 31.7, 36.3 + 36.8
(ArCH2CHCl), 44.7 + 45.2 (alkyl H), 55.3 (OCH3), 55.6 (OCH3), 61.3 + 61.4 (CHCl), 98.4
(aryl C-H), 109.0 (aryl C-H), 121.4 + 121.5 (aryl Cq), 126.5 (aryl C-H), 129.1 (aryl C-H),
129.8 (aryl C-H), 136.4 (aryl Cq), 136.5 + 136.6 (aryl Cq), 159.1 (aryl Cq), 159.2 (aryl Cq);
νmax (thin film/cm-1
) 1047 (s), 1146 (s), 1199 (s), 1296 (w), 1461 (m), 1477 (m), 1571 (s),
1597 (s), 2931 (m), 2959 (m); MS (ES+) m/z 379
35Cl, 381
37Cl [(M+H)
+]; HRMS
C21H27O2S [(M−Cl)+] Expected 343.1732, Found 343.1729.
[2-(8-Bromo-2-chlorooctyl)-3,5-dimethoxyphenyl] (phenyl)sulfide 99e
As described in General Procedure D, 91b (50.0 mg, 0.203 mmol), 8-bromo-1-octene (171
μL, 1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column
chromatography (30% CHCl3 in hexanes) gave 99e (53.8 mg, 0.114 mmol, 56%) as a
colourless oil; δH (400 MHz, CDCl3) 1.19 - 1.47 (5 H, m, CH2), 1.58 - 1.67 (1 H, m, CH2),
1.68 - 1.76 (2 H, m, CH2), 1.84 (2 H, quin, J 7.1 Hz, CH2CH2CH2Br), 3.23 (1 H, dd, J
13.6, 7.3 Hz, ArCH2CHCl), 3.33 (1 H, dd, J 13.6, 7.3 Hz ArCH2CHCl), 3.40 (2 H, t, J 7.1
145
Hz, CH2CH2Br), 3.68 (3 H, s, OCH3), 3.83 (3 H, s, OCH3), 4.20 - 4.31 (1 H, m, CHCl),
6.41 (1 H, d, J 2.3 Hz, aryl H), 6.43 (1 H, d, J 2.3 Hz, aryl H), 7.18 - 7.32 (5 H, m, aryl H);
δC (100 MHz, CDCl3) 26.5 (CH2), 28.0 (CH2), 28.2 (CH2), 32.7 (CH2CH2Br), 34.0
(CH2Br), 36.2 (ArCH2CHCl), 37.4 (CH2), 55.3 (OCH3), 55.6 (OCH3), 63.1 (CHCl), 98.3
(aryl C-H), 108.8 (aryl C-H), 121.1 (aryl Cq), 126.6 (aryl C-H), 129.1 (aryl C-H), 130.0
(aryl C-H), 136.3 (aryl Cq), 136.5 (aryl Cq), 159.1 (aryl Cq), 159.3 (aryl Cq); νmax (thin
film/cm-1
) 1046 (s), 1146 (s), 1198 (s), 1296 (w), 1461 (m), 1571 (s), 1596 (s), 2856 (w),
2933.67 (w); MS (ES+) m/z 471
35Cl
79Br, 473
37Cl
79Br and
35Cl
81Br, 475
37Cl
81Br
[(M+H)+]; HRMS C22H28BrO2S [(M−Cl)
+] Expected 435.0993, Found 435.1008.
[2-(6-Bromo-2-chlorohexyl)-3,5-dimethoxyphenyl] (phenyl)sulfide 99f
As described in General Procedure D, 91b (50.0 mg, 0.203 mmol), 6-bromo-1-octene
(136 μL, 1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column
chromatography (30% CHCl3 in hexanes), gave 99f (47.9 mg, 0.108 mmol, 53%) as a
colourless oil; δH (500 MHz, CDCl3) 1.46 - 1.56 (1 H, m, CH2), 1.69 - 1.91 (5 H, m, CH2),
3.24 (1 H, dd, J 13.6, 7.6 Hz, ArCH2CHCl), 3.33 (1 H, dd, J 13.6, 7.3 Hz, ArCH2CHCl),
3.38 (2 H, t, J 6.8 Hz, CH2CH2Br), 3.69 (3 H, s, OCH3), 3.83 (3 H, s, OCH3), 4.22 - 4.30 (1
H, m, CHCl), 6.41 (1 H, d, J 2.2 Hz, aryl H), 6.44 (1 H, d, J 2.2 Hz, aryl H), 7.20 - 7.32 (5
H, m, aryl H); δC (125 MHz, CDCl3) 25.5 (CH2), 32.3 (CH2), 33.5 (CH2CH2Br), 36.2
(ArCH2CHCl), 36.6 (CH2), 55.3 (OCH3), 55.6 (OCH3), 62.6 (CHCl), 98.3 (aryl C-H),
108.9 (aryl C-H), 120.9 (aryl Cq), 126.7 (aryl C-H), 129.2 (aryl C-H), 130.0 (aryl C-H),
136.2 (aryl Cq), 136.6 (aryl Cq), 159.1 (aryl Cq), 159.4 (aryl Cq); νmax (thin film/cm-1
) 1046
(s), 1146 (s), 1197 (s), 1295 (w), 1459 (m), 1571 (s), 1596 (s), 2835 (w), 2937 (w), 3001
(w); MS (ES+) m/z 443
35Cl
79Br, 445
37Cl
79Br and
35Cl
81Br, 447
37Cl
81Br [(M+H)
+];
HRMS C20H24O2BrS [(M−Cl)+] Expected 407.0680, Found 407.0663.
146
[2-(2,6-Dichlorohexyl)-3,5-dimethoxyphenyl] (phenyl)sulfide 99g
As described in general procedure D, 91b (50.0 mg, 0.203 mmol), 6-chloro-1-hexene
(135 μl, 1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column
chromatography (30% CHCl3 in hexanes) gave 99g (36.8 mg, 92.1 µmol, 45%) as a
colourless oil; δH (500 MHz, CDCl3) 1.39 - 1.46 (1 H, m, CH2) 1.61 - 1.73 (5 H, m, CH2),
3.16 (1 H, dd, J 13.9, 7.6 Hz, ArCH2CHCl), 3.25 (1 H, dd, J 13.9, 7.3 Hz, ArCH2CHCl),
3.42 (2 H, t, J 6.6 Hz, CH2CH2Cl), 3.60 (3 H, s, OCH3), 3.75 (3 H, m, OCH3), 4.18 (1 H,
m, CHCl), 6.33 (1 H, d, J 2.5 Hz, aryl H), 6.35 (1 H, d, J 2.5 Hz, aryl H), 7.11 - 7.23 (5 H,
m, aryl H); δC (125 MHz, CDCl3) 24.2 (CH2), 32.2 (CH2), 36.2 (ArCH2CHCl), 36.8 (CH2),
44.8 (CH2Cl), 55.3 (OCH3), 55.7 (OCH3), 62.6 (CHCl), 98.4 (aryl C-H), 109.0 (aryl C-H),
121.0 (aryl Cq), 126.7 (aryl C-H), 129.2 (aryl C-H), 130.0 (aryl C-H), 136.3 (aryl Cq),
136.6 (aryl Cq), 159.1 (aryl Cq), 159.4 (aryl Cq); νmax (thin film/cm-1
) 1046 (s), 1148 (s),
1198 (s), 1295 (w), 1460 (m), 1477 (m), 1571 (s), 1596 (s), 2835 (w), 2938 (w); MS (ES+)
m/z 399 35
Cl35
Cl, 401 37
Cl35
Cl, 403 37
Cl37
Cl [(M+H)+]; HRMS C20H24O2ClS [(M−Cl)
+]
Expected 363.1186, Found 363.1201.
[2-(2-Chloro-6-iodohexyl)-3,5-dimethoxyphenyl] (phenyl)sulfide 99h
As described in general procedure D, 91b (50.0 mg, 0.203 mmol), 6-iodo-1-hexene (135
μl, 1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column
chromatography (30% CHCl3 in hexanes) gave 99h (49.1 mg, 0.100 mmol, 49%) as a
yellow oil; δH (500 MHz, CDCl3) 1.49 (1 H, m, CH2), 1.66 - 1.89 (5 H, m, CH2), 3.15 (2 H,
m, CH2CH2I), 3.24 (1 H, dd, J 13.6, 7.3 Hz, ArCH2CHCl), 3.33 (1 H, dd, J 13.6, 7.3 Hz,
ArCH2CHCl), 3.69 (3 H, s, OCH3), 3.84 (3 H, m, OCH3), 4.22 - 4.29 (1 H, m, CHCl), 6.42
147
(1 H, d, J 2.5 Hz, aryl H), 6.44 (1 H, d, J 2.5 Hz, aryl H), 7.20 - 7.32 (5 H, m, aryl H); δC
(125 MHz, CDCl3) 6.4 (CH2I), 27.8 (CH2), 33.1 (CH2), 36.3 (ArCH2CHCl), 36.4 (CH2),
55.3 (OCH3), 55.7 (OCH3), 62.3 (CHCl), 98.4 (aryl C-H), 109.0 (aryl C-H), 121.0 (aryl
Cq), 126.7 (aryl C-H), 129.2 (aryl C-H), 130.0 (aryl C-H), 136.3 (aryl Cq), 136.6 (aryl Cq),
159.1 (aryl Cq), 159.4 (aryl Cq); νmax (thin film/cm-1
) 1045 (s), 1147 (s), 1198 (s), 1295 (w),
1437 (m), 1458 (m), 1478 (m), 1571 (s), 1595 (s), 2834 (w), 2936 (w), 3000 (w); MS (ES+)
m/z 491 35
Cl, 493 37
Cl [(M+H)+]; HRMS C20H25IO2ClS [(M+H)
+] Expected 491.0303,
Found 491.0298.
[2-(2-Chloro-8-nitrooctyl)-3,5-dimethoxyphenyl] (phenyl)sulfide 99i
As described in general procedure D, 91b (50.0 mg, 0.203 mmol), 6-nitro-1-octene (160.4
mg, 1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column
chromatography (10% EtOAc in hexanes) gave 99i (42.1 mg, 96.1 µmol, 47%) as a yellow
oil; δH (500 MHz, CDCl3) 1.23 - 1.44 (5 H, m, CH2), 1.56 - 1.66 (1 H, m, CH2), 1.67 - 1.77
(2 H, m, CH2), 1.99 (2 H, quin, J 7.2 Hz, CH2CH2CH2NO2), 3.23 (1 H, dd, J 13.6, 7.3 Hz,
ArCH2CHCl), 3.33 (1 H, dd, J 13.6, 7.3 Hz, ArCH2CHCl), 3.69 (3 H, s, OCH3), 3.83 (3 H,
s, OCH3), 4.26 (1 H, m, CHCl), 4.36 (2 H, t, J 7.2 Hz, CH2CH2NO2), 6.41 (1 H, d, J 2.2
Hz, aryl H), 6.44 (1 H, d, J 2.2 Hz, aryl H), 7.19 - 7.32 (5 H, m, aryl H); δC (125 MHz,
CDCl3) 26.1 (CH2), 26.3 (CH2), 27.3 (CH2CH2NO2), 28.3 (CH2), 36.3 (ArCH2CHCl), 37.3
(CH2), 55.3 (OCH3), 55.7 (OCH3), 62.9 (CHCl), 75.6 (CH2NO2), 98.4 (aryl C-H), 108.9
(aryl C-H), 121.1 (aryl Cq), 126.7 (aryl C-H), 129.2 (aryl C-H), 130.0 (aryl C-H), 136.3
(aryl Cq), 136.6 (aryl Cq), 159.1 (aryl Cq), 159.4 (aryl Cq); νmax (thin film/cm-1
) 1046 (s),
1144 (s), 1198 (s), 1295 (w), 1390 (m), 1458 (m), 1560 (s), 2844 (w), 2926 (m); MS (ES+)
m/z 438 35
Cl, 440 37
Cl [(M+H)+]; HRMS C22H28NO4S [(M−Cl)
+] Expected 402.1739,
Found 402.1741.
148
[2-(2-Chloro-9-phenylnonyl)-3,5-dimethoxyphenyl] (phenyl)sulfide 99j
As described in general procedure D, 91b (50.0 mg, 0.203 mmol), 9-phenyl-1-nonene (206
mg, 1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column
chromatography (30% CHCl3 in hexanes) gave 99j (61.9 mg, 0.128 mmol, 63%) as a
colourless oil; δH (400 MHz, CDCl3) 1.18 - 1.44 (7 H, m, CH2), 1.59 - 1.67 (3 H, m, CH2),
1.69 - 1.78 (2 H, m, CH2), 2.61 (2 H, t, J 7.5 Hz, CH2CH2Ph), 3.24 (1 H, dd, J 13.6, 7.0
Hz, ArCH2CHCl), 3.34 (1 H, dd, J 13.6, 7.5 Hz, ArCH2CHCl), 3.69 (3 H, s, OCH3), 3.83
(3 H, s, OCH3), 4.28 (1 H, m, CHCl), 6.42 (1 H, d, J 2.3 Hz, aryl H), 6.45 (1 H, d, J 2.3
Hz, aryl H), 7.16 - 7.33 (10 H, m, aryl H); δC (100 MHz, CDCl3) 26.8 (CH2), 29.1 (CH2),
29.3 (CH2), 29.4 (CH2), 31.6 (CH2), 36.0 (CH2CH2Ph), 36.3 (ArCH2CHCl), 37.7 (CH2),
55.4 (OCH3), 55.7 (OCH3), 63.4 (CHCl), 98.3 (aryl C-H), 108.8 (aryl C-H), 121.3 (aryl
Cq), 125.6 (aryl C-H), 126.6 (aryl C-H), 128.3 (aryl C-H), 128.5 (aryl C-H), 129.2 (aryl C-
H), 130.0 (aryl C-H), 136.4 (aryl Cq), 136.6 (aryl Cq), 142.9 (aryl Cq), 159.1 (aryl Cq),
159.3 (aryl Cq); νmax (thin film/cm-1
) 1047 (s), 1146 (s), 1198 (s), 1296 (w), 1454 (m), 1495
(m), 1571 (s), 1596 (s), 2854 (m), 2928 (s); MS (ES+) m/z 483
35Cl, 485
37Cl [(M+H)
+];
HRMS C29H35O2S [(M−Cl)+] Expected 447.2358, Found 447.2323.
[2-(2-Chloro-3-phenylpropyl)-3,5-dimethoxyphenyl](phenyl)sulfide 99k
As described in general procedure D, 91b (50.0 mg, 0.203 mmol), allylbenzene (135 μL,
1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column
chromatography (30% CHCl3 in hexanes) gave 99k (30.1 mg, 75.4 µmol, 37%) as a
colourless oil; δH (500 MHz, CDCl3) 3.02 (1 H, dd, J 14.5, 8.8 Hz, ArCH2CHCl), 3.08 (1
H, dd, J 14.5, 4.7 Hz, ArCH2CHCl), 3.29 (1 H, dd, J 13.6, 6.6 Hz, ArCH2CHCl), 3.39 (1
149
H, dd, J 13.6, 7.6 Hz, ArCH2CHCl), 3.69 (3 H, s, OCH3), 3.81 (3 H, s, OCH3), 4.45 - 4.52
(1 H, m, CHCl), 6.41 (1 H, d, J 2.5 Hz, aryl H), 6.45 (1 H, d, J 2.5 Hz, aryl H), 7.15 - 7.31
(10 H, m); δC (125 MHz, CDCl3) 36.1 (ArCH2CHCl), 44.3 (ArCH2CHCl), 55.3 (OCH3),
55.6 (OCH3), 63.1 (CHCl), 98.4 (aryl C-H), 109.0 (aryl C-H), 121.0 (aryl Cq), 126.5 (aryl
C-H), 126.6 (aryl C-H), 128.2 (aryl C-H), 129.1 (aryl C-H), 129.2 (aryl C-H), 130.0 (aryl
C-H), 136.3 (aryl Cq), 136.6 (aryl Cq), 138.7 (aryl Cq), 159.1 (aryl Cq), 159.4 (aryl Cq); νmax
(thin film/cm-1
) 1046 (vs), 1154 (s), 1198 (s), 1296 (m), 1437 (m), 1454 (s), 1477 (s), 1571
(vs), 1596 (vs), 2835 (w), 2935 (w), 2957 (w), 3000 (w), 3025 (w); MS (APCI) m/z 399
35Cl, 401
37Cl [(M+H)
+]; HRMS C23H24O2ClS [(M+H)
+] Expected 399.1180, Found
399.1169.
(E)-[2-(4,4-Dimethylhepta-2,6-dien-1-yl)-3,5-
dimethoxyphenyl](phenyl)sulfide 147a
As described in general procedure D, 91b (50.0 mg, 0.203 mmol), 4,4-dimethylhepta-1,6-
diene (127 mg, 1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column
chromatography (30% CHCl3 in hexanes) gave 147a (15.3 mg, 41.5 µmol, 21%) as a
colourless oil; δH (400 MHz, CDCl3) 0.89 (6 H, s, C(CH3)2), 1.95 (2 H, d, J 7.3 Hz,
CH2CH=CH2), 3.50 (2 H, dd, J 6.1, 1.0 Hz, ArCH2CH=CH), 3.69 (3 H, s, OCH3), 3.81 (3
H, s, OCH3), 4.90 - 4.97 (2 H, m, CH=CH2), 5.29 (1 H, dt, J 15.6, 6.1 Hz, ArCH2CH=CH),
5.40 (1 H, dt, J 15.6, 1.0 Hz, ArCH2CH=CH), 5.72 (1 H, ddt, J 16.6, 10.6, 7.3 Hz,
CH=CH2), 6.41 (1 H, d, J 2.5 Hz, aryl H), 6.43 (1 H, d, J 2.5 Hz, aryl H), 7.16 - 7.30 (5 H,
m, aryl H); δC (100 MHz, CDCl3) 26.9 (C(CH3)2), 30.5 (ArCH2CH=CH), 35.6 (alkyl Cq),
47.5 (CH2CH=CH2), 55.3 (OCH3), 55.7 (OCH3), 98.5 (aryl C-H), 108.7 (aryl C-H), 116.2
(CH=CH2), 123.4 (ArCH2CH=CH), 124.1 (aryl Cq), 126.4 (aryl C-H), 129.0 (aryl C-H),
130.0 (aryl C-H), 135.5 (aryl Cq), 136.1 (CH=CH2), 136.8 (aryl Cq), 140.4
(ArCH2CH=CH), 158.7 (aryl Cq), 158.8 (aryl Cq); νmax (thin film/cm-1
) 1050 (s), 1150 (m),
1274 (w), 1295 (w), 1409 (m), 1436 (m), 1477 (m), 1571 (s), 1596 (s), 2834 (w), 2935 (m),
2957 (m), 3000 (w), 3072 (w); MS (ES+) m/z 369 [(M+H)
+]; HRMS C23H29O2S [(M+H)
+]
Expected 369.1883, Found 369.1881.
150
(E)-[2-(3-(1-Allylcyclohexyl)allyl)-3,5-dimethoxyphenyl](phenyl)sulfide
147b
As described in general procedure D, 91b (50.0 mg, 0.203 mmol), 1,1-diallylcyclohexane
(168 mg, 1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column
chromatography (30% CHCl3 in hexanes) gave 147b (19.1 mg, 46.7 µmol, 23%) as a
colourless oil; δH (400 MHz, CDCl3) 1.15 - 1.31 (4 H, m, CH2), 1.33 - 1.48 (6 H, m, CH2),
1.97 (2 H, d, J 7.3 Hz, CH2CH=CH2), 3.53 (2 H, d, J 5.3 Hz, ArCH2CH=CH), 3.69 (3 H, s,
OCH3), 3.81 (3 H, s, OCH3), 4.89 - 4.96 (2 H, m, CH=CH2), 5.22 (1 H, d, J 15.9 Hz,
ArCH2CH=CH), 5.29 (1 H, dt, J 15.9, 5.3 Hz, ArCH2CH=CH), 5.63 – 5.76 (1 H, m,
CH=CH2), 6.41 (1 H, d, J 2.5, Hz aryl H), 6.42 (1 H, d, J 2.5 Hz, aryl H), 7.16 - 7.22 (1 H,
m, aryl H), 7.24 - 7.29 (4 H, m); δC (100 MHz, CDCl3) 22.1 (CH2), 26.5 (CH2), 30.7
(ArCH2CH=CH), 35.8 (CH2), 38.7 (alkyl Cq), 46.5 (CH2CH=CH2), 55.3 (OCH3), 55.6
(OCH3), 98.4 (aryl C-H), 108.5 (aryl C-H), 116.0 (CH=CH2), 123.9 (aryl Cq), 125.7
(ArCH2CH=CH), 126.4 (aryl C-H), 129.0 (aryl C-H), 130.1 (aryl C-H), 135.5 (aryl Cq),
135.8 (CH=CH2), 136.7 (aryl Cq), 138.4 (ArCH2CH=CH), 158.7 (aryl Cq), 158.8 (aryl Cq);
νmax (thin film/cm-1
) 1050 (s), 1144 (m), 1204 (s), 1275 (w), 1295 (w), 1460 (m), 1572 (s),
1597 (s), 2852 (m), 2925 (vs), 3000 (w), 3071 (w); MS (ES+) m/z 409 [(M+H)
+]; HRMS
C26H33O2S [(M+H)+] Expected 409.2196, Found 409.2196.
(E)-[2-(4,4-Dimethylpent-2-en-1-yl)-3,5-dimethoxyphenyl](phenyl)sulfide
147c
As described in general procedure D, 91b (50.0 mg, 0.203 mmol), 4,4-dimethyl-1-pentene
(147 µL, 1.02 mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column
151
chromatography (30% CHCl3 in hexanes) gave 147c (13.9 mg, 40.6 µmol, 20%) as a
colourless oil; δH (400 MHz, CDCl3) 0.92 (9 H, s, (CH3)3), 3.49 (2 H, dd, J 6.4, 1.1 Hz,
ArCH2CH=CH), 3.69 (3 H, s, OCH3), 3.82 (3 H, s, OCH3), 5.30 (1 H, dt, J 15.6, 6.4 Hz,
ArCH2CH=CH), 5.45 (1 H, dt, J 15.6, 1.1 Hz, ArCH2CH=CH), 6.42 (1 H, d, J 2.5 Hz, aryl
H), 6.45 (1 H, d, J 2.5 Hz, aryl H), 7.15 - 7.22 (1 H, m, aryl H), 7.22 - 7.30 (4 H, m, aryl
H); δC (100 MHz, CDCl3) 29.6 ((CH3)3), 30.5 (ArCH2CH=CH), 51.4 (alkyl Cq), 55.3
(OCH3), 55.8 (OCH3), 98.6 (aryl C-H), 108.9 (aryl C-H), 121.9 (ArCH2CH=CH), 124.3
(aryl Cq), 126.3 (aryl C-H), 129.0 (aryl C-H), 129.9 (aryl C-H), 135.4 (aryl Cq), 136.9 (aryl
Cq), 142.1 (ArCH2CH=CH), 158.7 (aryl Cq), 158.8 (aryl Cq); νmax (thin film/cm-1
) 1049 (s),
1136 (m), 1157 (m), 1194 (m), 1207 (m), 1460 (m), 1476 (m), 1570 (s), 1596 (s), 2834
(w), 2864 (w), 2955 (m), 3000 (w); MS (ES+) m/z 343 [(M+H)
+]; HRMS C21H27O2S
[(M+H)+] Expected 343.1726, Found 343.1727.
[2-(2-Chlorooctyl)-3,5-dimethoxyphenyl] (p-tolyl)sulfide 164a
As described in general procedure D, 91v (52.9 mg, 0.203 mmol), 1-octene (160 μL, 1.02
mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography
(30% CHCl3 in hexanes) gave 164a (43.6 mg, 0.107 mmol, 53%) as a colourless oil; δH
(500 MHz, CDCl3) 0.89 (3 H, t, J 6.9 Hz, CH2CH3), 1.20 - 1.43 (7 H, m, CH2), 1.60 (1 H,
m, CH2), 1.70 - 1.77 (2 H, m, CH2), 2.34 (3 H, s, ArCH3), 3.24 (1 H, dd, J 13.6, 7.3 Hz,
ArCH2CHCl), 3.32 (1 H, dd, J 13.6, 7.6 Hz, ArCH2CHCl), 3.66 (3 H, s, OCH3), 3.82 (3 H,
m, OCH3), 4.29 (1 H, m, CHCl), 6.34 (1 H, d, J 2.5 Hz, aryl H), 6.36 (1 H, d, J 2.5 Hz, aryl
H), 7.12 (2 H, d, J 7.9 Hz, aryl H), 7.21 (2 H, d, J 7.9 Hz, aryl H); δC (125 MHz, CDCl3)
14.1 (CH3), 21.1 (ArCH3), 22.6 (CH2), 26.7 (CH2), 28.8 (CH2), 31.7 (CH2), 36.2
(ArCH2CHCl), 37.7 (CH2), 55.3 (OCH3), 55.6 (OCH3), 63.3 (CHCl), 97.6 (aryl C-H),
107.9 (aryl C-H), 120.3 (aryl Cq), 130.0 (aryl C-H), 131.3 (aryl C-H), 131.9 (aryl Cq),
137.1 (aryl Cq), 138.0 (aryl Cq), 159.0 (aryl Cq), 159.2 (aryl Cq); νmax (thin film/cm-1
) 1048
(s), 1145 (s), 1199 (s), 1295 (w), 1460 (m), 1572 (s), 1596 (s), 2867 (w), 2929 (m); MS
152
(ES+) m/z 407
35Cl, 409
37Cl [(M+H)
+]; HRMS C23H32O2ClS [(M+H)
+] Expected
407.1808, Found 407.1806.
(4-Bromophenyl)[2-(2-chlorooctyl)-3,5-dimethoxyphenyl]sulfide 164b
As described in general procedure D, 91w (66.0 mg, 0.203 mmol), 1-octene (160 μL, 1.02
mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography
(30% CHCl3 in hexanes) gave 164b (62.7 mg, 0.133 mmol, 65%) as a colourless oil; δH
(400 MHz, CDCl3) 0.88 (3 H, t, J 6.8 Hz, CH2CH3) 1.17 - 1.43 (7 H, m, CH2), 1.51 - 1.64
(1 H, m, CH2), 1.65 - 1.77 (2 H, m, CH2), 3.20 (1 H, dd, J 13.7, 6.7 Hz, ArCH2CHCl), 3.30
(1 H, dd, J 13.7, 7.7 Hz, ArCH2CHCl), 3.71 (3 H, s, OCH3), 3.83 (3 H, s, OCH3), 4.24 (1
H, m, CHCl), 6.44 (1 H, d, J 2.3 Hz, aryl H), 6.45 (1 H, d, J 2.3 Hz, aryl H), 7.08 (2 H, d, J
8.4 Hz, aryl H), 7.39 (2 H, d, J 8.4 Hz, aryl H); δC (100 MHz, CDCl3) 14.1 (CH3), 22.6
(CH2), 26.7 (CH2), 28.8 (CH2), 31.8 (CH2), 36.3 (ArCH2CHCl), 37.8 (CH2), 55.4 (OCH3),
55.7 (OCH3), 63.3 (CHCl), 98.8 (aryl C-H), 109.3 (aryl C-H), 120.2 (aryl Cq), 121.9 (aryl
Cq), 130.9 (aryl C-H), 132.1 (aryl C-H), 135.6 (aryl Cq), 136.2 (aryl Cq), 159.2 (aryl Cq),
159.4 (aryl Cq); νmax (thin film/cm-1
) 1007 (s), 1047 (s), 1144 (s), 1198 (s), 1295 (m), 1434
(m), 1471 (s), 1570 (s), 1596 (s), 2856 (w), 2929 (m); MS (ES+) m/z 471
35Cl
79Br, 473
37Cl
79Br and
35Cl
81Br, 475
37Cl
81Br [(M+H)
+]; HRMS C22H29BrO2ClS [(M+H)
+] Expected
471.0755, Found 471.0751.
153
[2-(2-Chlorooctyl)-3,5-dimethoxyphenyl] (4-fluorophenyl)sulfide 164c
As described in general procedure D, 91x (53.7 mg, 0.203 mmol), 1-octene (160 μL, 1.02
mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography
(30% CHCl3 in hexanes) gave 164c (55.9 mg, 0.136 mmol, 66%) as a colourless oil; δH
(400 MHz, CDCl3) 0.89 (3 H, t, J 6.8 Hz, CH2CH3), 1.20 - 1.45 (7 H, m, CH2), 1.54 - 1.67
(1 H, m, CH2), 1.68 - 1.78 (2 H, m, CH2), 3.22 (1 H, dd, J 13.8, 6.8 Hz, ArCH2CHCl), 3.31
(1 H, dd, J 13.8, 7.5 Hz, ArCH2CHCl), 3.67 (3 H, s, OCH3), 3.83 (3 H, s, OCH3), 4.28 (1
H, m, CHCl), 6.30 (1 H, d, J 2.3 Hz, aryl H), 6.38 (1 H, d, J 2.3 Hz, aryl H), 7.02 (2 H, t, J
8.7 Hz, aryl H), 7.25 - 7.33 (2 H, dd, J 8.7, 5.3 Hz, aryl H); δC (100 MHz, CDCl3) 14.1
(CH3), 22.6 (CH2), 26.7 (CH2), 28.8 (CH2), 31.7 (CH2), 36.2 (ArCH2CHCl), 37.8 (CH2),
55.3 (OCH3), 55.6 (OCH3), 63.3 (CHCl), 97.7 (aryl C-H), 107.8 (aryl C-H), 116.4 (d, J
22.0 Hz, aryl C-H), 120.3 (aryl Cq), 130.8 (d, J 2.9 Hz, aryl Cq), 133.2 (d, J 8.1 Hz, aryl C-
H), 137.7 (aryl Cq), 159.1 (aryl Cq), 159.3 (aryl Cq), 162.2 (d, J 247.2 Hz, aryl C-F); νmax
(thin film/cm-1
) 1047 (s), 1145 (s), 1198 (m), 1226 (m), 1295 (w), 1460 (w), 1488 (s), 1571
(m), 1590 (m), 2856 (w), 2929 (w); MS (ES+) m/z 411
35Cl, 413
37Cl [(M+H)
+]; HRMS
C22H29O2ClFS [(M+H)+] Expected 411.1555, Found 411.1556.
[2-(2-Chlorooctyl)-3,5-dimethoxyphenyl] (2-fluorophenyl)sulfide 164d
As described in general procedure D, 91y (53.7 mg, 0.203 mmol), 1-octene (160 μL, 1.02
mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography
(30% CHCl3 in hexanes) gave 164d (53.5 mg, 0.130 mmol, 64%) as a colourless oil; δH
(500 MHz, CDCl3) 0.89 (3 H, t, J 6.9 Hz, CH3), 1.19 - 1.44 (7 H, m, CH2), 1.55-1.64 (1 H,
154
m, CH2), 1.68 - 1.80 (2 H, m, CH2), 3.25 (1 H, dd, J 13.9, 6.9 Hz, ArCH2CHCl), 3.35 (1 H,
dd, J 13.9, 7.6 Hz, ArCH2CHCl), 3.69 (3 H, s, OCH3), 3.83 (3 H, s, OCH3), 4.29 (1 H, m,
CHCl), 6.39 (1 H, d, J 2.5 Hz, aryl H), 6.42 (1 H, d, J 2.5 Hz, aryl H), 7.03 - 7.15 (3 H, m,
aryl H), 7.21 - 7.26 (1 H, m, aryl H); δC (125 MHz, CDCl3) 14.1 (CH3), 22.6 (CH2), 26.7
(CH2), 28.9 (CH2), 31.7 (CH2), 36.3 (ArCH2CHCl), 37.7 (CH2), 55.3 (OCH3), 55.6
(OCH3), 63.2 (CHCl), 98.4 (aryl C-H), 108.6 (aryl C-H), 115.8 (d, J 21.8 Hz, aryl C-H),
121.4 (aryl Cq), 123.4 (d, J 17.3 Hz, aryl Cq), 124.7 (d, J 3.6 Hz, aryl C-H), 128.8 (d, J 7.3
Hz, aryl C-H), 132.4 (aryl C-H), 135.2 (aryl Cq), 159.2 (aryl Cq), 159.4 (aryl Cq), 160.7 (d,
J 246.1 Hz, aryl C-F); νmax (thin film/cm-1
) 1047 (s), 1145 (s), 1221 (m), 1297 (w), 1472
(s), 1572 (s), 1597 (s), 2857 (w), 2930 (m); MS (ES+) m/z 411
35Cl, 413
37Cl [(M+H)
+];
HRMS C22H29O2ClFS [(M+H)+] Expected 411.1555, Found 411.1557.
[2-(2-Chlorooctyl)-3,5-dimethoxyphenyl] (3-methoxyphenyl)sulfide 164e
As described in general procedure D, 91z (56.1 mg, 0.203 mmol), 1-octene (160 μL, 1.02
mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography
(30% CHCl3 in hexanes) gave 164e (52.7 mg, 0.125 mmol, 60%) as a colourless oil; δH
(500 MHz, CDCl3) 0.90 (3 H, t, J 7.1 Hz, CH3), 1.20 - 1.44 (7 H, m, CH2), 1.56-1.66 (1 H,
m, CH2), 1.70 - 1.78 (2 H, m, CH2), 3.26 (1 H, dd, J 13.6, 6.9 Hz, ArCH2CHCl), 3.35 (1 H,
dd, J 13.6, 7.3 Hz, ArCH2CHCl), 3.71 (3 H, s, OCH3), 3.77 (3 H, s, OCH3), 3.84 (3 H, s,
OCH3), 4.30 (1 H, m, CHCl), 6.44 (1 H, d, J 2.5 Hz, aryl H), 6.52 (1 H, d, J 2.5 Hz, aryl
H), 6.76 (1 H, ddd, J 8.0, 2.5, 0.9 Hz, aryl H), 6.80 (1 H, dd, J 3.5, 2.5 Hz, aryl H), 6.82 -
6.85 (1 H, m, aryl H), 7.20 (1 H, t, J 8.0 Hz, aryl H); δC (125 MHz, CDCl3) 14.1 (CH3),
22.6 (CH2), 26.7 (CH2), 28.8 (CH2), 31.8 (CH2), 36.3 (ArCH2CHCl), 37.8 (CH2), 55.26
(OCH3), 55.4 (OCH3), 55.6 (OCH3), 63.4 (CHCl), 98.6 (aryl C-H), 109.4 (aryl C-H), 112.2
(aryl C-H), 115.0 (aryl C-H), 121.7 (aryl Cq), 122.0 (aryl C-H), 129.9 (aryl C-H), 136.0
(aryl Cq), 138.0 (aryl Cq), 159.2 (aryl Cq), 159.4 (aryl Cq), 160.1 (aryl Cq); νmax (thin
film/cm-1
) 1045 (s), 1144 (m), 1199 (m), 1247 (m), 1462 (m), 1476 (m), 1572 (s), 1585 (s),
155
2856 (w), 2930 (m), 3000 (w); MS (ES+) m/z 423
35Cl, 425
37Cl [(M+H)
+]; HRMS
C23H31O3S [(M−Cl)+] Expected 387.1994, Found 387.1992.
[2-(2-Chlorooctyl)-3,5-dimethoxyphenyl] (3,5-dimethoxyphenyl)sulfide 164f
As described in general procedure D, 91aa (62.2 mg, 0.203 mmol), 1-octene (160 μL, 1.02
mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography
(50% CHCl3 in hexanes) gave 164f (43.0 mg, 94.9 µmol, 47%) as a white solid; m.p 62.1-
64.3 ⁰C; δH (400 MHz, CDCl3) 0.88 (3 H, t, J 6.9 Hz, CH2CH3), 1.16 - 1.41 (7 H, m, CH2),
1.51-1.64 (1 H, m, CH2), 1.65 - 1.76 (2 H, m, CH2), 3.21 (1 H, dd, J 13.8, 7.0 Hz,
ArCH2CHCl), 3.31 (1 H, dd, J 13.8, 7.5 Hz, ArCH2CHCl), 3.72 (3 H, s, OCH3), 3.74 (6 H,
s, OCH3), 3.83 (3 H, s, OCH3), 4.25 (1 H, m, CHCl), 6.29 (1 H, t, J 2.0 Hz, aryl H), 6.35 (2
H, d, J 2.0 Hz, aryl H), 6.43 (1 H, d, J 2.3 Hz, aryl H), 6.55 (1 H, d, J 2.3 Hz, aryl H); δC
(100 MHz, CDCl3) 14.2 (CH3), 22.7 (CH2), 26.7 (CH2), 28.8 (CH2), 31.2 (CH2), 36.3
(ArCH2CHCl), 37.8 (CH2), 55.4 (OCH3), 55.4 (OCH3), 55.6 (OCH3), 63.5 (CHCl), 98.6
(aryl C-H), 98.9 (aryl C-H), 107.0 (aryl C-H), 109.7 (aryl C-H), 122.0 (aryl Cq), 135.3
(aryl Cq), 139.0 (aryl Cq), 159.1 (aryl Cq), 159.3 (aryl Cq), 161.0 (aryl Cq); νmax (thin
film/cm-1
) 1044 (s), 1154 (s), 1202 (s), 1279 (m), 1417 (m), 1454 (m), 1570 (s), 1585 (s),
2856 (w), 2930 (m); MS (ES+) m/z 453
35Cl, 455
37Cl [(M+H)
+]; HRMS C24H34O4ClS
[(M+H)+] Expected 453.1866, Found 453.1873.
[2-(2-Chlorooctyl)-3,5-dimethoxyphenyl] (4-nitrophenyl)sulfide 164g
As described in general procedure D, 91d (59.1 mg, 0.203 mmol), 1-octene (160 μL, 1.02
mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography
156
(30% CHCl3 in hexanes) gave 164g (66.9 mg, 0.153 mmol, 75%) as a yellow solid; m.p
50.2-52.6 ⁰C; δH (400 MHz, CDCl3) 0.87 (3 H, t, J 6.8 Hz, CH2CH3), 1.14 - 1.42 (7 H, m,
CH2), 1.47 - 1.62 (1 H, m, CH2), 1.65 - 1.75 (2 H, m, CH2), 3.17 (1 H, dd, J 13.7, 6.1 Hz,
ArCH2CHCl), 3.26 (1 H, dd, J 13.7, 8.2 Hz, ArCH2CHCl), 3.78 (3 H, s, OCH3), 3.87 (3 H,
s, OCH3), 4.21 (1 H, m, CHCl), 6.57 (1 H, d, J 2.2 Hz, aryl H), 6.66 (1 H, d, J 2.2 Hz, aryl
H), 7.13 (2 H, d, J 8.9 Hz, aryl H), 8.06 (2 H, d, J 8.9 Hz, aryl H); δC (100 MHz, CDCl3)
14.0 (CH3), 22.6 (CH2), 26.6 (CH2), 28.7 (CH2), 31.6 (CH2), 36.5 (ArCH2CHCl), 38.0
(CH2), 55.5 (OCH3), 55.7 (OCH3), 63.1 (CHCl), 100.6 (aryl C-H), 111.3 (aryl C-H), 123.9
(aryl Cq), 124.0 (aryl C-H), 126.2 (aryl C-H), 131.6 (aryl Cq), 145.1 (aryl Cq), 148.6 (aryl
Cq), 159.5 (aryl Cq), 159.8 (aryl Cq); νmax (thin film/cm-1
) 1044 (m), 1086 (m), 1144 (m),
1198 (m), 1298 (w), 1334 (s), 1460 (w), 1513 (m), 1595 (m), 2855 (w), 2929 (w); MS
(ES+) m/z 438
35Cl, 440
37Cl [(M+H)
+]; HRMS C22H29NO4ClS [(M+H)
+] Expected
438.1506, Found 438.1500.
[(2-(2-Chlorooctyl)-3,5-dimethoxyphenyl] (4-trifluoromethylphenyl)sulfide
164h
As described in general procedure D, 91e (63.8 mg, 0.203 mmol), 1-octene (160 μL, 1.02
mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography
(30% CHCl3 in hexanes) gave 164h (69.8 mg, 0.151 mmol, 75%) as a colourless oil; δH
(400 MHz, CDCl3) 0.88 (3 H, t, J 6.9 Hz, CH2CH3), 1.16 - 1.42 (7 H, m, CH2), 1.50 - 1.63
(1 H, m, CH2), 1.63 - 1.78 (2 H, m, CH2), 3.20 (1 H, dd, J 13.6, 6.5 Hz, ArCH2CHCl), 3.30
(1 H, dd, J 13.6, 8.0 Hz, ArCH2CHCl), 3.75 (3 H, s, OCH3), 3.86 (3 H, s, OCH3), 4.23 (1
H, m, CHCl), 6.52 (1 H, d, J 2.5 Hz, aryl H), 6.61 (1 H, d, J 2.5 Hz, aryl H), 7.18 (2 H, d, J
8.3 Hz, aryl H), 7.47 (2 H, d, J 8.3 Hz, aryl H); δC (100 MHz, CDCl3) 14.1 (CH3), 22.6
(CH2), 26.7 (CH2), 28.8 (CH2), 31.7 (CH2), 36.4 (ArCH2CHCl), 37.9 (CH2), 55.5 (OCH3),
55.7 (OCH3), 63.3 (CHCl), 99.9 (aryl C-H), 110.8 (aryl C-H), 123.3 (aryl Cq), 124.3 (q, J
271.4 Hz, CF3), 125.7 (q, J 3.7 Hz, aryl C-H), 127.3 (aryl C-H), 128.3 (q, J 32.3 Hz, aryl
Cq), 133.3 (aryl Cq), 143.3 (aryl Cq), 159.4 (aryl Cq), 159.6 (aryl Cq); νmax (thin film/cm-1
)
157
1013 (m), 1047 (m), 1063 (m), 1123 (m), 1163 (m), 1324 (s), 1461 (w), 1570 (m), 1598
(m), 2857 (w), 2931 (w); MS (ES+) m/z 461
35Cl, 463
37Cl [(M+H)
+]; HRMS C23H28O2F3S
[(M−Cl)+] Expected 425.1757, Found 425.1755.
[2-(2-Chlorooctyl)-3,5-diisopropoxyphenyl](phenyl)sulfide 164i
As described in general procedure D, 91ab (61.4 mg, 0.203 mmol), 1-octene (160 μL, 1.02
mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography
(30% CHCl3 in hexanes) gave 164i (59.5 mg, 0.132 mmol, 65%) as a colourless oil; δH
(400 MHz, CDCl3) 0.89 (3 H, t, J 6.8 Hz, CH3), 1.20 - 1.33 (12 H, m, OCH(CH3)2), 1.33 -
1.41 (7 H, m, CH2), 1.50 - 1.65 (1 H, m, CH2), 1.68-1.77 (2 H, q, J 7.4 Hz, CH2), 3.23 (1
H, dd, J 13.6, 7.3 Hz, ArCH2CHCl), 3.30 (1 H, dd, J 13.6, 7.0 Hz, ArCH2CHCl), 4.23 -
4.40 (2 H, m, CHCl and OCH(CH3)2), 4.53 (1 H, sept, J 6.0 Hz, OCH(CH3)2), 6.36 (2 H,
app. s, aryl H), 7.17 - 7.32 (5 H, m, aryl H); δC (100 MHz, CDCl3) 14.2 (CH3), 21.9
(OCH(CH3)2), 22.0 (OCH(CH3)2), 22.1 (OCH(CH3)2), 22.7 (CH2), 26.8 (CH2), 28.8 (CH2),
31.8 (CH2), 36.6 (ArCH2CHCl), 37.8 (CH2), 63.6 (CHCl), 69.8 (OCH(CH3)2), 69.9
(OCH(CH3)2), 101.3 (aryl C-H), 110.1 (aryl C-H), 121.6 (aryl Cq), 126.5 (aryl C-H), 129.1
(aryl C-H), 130.1 (aryl C-H), 136.6 (aryl Cq), 136.7 (aryl Cq), 157.3 (aryl Cq), 157.4 (aryl
Cq); νmax (thin film/cm-1
) 1037 (m), 1113 (s), 1135 (s), 1179 (m), 1273 (w), 1373 (w), 1384
(w), 1464 (m), 1566 (s), 1593 (w), 2857 (w), 2929 (m), 2975 (m); MS (ES+) m/z 449
35Cl,
451 37
Cl [(M+H)+]; HRMS C26H38O2ClS [(M+H)
+] Expected 449.2281, Found 449.2293.
158
[3,5-bis(Allyloxy)-2-(2-chlorooctyl)phenyl](phenyl)sulfide 164j
As described in general procedure D, 91ad (59.6 mg, 0.203 mmol), 1-octene (160 μL, 1.02
mmol) and FeCl3 (131 mg, 0.815 mmol), after purification by column chromatography
(30% CHCl3 in hexanes) gave 164j (46.7 mg, 0.105 mmol, 50%) as a colourless oil; δH
(400 MHz, CDCl3) 0.88 (3 H, t, J 6.8 Hz, CH3), 1.20 - 1.42 (7 H, m, CH2), 1.53 - 1.65 (1
H, m, CH2), 1.70 - 1.78 (2 H, m, CH2), 3.26 (1 H, dd, J 13.6, 7.2 Hz, ArCH2CHCl), 3.36 (1
H, dd, J 13.6, 7.2 Hz, ArCH2CHCl), 4.30 (1 H, m, CHCl), 4.37 (2 H, dt, J 5.4, 1.3 Hz,
OCH2), 4.53 (2 H, dt, J 5.0, 1.5 Hz, OCH2), 5.23 (1 H, dq, J 10.4, 1.3 Hz, CH=CH2), 5.29
(1 H, dq, J 10.7, 1.5 Hz, CH=CH2), 5.32 (1 H, dq, J 17.2, 1.3 Hz, CH=CH2), 5.45 (1 H, dq,
J 17.2, 1.5 Hz, CH=CH2), 5.95 (1 H, ddt, J 17.2, 10.4, 5.4 Hz, CH=CH2), 6.06 (1 H, ddt, J
17.2, 10.7, 5.0 Hz, CH=CH2), 6.42 (1 H, d, J 2.4 Hz, aryl H), 6.43 (1 H, d, J 2.4 Hz, aryl
H), 7.19 - 7.33 (5 H, m, aryl H); δC (125 MHz, CDCl3) 14.1 (CH3), 22.6 (CH2), 26.7 (CH2),
28.7 (CH2), 31.7 (CH2), 36.4 (ArCH2CHCl), 37.8 (CH2), 63.3 (CHCl), 68.9 (OCH2), 69.0
(OCH2), 99.9 (CH=CH2), 109.7 (CH=CH2), 117.3 (CH=CH2), 118.0 (CH=CH2), 121.4
(aryl Cq), 126.7 (aryl C-H), 129.1 (aryl C-H), 130.3 (aryl C-H), 132.8 (aryl C-H), 132.9
(aryl C-H), 136.2 (aryl Cq), 136.8 (aryl Cq), 158.0 (aryl Cq), 158.1 (aryl Cq); νmax (thin
film/cm-1
); 924 (s), 1023 (s), 1044 (s), 1140 (w), 1172 (s), 1274 (w), 1416 (w), 1455 (w),
1569 (s), 1595 (s), 2856 (w), 2926 (w), 2953 (w), 3060 (w), 3074 (w); MS (ES+) m/z 455
35Cl, 457
37Cl [(M+H)
+]; HRMS C26H33O2S [(M−Cl)
+] Expected 409.2201, Found
409.2193.
159
[3,5-bis(Allyloxy)-2-(2-chlorohexyl)phenyl](phenyl)sulfide 164k
As described in general procedure D, 91ad (1.00 g, 3.35 mmol), 1-hexene (2.10 mL, 16.8
mmol) and FeCl3 (2.16 g, 13.4 mmol), after purification by column chromatography (30%
CHCl3 in hexanes) gave 164k (700 mg, 1.68 mmol 50%) as a colourless oil; δH (400 MHz,
CDCl3) 0.88 (3 H, t, J 7.2 Hz, CH3), 1.20 - 1.42 (3 H, m, CH2), 1.51 - 1.64 (1 H, m, CH2),
1.70 - 1.78 (2 H, m, CH2), 3.26 (1 H, dd, J 13.7, 7.0 Hz, ArCH2CHCl), 3.36 (1 H, dd, J
13.7, 7.6 Hz, ArCH2CHCl), 4.24 - 4.34 (1 H, m, CHCl), 4.37 (2 H, dt, J 5.4, 1.3 Hz,
OCH2), 4.53 (2 H, dt, J 5.1, 1.6 Hz, OCH2), 5.23 (1 H, dq, J 10.4, 1.3 Hz, CH=CH2), 5.27-
5.34 (2 H, m, CH=CH2), 5.45 (1 H, dq, J 17.2, 1.6 Hz, CH=CH2), 5.95 (1 H, ddt, J 17.2,
10.4, 5.4 Hz, CH=CH2), 6.06 (1 H, ddt, J 17.2, 10.6, 5.1 Hz, CH=CH2), 6.39 - 6.44 (2 H,
m, aryl H), 7.19 - 7.32 (5 H, m, aryl H); δC (100 MHz, CDCl3) 14.0 (CH3), 22.2 (CH2),
28.9 (CH2), 36.4 (ArCH2CHCl), 37.5 (CH2), 63.3 (CHCl), 68.8 (OCH2), 68.9 (OCH2), 99.8
(aryl C-H), 109.6 (aryl C-H), 117.3 (CH=CH2), 118.1 (CH=CH2), 121.4 (aryl Cq), 126.7
(aryl C-H), 129.1 (aryl C-H), 130.3 (aryl C-H), 132.8 (CH=CH2 x 2), 136.2 (aryl Cq), 136.8
(aryl Cq), 157.9 (aryl Cq), 158.1 (aryl Cq); νmax (thin film/cm-1
) 928 (m), 1024 (s), 1045 (s),
1142 (s), 1176 (s), 1276 (w), 1412 (m), 1456 (m), 1477 (m), 1570 (s), 1595 (s), 2860 (w),
2929 (w), 2956 (w), 3080 (w); MS (ES+) m/z 417
35Cl, 419
37Cl [(M+H)
+]; HRMS
C24H30ClO2S [(M+H)+] Expected 417.1650, Found 417.1649.
[3,5-bis(Allyloxy)-2-(2-chloro-5-nitropentyl)phenyl](phenyl)sulfide 164l
As described in general procedure D, 91ad (95.5 mg, 0.320 mmol), 5-nitro-1-pentene (193
mg, 1.70 mmol) and FeCl3 (217 mg, 1.35 mmol), after purification by column
chromatography (50% CHCl3 in hexanes) gave 164l (42.3 mg, 94.4 µmol, 30%) as a
160
yellow oil; δH (400 MHz, CDCl3) 1.72 - 1.87 (2 H, m, CH2), 2.01 - 2.15 (1 H, m, CH2),
2.27 - 2.41 (1 H, m, CH2), 3.28 (1 H, dd, J 13.6, 7.8 Hz, ArCH2CHCl), 3.38 (1 H, dd, J
13.6, 6.6 Hz, ArCH2CHCl), 4.25 - 4.40 (5 H, m, CH2NO2 + CHCl + OCH2), 4.54 (2 H, dt,
J 5.1, 1.6 Hz, OCH2), 5.24 (1 H, dq, J 10.5, 1.3 Hz, CH=CH2), 5.27 - 5.36 (2 H, m,
CH=CH2), 5.44 (1 H, dq, J 17.2, 1.6 Hz, CH=CH2), 5.95 (1 H, ddt, J 17.2, 10.5, 5.4 Hz,
CH=CH2), 6.06 (1 H, ddt, J 17.2, 10.5, 5.1 Hz, CH=CH2), 6.42 (2 H, s, aryl H), 7.21 - 7.34
(5 H, m, aryl H); δC (100 MHz, CDCl3) 24.6 (CH2), 33.7 (CH2), 36.2 (ArCH2CHCl), 61.3
(CHCl), 68.9 (OCH2), 69.0 (OCH2), 75.0 (CH2NO2), 99.9 (aryl C-H), 109.8 (aryl C-H),
117.6 (CH=CH2), 118.1 (CH=CH2), 120.3 (aryl Cq), 126.9 (aryl C-H), 129.2 (aryl C-H),
130.3 (aryl C-H), 132.7 (CH=CH2), 132.8 (CH=CH2), 135.7 (aryl Cq), 136.8 (aryl Cq),
157.9 (aryl Cq), 158.4 (aryl Cq); νmax (thin film/cm-1
) 1138 (s), 1169 (s), 1417 (m), 1551
(vs), 1569 (s), 1595 (s), 2864 (w), 2920 (w), 3075 (w); MS (APCI) m/z 448 35
Cl, 450 37
Cl
[(M+H)+]; HRMS C23H27NO4ClS [(M+H)
+] Expected 448.1344, Found 448.1339.
[3,5-bis(Allyloxy)-2-(5-bromo-2-chloropentyl)phenyl](phenyl)sulfide 164m
As described in general procedure D, 91ad (95.5 mg, 0.320 mmol), 5-bromo-1-pentene
(250 mg, 1.70 mmol) and FeCl3 (217 mg, 1.35 mmol), after purification by column
chromatography (30% CHCl3 in hexanes) gave 164m (59.6 mg, 0.124 mmol, 39%) as a
colourless oil; δH (400 MHz, CDCl3) 1.70 - 1.93 (3 H, m, CH2), 2.03 - 2.17 (1 H, m, CH2),
3.20 (1 H, dd, J 13.9, 7.6 Hz, ArCH2CHCl), 3.25 - 3.36 (3 H, m, ArCH2CHCl + CH2Br),
4.17 - 4.26 (1 H, m, CHCl), 4.29 (2 H, dt, J 5.4, 1.3 Hz, OCH2), 4.46 (2 H, dt, J 5.0, 1.5
Hz, OCH2), 5.15 (1 H, dq, J 10.6, 1.3 Hz, CH=CH2), 5.18 - 5.27 (2 H, m, CH=CH2), 5.36
(1 H, dq, J 17.2, 1.5 Hz, CH=CH2), 5.81 - 5.92 (1 H, m, CH=CH2) 5.93 - 6.04 (1 H, m,
CH=CH2), 6.32 - 6.35 (2 H, m, aryl H), 7.12 - 7.25 (5 H, m, aryl H); δC (100 MHz, CDCl3)
29.8 (CH2), 33.2 (CH2Br), 35.9 (CH2), 36.2 (ArCH2CHCl), 61.8 (CHCl), 68.9 (OCH2),
69.0 (OCH2), 99.9 (aryl C-H), 109.8 (aryl C-H), 117.8 (CH=CH2), 118.0 (CH=CH2), 120.8
(aryl Cq), 126.8 (aryl C-H), 129.2 (aryl C-H), 130.3 (aryl C-H), 132.7 (CH=CH2), 132.8
(CH=CH2), 135.9 (aryl Cq), 136.8 (aryl Cq), 157.9 (aryl Cq), 158.2 (aryl Cq); νmax (thin
film/cm-1
) 927.0 (m), 1023 (s), 1044 (s), 1275 (m), 1417 (m), 1439 (m), 1455 (m), 1476
161
(m), 1569 (s), 1595 9s), 2863 (w), 2916 (w), 2959 (w), 3075 (w); MS (APCI) m/z 481
35Cl
79Br, 483
37Cl
79Br and
35Cl
81Br, 485
37Cl
81Br [(M+H)
+]; HRMS C23H27ClBrO2S
[(M+H)+] Expected 481.0598, Found 481.0612.
[3,5-bis(Allyloxy)-2-(2-chloro-9-phenylnonyl)phenyl](phenyl)sulfide 164n
As described in general procedure D, 91ad (103 mg, 0.345 mmol), 9-phenyl-1-nonene
(346 mg, 1.70 mmol) and FeCl3 (217 mg, 1.35 mmol), after purification by column
chromatography (30% CHCl3 in hexanes) gave 164n (78.1 mg, 0.146 mmol, 42%) as a
colourless oil; δH (500 MHz, CDCl3) 1.23 - 1.41 (7 H, m, CH2), 1.57 - 1.65 (3 H, m, CH2),
1.71 - 1.78 (2 H, m, CH2), 2.59 - 2.64 (2 H, m, ArCH2CH2), 3.28 (1 H, dd, J 13.7, 6.9 Hz,
ArCH2CHCl), 3.37 (1 H, dd, J 13.7, 7.6 Hz, ArCH2CHCl), 4.26 - 4.34 (1 H, m, CHCl),
4.39 (2 H, dt, J 5.4, 1.4 Hz, OCH2), 4.54 (2 H, dt, J 5.1, 1.5 Hz, OCH2), 5.24 (1 H, dq, J
10.4, 1.5 Hz, CH=CH2), 5.26 – 5.33 (2 H, m, CH=CH2), 5.45 (1 H, dq, J 17.3, 1.4 Hz,
CH=CH2), 5.96 (1 H, ddt, J 17.3, 10.6, 5.4 Hz, CH=CH2), 6.06 (1 H, ddt, J 17.2, 10.4, 5.1
Hz, CH=CH2), 6.42 - 6.45 (2 H, m, aryl H), 7.16 - 7.27 (5 H, m, aryl H), 7.27 - 7.32 (5 H,
m, aryl H); δC (125 MHz, CDCl3) 26.7 (CH2), 29.0 (CH2), 29.2 (CH2), 29.3 (CH2), 31.5
(CH2), 36.0 (ArCH2CH2), 36.4 (ArCH2CHCl), 37.8 (CH2), 63.2 (CHCl), 68.9 (OCH2), 69.0
(OCH2), 100.0 (aryl C-H), 109.8 (aryl C-H), 117.3 (CH=CH2), 118.0 (CH=CH2), 121.4
(aryl Cq), 125.6 (aryl C-H), 126.7 (aryl C-H), 128.2 (aryl C-H), 128.4 (aryl C-H), 129.1
(aryl C-H), 130.3 (aryl C-H), 132.9 (CH=CH2), 132.9 (CH=CH2), 136.2 (aryl Cq), 136.9
(aryl Cq), 142.9 (aryl Cq), 158.0 (aryl Cq), 158.2 (aryl Cq); νmax (thin film/cm-1
) 925 (m),
1024 (s), 1045 (s), 1106 (w), 1145 (s), 1175 (s), 1215 (s), 1275 (w), 1380 (vw), 1416 (m),
1476 (s), 1495 (m), 1569 (vs), 1648 (vw), 2854 (m), 2926 (m), 3024 (w), 3082 (w); MS
(APCI) m/z 535 35
Cl, 537 37
Cl [(M+H)+]; HRMS C33H40ClO2S [(M+H)
+] Expected
535.2432, Found 535.2423.
162
[3,5-bis(Allyloxy)-2-(2-chlorohept-6-en-1-yl)phenyl](phenyl)sulfide 164o
As described in general procedure D, 91ad (95.5 mg, 0.320 mmol), 1,6-heptadiene (162
mg, 1.70 mmol) and FeCl3 (217 mg, 1.35 mmol), after purification by column
chromatography (20% CHCl3 in hexanes) gave 164o (70.5 mg, 0.164 mmol, 52%) as a
colourless oil; δH (400 MHz, CDCl3) 1.31 - 1.44 (1 H, m, CH2), 1.56 - 1.72 (3 H, m, CH2),
1.88 - 2.01 (2 H, m, CH2CH=CH2), 3.18 (1 H, dd, J 13.9, 7.3 Hz, ArCH2CHCl), 3.27 (1 H,
dd, J 13.9, 7.3 Hz, ArCH2CHCl), 4.17 – 4.25 (1 H, m, CHCl), 4.28 (2 H, dt, J 5.3, 1.3 Hz,
OCH2), 4.44 (2 H, dt, J 5.0, 1.5 Hz, OCH2), 4.82 - 4.93 (2 H, m, CH=CH2), 5.14 (1 H, dq,
J 10.6, 1.3 Hz, OCH2CH=CH2), 5.17 - 5.25 (2 H, m, OCH2CH=CH2), 5.35 (1 H, dq, J
17.2, 1.5 Hz, OCH2CH=CH2), 5.68 (1 H, ddt, J 17.0, 10.2, 6.7 Hz, CH=CH2), 5.86 (1 H,
ddt, J 17.2, 10.6, 5.3 Hz, OCH2CH=CH2), 5.96 (1 H, ddt, J 17.2, 10.5, 5.0 Hz,
OCH2CH=CH2), 6.31 - 6.34 (2 H, m, aryl H), 7.10 - 7.23 (5 H, m, aryl H); δC (100 MHz,
CDCl3) 25.9 (CH2), 33.1 (CH2CH=CH2), 36.4 (ArCH2CHCl), 37.1 (CH2), 62.9 (CHCl),
68.8 (OCH2), 69.0 (OCH2), 99.8 (aryl C-H), 109.7 (aryl C-H), 114.6 (CH=CH2), 117.3
(OCH2CH=CH2), 118.0 (OCH2CH=CH2), 121.2 (aryl Cq), 126.7 (aryl C-H), 129.1 (aryl C-
H), 130.3 (aryl C-H), 132.8 (OCH2CH=CH2), 132.9 (OCH2CH=CH2), 136.1 (aryl Cq),
136.9 (aryl Cq), 138.4 (CH=CH2), 157.9 (aryl Cq), 158.2 (aryl Cq); νmax (thin film/cm-1
) 919
(m), 1024 (m), 1045 (m), 1141 (s), 1172 (s), 1275 (m), 1417 9m), 1439 (m), 1477 (m),
1569 (s), 1595 (s), 2859 (w), 2927 (w), 3075 (w); MS (APCI) m/z 429 35
Cl, 431 37
Cl
[(M+H)+]; HRMS C25H30ClO2S [(M+H)
+] Expected 429.1650, Found 429.1657.
163
[2-(2-Bromooctyl)-3,5-dimethoxyphenyl] (phenyl)sulfide 144
FeBr3 (130 mg, 0.440 mmol) was added to a stirred mixture of 91b (50.0 mg, 0.203 mmol)
and 1-octene (160 μL, 1.02 mmol) in CH2Cl2 (2 mL) under N2 atmosphere. The mixture
was stirred for 1.5 h. The reaction mixture was then quenched with H2O (2 ml) and diluted
with CH2Cl2 (2 mL). The organic layer was then washed twice more with H2O (2 ml) and
the combined aqueous washes extracted with CH2Cl2 (3 × 2 mL). The combined organic
extracts were dried with Na2SO4, filtered and the solvent removed in vacuo. The crude
mixture was then passed through a silica plug with CHCl3 eluent. The crude product was
purified by column chromatography on silica gel (30% CHCl3 in hexanes) to give 144
(17.4 mg, 39.8 µmol, 20%) as a colourless oil; δH (500 MHz, CDCl3) 0.89 (3 H, t, J 6.9 Hz,
CH2CH3), 1.20 - 1.43 (7 H, m, CH2), 1.56 - 1.67 (1 H, m, CH2), 1.72 - 1.81 (1 H, m, CH2),
1.81 - 1.89 (1 H, m, CH2), 3.37 (1 H, dd, J 13.9, 7.6 Hz, ArCH2CHBr), 3.47 (1 H, dd, J
13.9, 7.3 Hz, ArCH2CHBr), 3.69 (3 H, s, OCH3), 3.84 (3 H, m, OCH3), 4.38 - 4.45 (1 H,
m, CHBr), 6.42 (1 H, d, J 2.5 Hz, aryl H), 6.45 (1 H, d, J 2.5 Hz, aryl H), 7.20 - 7.32 (5 H,
m, aryl H); δC (125 MHz, CDCl3) 14.1 (CH3), 22.6 (CH2), 27.8 (CH2), 28.6 (CH2), 31.7
(CH2), 37.0 (ArCH2CHBr), 38.1 (CH2), 55.3 (OCH3), 55.6 (OCH3), 57.4 (CHBr), 98.3
(aryl C-H), 108.9 (aryl C-H), 121.9 (aryl Cq), 126.7 (aryl C-H), 129.1 (aryl C-H), 130.0
(aryl C-H), 136.3 (aryl Cq), 136.5 (aryl Cq), 159.0 (aryl Cq), 159.3 (aryl Cq); νmax (thin
film/cm-1
) 1047 (s), 1156 (s), 1196 (s), 1459 (w), 1596 (s), 2856 (w), 2920 (w); MS (ES+)
m/z 437 79
Br, 439 81
Br [(M+H)+]; HRMS C22H30O2BrS [(M+H)
+] Expected 437.1144,
Found 437.1143.
164
1-[2,4-Dimethoxy-6-(phenylsulfanyl)phenyl]octan-2-yl nitrate 178a
Ceric ammonium nitrate (223 mg, 0.407 mmol) was added to a stirred mixture of 91b (50.0
mg, 0.203 mmol) and 1-octene (160 μL, 1.02 mmol) in MeCN (2 mL) and stirred for 2 h.
The reaction mixture was then quenched with H2O (2 ml) and diluted with EtOAc (5 mL).
The organic layer was then washed twice more with H2O (2 ml). The aqueous layer was
extracted with EtOAc (3 × 2 mL). The combined organic extracts were dried with Na2SO4,
filtered and solvent removed in vacuo. The crude product was then purified by column
chromatography on silica gel (50% CHCl3 in hexanes) to give 178a (39.8 mg, 94.9 µmol,
47%) as a colourless oil; δH (500 MHz, CDCl3) 0.88 (3 H, t, J 6.9 Hz, CH3), 1.19 - 1.38 (7
H, m, CH2), 1.43 (1 H, m, CH2), 1.63 - 1.70 (2 H, m, CH2), 3.14 (1 H, dd, J 14.2, 5.4 Hz,
ArCH2CH(ONO2)), 3.21 (1 H, dd, J 14.2, 7.6 Hz, ArCH2CH(ONO2)CH2), 3.68 (3 H, s,
OCH3), 3.83 (3 H, s, OCH3), 5.31 - 5.39 (1 H, m, CH(ONO2)), 6.40 (1 H, d, J 2.2 Hz, aryl
H), 6.42 (1 H, d, J 2.2 Hz, aryl H), 7.19 - 7.32 (5 H, m, aryl H); δC (500 MHz, CDCl3) 14.0
(CH3), 22.5 (CH2), 25.3 (CH2), 29.0 (CH2), 30.6 (ArCH2CH(ONO2)), 31.7 (CH2), 32.5
(CH2), 55.3 (OCH3), 55.6 (OCH3), 84.5 (CH(ONO2)), 98.2 (aryl C-H), 108.9 (aryl C-H),
119.2 (aryl Cq), 126.7 (aryl C-H), 129.2 (aryl C-H), 130.1 (aryl C-H), 136.0 (aryl Cq),
136.7 (aryl Cq), 159.3 (aryl Cq), 159.5 (aryl Cq); νmax (thin film/cm-1
) 1046 (s), 1147 (s),
1196 (m), 1274 (s), 1459 (m), 1571 (s), 1596 (s), 1620 (s), 2857 (w), 2930 (w); MS (ES+)
m/z 420 [(M+H)+]; HRMS C22H29O2S [(M−NO3)
+] Expected 357.1888, Found 357.1879.
5.8 Manipulation of Products
General Procedure E
A solution of n-BuLi (1.60 M in hexanes, 1.2 eq.) was added to a solution of 99a (0.1 M in
THF) precooled to −78 °C. The mixture was warmed to room temperature, quenched with
the corresponding electrophile (9 eq.) and left to stir for 10 min., after which sat. aq.
NH4Cl (2 mL) and EtOAc (2 mL) were added. The organic layer was then washed with sat.
aq. NH4Cl (2 × 2 ml). The aqueous layers were extracted with EtOAc (2 × 2 mL). The
combined organic extracts were dried with Na2SO4, filtered and solvent removed in vacuo.
165
2-(2-Chlorooctyl)-1,5-dimethoxy-3-(phenylsulfonyl)benzene 181
m-CPBA (≤77%, 87.4 mg, 0.390 mmol) was added to a solution of 99a (50.0 mg, 0.127
mmol) in CH2Cl2 (1 mL). The mixture was stirred under reflux for 18 h and then quenched
with aq. NaHCO3 (2 mL). The aqueous layer was washed with CH2Cl2 (3 × 2 mL) and the
combined organic extracts were dried with MgSO4, filtered and the solvent removed in
vacuo. The crude product was purified by column chromatography (20% EtOAc in
hexanes) to give 181 (52.6 mg, 0.124 mmol, 95%) as a colourless oil; δH (500 MHz,
CDCl3) 0.87 (3 H, t, J 7.1 Hz, CH3), 1.11 - 1.36 (7 H, m, CH2), 1.45 - 1.58 (3 H, m, CH2),
3.21 (1 H, dd, J 13.6, 7.3 Hz, ArCH2CHCl), 3.28 (1 H, dd, J 13.6, 7.6 Hz, ArCH2CHCl),
3.80 (3 H, s, OCH3), 3.89 (3 H, s, OCH3), 4.25 - 4.34 (1 H, m, CHCl), 6.67 (1 H, d, J 2.5
Hz, aryl H), 7.40 (1 H, d, J 2.5 Hz, aryl H), 7.50 (2 H, t, J 7.3 Hz, aryl H), 7.58 (1 H, t, J
7.3 Hz, aryl H), 7.86 (2 H, d, J 7.3 Hz, aryl H); δC (125 MHz, CDCl3) 14.1 (CH3), 22.6
(CH2), 26.8 (CH2), 28.7 (CH2), 31.7 (CH2), 34.5 (ArCH2CHCl), 37.4 (CH2), 55.8 (OCH3),
55.9 (OCH3), 63.0 (CHCl), 103.4 (aryl C-H), 105.5 (aryl C-H), 119.6 (aryl Cq), 127.4 (aryl
C-H), 129.2 (aryl C-H), 133.2 (aryl C-H), 141.1 (aryl Cq), 141.9 (aryl Cq), 159.1 (aryl Cq),
160.1 (aryl Cq); νmax (thin film/cm-1
) 1041 (m), 1057 (w), 1154 (s), 1204 (m), 1305 (s),
1461 (m), 1600 (m), 2856 (w), 2930 (m); MS (ES+) m/z 447
35Cl, 449
37Cl [(M+Na)
+];
HRMS C22H29O4SClNa [(M+Na)+] Expected 447.1385, Found 447.1373.
[2-(2-Chlorooctyl)-3,5-dimethoxyphenyl-4-d](phenyl)sulfide 184a
As described in general procedure E, the reaction of 99a (50.0 mg, 0.127 mmol) was
quenched with MeOD (48.0 μL, 1.17 mmol) and, after purification by column
chromatography (30% CHCl3 in hexanes), gave 184a (49.6 mg, 0.126 mmol, 99%) as a
166
colourless oil; δH (400 MHz, CDCl3) 0.88 (3 H, t, J 6.9 Hz, CH3), 1.16 - 1.44 (7 H, m,
CH2), 1.53 - 1.65 (1 H, m, CH2), 1.66 - 1.77 (2 H, m, CH2), 3.23 (1 H, dd, J 13.8, 7.0 Hz,
ArCH2CHCl), 3.33 (1 H, dd, J 13.8, 7.5 Hz, ArCH2CHCl), 3.68 (3 H, s, OCH3), 3.83 (3 H,
s, OCH3), 4.23 - 4.32 (1 H, m, CHCl), 6.44 (1 H, s, aryl H), 7.17 - 7.33 (5 H, m, aryl H); δC
(100 MHz, CDCl3) 14.1 (CH3), 22.7 (CH2), 26.7 (CH2), 28.8 (CH2), 31.8 (CH2), 36.3
(ArCH2CHCl), 37.7 (CH2), 55.3 (OCH3), 55.6 (OCH3), 63.4 (CHCl), 98.0 (t, J 24.2 Hz,
aryl C-D), 108.8 (aryl C-H), 121.3 (aryl Cq), 126.6 (aryl C-H), 129.2 (aryl C-H), 130.0
(aryl C-H), 136.4 (aryl Cq), 136.5 (aryl Cq), 159.0 (aryl Cq), 159.2 (aryl Cq); νmax (thin
film/cm-1
) 1046 (s), 1094 (s), 1146 (m), 1199 (s), 1295 (m), 1387 (m), 1458 (m), 1565 (s),
1587 (s), 2856 (w), 2929 (m); MS (ES+) m/z 394
35Cl, 396
37Cl [(M+H)
+]; HRMS
C22H29DO2ClS [(M+H)+] Expected 394.1718, Found 394.1703.
[2-(2-Chlorooctyl)-4-iodo-3,5-dimethoxyphenyl] (phenyl)sulfide 184b
As described in general procedure E, the reaction of 99a (50.0 mg, 0.127 mmol) was
quenched with I2 (1.17 mL, 1.17 M in THF, 1.17 mmol) and, after purification by column
chromatography (30% CHCl3 in hexanes), gave 184b (64.0 mg, 0.123 mmol, 95%) as a
yellow oil; δH (500 MHz, CDCl3) 0.88 (3 H, t, J 6.9 Hz, CH3), 1.19 - 1.43 (7 H, m, CH2),
1.53 - 1.63 (1 H, m, CH2), 1.67 - 1.80 (2 H, m, CH2), 3.24 (1 H, dd, J 13.9, 6.6 Hz,
ArCH2CHCl), 3.36 (1 H, dd, J 13.9, 7.7 Hz, ArCH2CHCl), 3.68 (3 H, s, OCH3), 3.85 (3 H,
s, OCH3), 4.31 - 4.39 (1 H, m, CHCl), 6.51 (1 H, s, aryl H), 7.24 - 7.36 (5 H, m, aryl H); δC
(125 MHz, CDCl3) 14.1 (CH3), 22.6 (CH2), 26.7 (CH2), 28.7 (CH2), 31.7 (CH2), 37.7
(CH2), 37.9 (ArCH2CHCl), 56.5 (OCH3), 61.1 (OCH3), 62.9 (CHCl), 83.5 (aryl Cq), 110.9
(aryl C-H), 126.4 (aryl Cq), 127.3 (aryl C-H), 129.4 (aryl C-H), 130.7 (aryl C-H), 135.4,
(aryl Cq), 138.0 (aryl Cq), 158.2 (aryl Cq), 160.3 (aryl Cq); νmax (thin film/cm-1
) 1018 (w),
1086 (s), 1136 (m), 1198 (w), 1372 (m), 1456 (m), 1567 (m), 2855 (w), 2930 (m); MS
(ES+) m/z 541
35Cl, 543
37Cl [(M+Na)
+]; HRMS C22H29O2ClIS [(M+H)
+] Expected
519.0616, Found 519.0610.
167
[2-(2-Chlorooctyl)-3,5-dimethoxy-4-methylphenyl] (phenyl)sulfide 184c
As described in general procedure E, the reaction of 99a (50.0 mg, 0.127 mmol) was
quenched with MeI (73.0 μL, 1.17 mmol) and, after purification by column
chromatography (30% CHCl3 in hexanes), gave 184c (46.1 mg, 0.113 mmol, 87%) as a
colourless oil; δH (500 MHz, CDCl3) 0.88 (3 H, t, J 6.9 Hz, CH3) 1.18 - 1.41 (7 H, m,
CH2), 1.51-1.63 (1 H, m, CH2), 1.66 - 1.78 (2 H, m, CH2), 2.19 (3 H, s, ArCH3), 3.19 (1 H,
dd, J 13.7, 6.8 Hz, ArCH2CHCl), 3.31 (1 H, dd, J 13.7, 7.6 Hz, ArCH2CHCl), 3.70 (3 H, s,
OCH3), 3.75 (3 H, s, OCH3), 4.28 - 4.36 (1 H, m, CHCl), 6.70 (1 H, s, aryl H), 7.15 - 7.21
(3 H, m, aryl H), 7.24 - 7.29 (2 H, m, aryl H); δC (125 MHz, CDCl3) 9.6 (ArCH3), 14.1
(CH3), 22.6 (CH2), 26.7 (CH2), 28.7 (CH2), 31.7 (CH2), 37.1 (ArCH2CHCl), 37.8 (CH2),
55.6 (OCH3), 60.1 (OCH3), 63.6 (CHCl), 112.2 (aryl C-H), 120.5 (aryl Cq), 126.0 (aryl C-
H), 126.6 (aryl Cq), 128.6 (aryl C-H), 129.0 (aryl C-H), 131.6 (aryl Cq), 137.4 (aryl Cq),
157.6 (aryl Cq), 158.5 (aryl Cq); νmax (thin film/cm-1
) 1024 (m), 1120 (s), 1192 (w), 1268
(w), 1388(w), 1438 (m), 1464 (m), 1583 (m), 2856 (w), 2929 (m); MS (ES+) m/z 407
35Cl,
409 37
Cl [(M+H)+]; HRMS C23H31O2S [(M-Cl)
+] Expected 371.2045, Found 371.2039.
(E)-[3,5-Dimethoxy-2-(oct-1-en-1-yl)phenyl] (phenyl)sulfide 185 ,
(E)-[3,5-dimethoxy-2-(oct-2-en-1-yl)phenyl](phenyl)sulfide 186 and
[2-(2-ethoxyoctyl)-3,5-dimethoxyphenyl] (phenyl)sulfide 215
A solution of NaOEt in EtOH (21 wt%, 100 μL, 0.254 mmol) was added to a solution of
99a (50.0 mg, 0.127 mmol) in EtOH (1.2 mL). The solution was stirred under reflux for 18
h, then cooled to room temperature and quenched with H2O (2 mL) and diluted with
EtOAc (5 mL). The organic phase was washed with H2O (3 × 2 mL), dried over MgSO4,
168
filtered and solvent removed in vacuo. The crude mixture was purified by column
chromatography (10% EtOAc in hexanes) to give 185 (24.6 mg, 69.0 µmol, 53 %), 186
(15.3 mg, 42.9 µmol 33%) and 215 (4.2 mg, 10.4 µmol, 8%) as colourless oils; For 185, δH
(500 MHz, CDCl3) 0.89 (3 H, t, J 6.6 Hz, CH3), 1.23 - 1.37 (6 H, m, CH2), 1.37 - 1.45 (2
H, m, CH2), 2.19 (2 H, qd, J 6.9, 1.3 Hz, CH=CHCH2CH2), 3.66 (3 H, s, OCH3), 3.83 (3
H, s, OCH3), 6.27 (1 H, dt, J 16.1, 6.9 Hz, ArCH=CHCH2), 6.35 (1 H, d, J 2.5 Hz, aryl H),
6.39 (1 H, d, J 2.5 Hz, aryl H), 6.53 (1 H, dt, J 16.1, 1.3 Hz, ArCH=CHCH2), 7.21 - 7.33 (5
H, m, aryl H); δC (125 MHz, CDCl3) 14.2 (CH3), 22.7 (CH2), 28.9 (CH2), 29.4 (CH2), 31.8
(CH2), 34.1 (CH=CHCH2CH2), 55.3 (OCH3), 55.6 (OCH3), 98.0 (aryl C-H), 107.8 (aryl C-
H), 121.0 (aryl Cq), 122.7 (ArCH=CHCH2), 126.9 (aryl C-H), 129.1 (aryl C-H), 131.1 (aryl
C-H), 135.7 (aryl Cq), 136.1 (aryl Cq), 136.6 (ArCH=CHCH2), 158.6 (aryl Cq), 158.7 (aryl
Cq); νmax (thin film/cm-1
) 1046 (s), 1153 (s), 1200 (m), 1210 (m), 1298 (m), 1407 (w), 1434
(w), 1459 (m), 1563 (s), 1593 (s), 2854 (w), 2925 (m), 2954 (w), 3000 (w); MS (ES+) m/z
357 [(M+H)+]; HRMS C22H29O2S [(M+H)
+] Expected 357.1883, Found 357.1887; For
186, δH (400 MHz, CDCl3) 0.87 (3 H, t, J 7.0 Hz, CH3), 1.16 - 1.36 (6 H, m, CH2), 1.91 (2
H, q, J 6.6 Hz, CH=CHCH2CH2), 3.49 (2 H, d, J 5.8 Hz, ArCH2CH=CH), 3.68 (3 H, s,
OCH3), 3.82 (3 H, s, OCH3), 5.37 (1 H, dt, J 15.3, 6.6 Hz, CH=CHCH2CH2), 5.45 (1 H, dt,
J 15.3, 5.8 Hz, ArCH2CH=CH), 6.41 (1 H, d, J 2.3 Hz, aryl H), 6.42 (1 H, d, J 2.3 Hz, aryl
H), 7.16 - 7.31 (5 H, m, aryl H); δC (100 MHz, CDCl3) 14.1 (CH3), 22.5 (CH2), 29.1 (CH2),
30.2 (ArCH2CHCH), 31.4 (CH2), 32.5 (CHCHCH2), 55.3 (OCH3), 55.7 (OCH3), 98.4 (aryl
C-H), 108.6 (aryl C-H), 123.8 (aryl Cq), 126.4 (aryl C-H), 127.3 (CH2CH=CHCH2), 129.0
(aryl C-H), 130.1 (aryl C-H), 131.2 (CH2CH=CHCH2), 135.5 (aryl Cq), 136.6 (aryl Cq),
158.7 (aryl Cq), 158.8 (aryl Cq); νmax (thin film/cm-1
) 1050 (s), 1144 (s), 1166 (w), 1205
(m) 1274 (w), 1296 (w), 1409 (w), 1437 (w), 1460 (m), 1477 (m), 1572 (s), 1596 (s), 2854
(w), 2925 (m), 2955 (w); MS (ES+) m/z 357 [(M+H)
+]; HRMS C22H29O2S [(M+H)
+]
Expected 357.1883, Found 357.1886; For 215, δH (400 MHz, CDCl3) 0.87 (3 H, t, J 6.9
Hz, CH3), 1.12 (3 H, t, J 7.0 Hz, OCH2CH3), 1.17 - 1.33 (7 H, m, CH2), 1.35 - 1.54 (3 H,
m, CH2), 2.91 (1 H, dd, J 13.2, 7.2 Hz, ArCH2CH(OEt)), 3.07 (1 H, dd, J 13.2, 6.1 Hz,
ArCH2CH(OEt)), 3.39 - 3.55 (3 H, m, OCH2CH3 + CH(OEt)), 3.68 (3 H, s, OCH3), 3.82 (3
H, s, OCH3), 6.39 (1 H, d, J 2.5 Hz, aryl H), 6.41 (1 H, d, J 2.5 Hz, aryl H), 7.17 – 7.32 (5
H, m, aryl H); δC (100 MHz, CDCl3) 14.1 (CH3), 15.7 (OCH2CH3), 22.7 (CH2), 26.0
(CH2), 29.5 (CH2), 32.0 (CH2), 32.4 (ArCH2CH(OEt)), 34.8 (CH2), 55.3 (OCH3), 55.6
(OCH3), 64.9 (OCH2CH3), 79.6 (CH(OEt)), 98.2 (aryl C-H), 108.6 (aryl C-H), 122.4 (aryl
Cq), 126.4 (aryl C-H), 129.1 (aryl C-H), 130.0 (aryl C-H), 136.3 (aryl Cq), 136.8 (aryl Cq),
169
158.8 (aryl Cq), 159.2 (aryl Cq); νmax (thin film/cm-1
) 1050 (s), 1148 (s), 1195 (m), 1295
(w), 1408 (w), 1438 (m), 1461 (m), 1477 (m), 1571 (s), 1597 (s), 2855 (m), 2927 (s); MS
(ES+) m/z 425 [(M+Na)
+]; HRMS C24H35O3S [(M+H)
+] Expected 403.2301, Found
403.2303.
[2-(2-Azidooctyl)-3,5-dimethoxyphenyl] (phenyl)sulfide 187
NaN3 (42.3 mg, 0.651 mmol) was added to a solution of 99a (50.0 mg, 0.127 mmol) in
DMF (1.3 mL) and heated to 80 °C for 18 h. The mixture was cooled to room temperature
and diluted with EtOAc (5 mL) and 10% aq. LiCl (5 mL) was added. The organic phase
was washed with 10% aq. LiCl (3 × 5 mL), dried over MgSO4, filtered and the solvent
removed in vacuo. The crude product was purified by column chromatography (10%
EtOAc in hexanes) to give 187 (22.9 mg, 57.3 µmol, 44%) as a colourless oil; δH (500
MHz, CDCl3) 0.89 (3 H, t, J 6.9 Hz, CH3), 1.21 - 1.38 (7 H, m, CH2), 1.44 - 1.60 ( 3 H, m,
CH2), 2.98 (1 H, dd, J 13.6, 6.0 Hz, ArCH2CH(N3)), 3.09 (1 H, dd, J 13.6, 8.2 Hz,
ArCH2CH(N3)), 3.50 - 3.58 (1 H, m, CH(N3)), 3.69 (3 H, s, OCH3), 3.84 (3 H, s, OCH3),
6.42 (1 H, d, J 2.5 Hz, aryl H), 6.43 (1 H, d, J 2.5 Hz, aryl H), 7.19 - 7.32 (5 H, m, aryl H);
δC (125 MHz, CDCl3) 14.1 (CH3), 22.6 (CH2), 26.2 (CH2), 29.0 (CH2), 31.7 (CH2), 32.3
(ArCH2CH(N3)), 34.2 (CH2), 55.3 (OCH3), 55.6 (OCH3), 62.9 (CH(N3)), 98.2 (aryl C-H),
108.8 (aryl C-H), 121.0 (aryl Cq), 126.6 (aryl C-H), 129.1 (aryl C-H), 130.0 (aryl C-H),
136.2 (aryl Cq), 136.3 (aryl Cq), 159.1 (aryl Cq), 159.3 (aryl Cq); νmax (thin film/cm-1
) 1048
(s), 1146 (s), 1197 (m), 1276 (w), 1460 (m), 1571 (s), 1597 (s), 2100 (s), 2856 (w), 2929
(m); MS (ES+) m/z 400 [(M+H)
+]; HRMS C22H30O2N3S [(M+H)
+] Expected 400.2053,
Found 400.2056.
170
(3,5-Dimethoxy-2-octylphenyl)(3-methoxyphenyl)sulfide 189
AIBN (1.64 mg, 10.0 µmol) and Bu3SnH (64.6 μL, 0.240 mmol) were added to a solution
of 164e (50.0 mg, 0.127 mmol) in benzene (1 mL). The solution was stirred under reflux
for 18 h, then cooled to room temperature and solvent removed in vacuo. The crude
product mixture was then passed through a plug of 10% K2CO3/silica using first hexanes,
then EtOAc as eluents.207
The solvent was then removed in vacuo and the resultant crude
product purified by column chromatography (30% CHCl3 in hexanes) to give 189 (27.9
mg, 71.8 µmol, 55%) as a colourless oil; δH (400 MHz, CDCl3) 0.83 - 0.92 (3 H, t, J 7.0
Hz, CH3), 1.18 - 1.38 (10 H, m, CH2), 1.39 - 1.51 (2 H, m, ArCH2CH2), 2.69 - 2.78 (2 H,
m, ArCH2CH2), 3.70 (3 H, s, OCH3), 3.76 (3 H, s, OCH3), 3.81 (3 H, s, OCH3), 6.41 (1 H,
d, J 2.5 Hz, aryl H), 6.46 (1 H, d, J 2.5 Hz, aryl H), 6.71 - 6.76 (1 H, m, aryl H), 6.79 (1 H,
t, J 2.0 Hz, aryl H), 6.82 (1 H, d, J 7.8 Hz, aryl H), 7.18 (1 H, t, J 7.8 Hz, aryl H); δC (100
MHz, CDCl3) 14.1 (CH3), 22.7 (CH2), 27.3 (ArCH2CH2), 29.3 (CH2), 29.4 (CH2), 29.8
(CH2), 29.9 (CH2), 31.9 (CH2), 55.2 (OCH3), 55.2 (OCH3), 55.6 (OCH3), 98.6 (aryl C-H),
108.8 (aryl C-H), 112.0 (aryl C-H), 114.9 (aryl C-H), 121.9 (aryl C-H), 126.4 (aryl Cq),
129.8 (aryl C-H), 134.4 (aryl Cq), 138.2 (aryl Cq), 158.4 (aryl Cq). 158.8 (aryl Cq), 159.9
(aryl Cq); νmax (thin film/cm-1
) 1047 (s), 1147 (s), 1195 (w), 1230 (w), 1245 (w), 1282 (w),
1462 (m), 1476 (m), 1570 (s), 1590 (s), 2853 (w), 2925 (m), 2954 (m), 2999 (w); MS (ES+)
m/z 389 [(M+H)+]; HRMS C23H33O3S [(M+H)
+] Expected 389.2162, Found 389.2150.
171
5.9 Synthesis of Dihydrobenzofurans
2-Hexyl-4-(phenylsulfanyl)-2,3-dihydrobenzofuran-6-ol 191a
The compound was prepared according to a literature procedure.165
Pd(PPh3)4 (25.3 mg,
21.9 µmol) was added to a solution of 164j (85.6 mg, 0.192 mmol) in MeOH (2 mL) under
N2. After 5 min. of stirring, K2CO3 (170.8 mg, 1.20 mmol) was added and the resulting
mixture was stirred for 4 h. The mixture was then concentrated in vacuo, before treating
with 1 N HCl (2 mL), extracting with CH2Cl2 (3 × 2 mL), washing with brine (3 × 2 mL),
drying over MgSO4 and concentrating in vacuo. The crude product was purified by column
chromatography (20% EtOAc in hexanes) to give 191a (33.4 mg, 0.102 mmol, 53%) as a
yellow oil; δH (500 MHz, CDCl3) 0.89 (3 H, t, J 6.5 Hz, CH3), 1.23 - 1.37 (7 H, m, CH2),
1.41 - 1.49 (1 H, m, CH2), 1.59 - 1.68 (1 H, m, CH2), 1.74 - 1.84 (1 H, m, CH2), 2.64 (1 H,
dd, J 15.5, 7.6 Hz, ArCH2CH(O)), 3.08 (1 H, dd, J 15.5, 8.9 Hz, ArCH2CH(O)), 4.66 (1 H,
s, OH) 4.74 - 4.83 (1 H, m, CH(O)), 6.14 (1 H, s, aryl H), 6.19 (1 H, s, aryl H), 7.24 - 7.38
(5 H, m, aryl H); δC (125 MHz, CDCl3) 14.1 (CH3), 22.6 (CH2), 25.2 (CH2), 29.1 (CH2),
31.7 (CH2), 34.3 (ArCH2CH(O)), 36.1 (CH2), 84.6 (CH2CH(O)), 96.4 (aryl C-H), 108.5
(aryl C-H), 120.4 (aryl Cq), 127.2 (aryl C-H), 129.2 (aryl C-H), 131.2 (aryl C-H), 132.3
(aryl Cq) 133.9 (aryl Cq) 156.2 (aryl Cq) 161.0 (aryl Cq); νmax (thin film/cm-1
) 994 (w), 1025
(s), 1113 (w), 1174 (w), 1262 (s), 1377 (s), 1439 (w), 1478 (w), 1585 (s), 1609 (s), 2853
(w), 2923 (w), 3367 (w, br); MS (ES−) m/z 327 [(M−H)
+]; HRMS C20H23O2S [(M−H)
+]
Expected 327.1419, Found 327.1419.
General Procedure F – Pd-catalysed deallylation/cyclisation 166
Morpholine (2.2 eq.) was added to a stirred mixture of the corresponding sulfide (1.0 eq.),
Pd(PPh3)4 (0.1 eq.) and either NaBH4 or NaH (2.40 eq.) in THF (0.1 M) at room
temperature and stirred for 16 h. The reaction was then cooled to 0 °C and 1 N HCl (10
mL) was added slowly. The aqueous layer was extracted with CH2Cl2 (3 × 10 mL) and the
172
combined organic extracts were then washed with brine (10 mL), dried over MgSO4,
filtered and the solvent removed in vacuo.
2-Butyl-4-(phenylsulfanyl)-2,3-dihydrobenzofuran-6-ol 191b
As described in general procedure F, morpholine (23.0 µL, 0.263 mmol), 164k (50.0 mg,
0.112 mmol), Pd(PPh3)4 (13.9 mg, 12.0 µmol) and NaBH4 (10.9 mg, 0.288 mmol), after
purification by column chromatography on silica gel (10% EtOAc in hexanes) gave 191b
(30.1 mg, 0.100 mmol, 84%) as a pale yellow oil; δH (400 MHz, CDCl3) 0.90 (3 H, t, J 6.8
Hz, CH3), 1.29 - 1.49 (4 H, m, CH2), 1.58 - 1.71 (1 H, m, CH(O)CH2CH2), 1.72 - 1.86 (1
H, m, CH(O)CH2CH2), 2.65 (1 H, dd, J 15.4, 7.7 Hz, ArCH2CH(O)), 3.08 (1 H, dd, J 15.4,
8.9 Hz, ArCH2CH(O)), 4.73 - 4.89 (2 H, m, CH(O) + ArOH), 6.14 (1 H, d, J 2.3 Hz, aryl
H), 6.19 (1 H, d, J 2.3 Hz, aryl H), 7.24 - 7.37 (5 H, m, aryl H); δC (100 MHz, CDCl3) 14.0
(CH3), 22.6 (CH2), 27.3 (CH2), 34.2 (ArCH2CH(O)), 35.8 (CH(O)CH2CH2), 84.5 (CH(O)),
96.4 (aryl C-H), 108.6 (aryl C-H), 120.2 (aryl Cq), 127.2 (aryl C-H), 129.2 (aryl C-H),
131.2 (aryl C-H), 132.3 (aryl Cq), 134.0 (aryl Cq), 156.3 (aryl Cq), 160.9 (aryl Cq); νmax
(thin film/cm-1
) 994 (s), 1111 (s), 1216 (m), 1354 (w), 1439 (s), 1477 (s), 1591 (s), 1609
(s), 2848 (m), 2916 (m), 2955 (m), 3404 (s, br, O-H stretch); MS (ES+) m/z 301 [(M+H)
+];
HRMS C18H21O2S [(M+H)+] Expected 301.1257, Found 301.1255.
2-(3-Nitropropyl)-4-(phenylsulfanyl)-2,3-dihydrobenzofuran-6-ol 191c
As described in general procedure F, morpholine (20.0 µL, 0.229 mmol), 164l (41.8 mg,
93.3 µmol), Pd(PPh3)4 (10.3 mg, 8.91 µmol) and NaBH4 (8.6 mg, 0.227 mmol), after
purification by column chromatography on silica gel (20% EtOAc in hexanes) gave 191c
173
(25.2 mg, 76.0 µmol, 82%) as a yellow oil; δH (400 MHz, CDCl3) 1.71 - 1.87 (2 H, m,
CH2), 2.09 - 2.29 (2 H, m, CH2), 2.64 (1 H, dd, J 15.6, 7.3 Hz, ArCH2CH(O)), 3.12 (1 H,
dd, J 15.6, 9.0 Hz, ArCH2CH(O)), 4.39 - 4.53 (2 H, m, CH(O) + ArOH), 4.69 - 4.79 (2 H,
m, CH2NO2), 6.17 (1 H, d, J 2.3 Hz, aryl H), 6.19 (1 H, d, J 2.3 Hz, aryl H), 7.28 - 7.37 (5
H, m, aryl H); δC (100 MHz, CDCl3) 23.5 (CH2), 32.6 (CH2), 34.3 (ArCH2CH(O)), 75.2
(CH2NO2), 83.0 (CH(O)), 96.6 (aryl C-H), 109.0 (aryl C-H), 119.4 (aryl Cq), 127.4 (aryl C-
H), 129.3 (aryl C-H), 131.4 (aryl C-H), 132.7 (aryl Cq), 133.8 (aryl Cq), 156.6 (aryl Cq),
160.5 (aryl Cq); νmax (thin film/cm-1
) 993 (s), 1117 (s), 1221 (m), 1377 (m), 1437 (s), 1477
(s), 1549 (s), 1609 (s), 2852 (m), 2934 (m), 3060 (m), 3419 (s, br, O-H stretch); MS
(APCI) m/z 332 [(M+H)+]; HRMS C17H18O4NS [(M+H)
+] Expected 332.0951, Found
332.0936.
2-(3-Bromopropyl)-4-(phenylsulfanyl)-2,3-dihydrobenzofuran-6-ol 191d
As described in general procedure F, morpholine (24 µL, 0.274 mmol), 164m (60.7 mg,
0.126 mmol), Pd(PPh3)4 (14.9 mg, 12.9 µmol) and NaBH4 (11.8 mg, 0.312 mmol), after
purification by column chromatography on silica gel (10% EtOAc in hexanes) gave 191d
(36.3 mg, 99.4 µmol, 79%) as a colourless oil; δH (400 MHz, CDCl3) 1.78 - 2.14 (4 H, m,
CH2), 2.66 (1 H, dd, J 15.6, 7.3 Hz, ArCH2CH(O)), 3.11 (1 H, dd, J 15.6, 9.1 Hz,
ArCH2CH(O)), 3.40 - 3.52 (2 H, m, CH2Br), 4.76 (1 H, s, ArOH), 4.82 (1 H, dtd, J 9.1,
7.3, 5.3 Hz, CH(O)), 6.16 (1 H, d, J 2.0 Hz, aryl H), 6.19 (1 H, d, J 2.0 Hz, aryl H), 7.25 -
7.37 (5 H, m, aryl H); δC (100 MHz, CDCl3) 28.6 (CH2), 33.4 (CH2Br), 34.3
(ArCH2CH(O)), 34.6 (CH2), 83.3 (CH(O)), 96.5 (aryl C-H), 108.9 (aryl C-H), 119.8 (aryl
Cq), 127.4 (aryl C-H), 129.3 (aryl C-H), 131.3 (aryl C-H), 132.5 (aryl Cq), 133.9 (aryl Cq),
156.4 (aryl Cq), 160.7 (aryl Cq); νmax (thin film/cm-1
) 992 (s), 1113 (s), 1253 (w), 1437 (s),
1476 (m), 1591 (m), 1607 (m), 2849 (w), 2939 (w), 3396 (m, br, O-H stretch); MS (APCI)
m/z 365 79
Br, 367 81
Br [(M+H)+]; HRMS C17H18O2BrS [(M+H)
+] Expected 365.0205,
Found 365.0188.
174
2-(7-Phenylheptyl)-4-(phenylsulfanyl)-2,3-dihydrobenzofuran-6-ol 191e
As described in general procedure F, morpholine (18.0 µL, 0.206 mmol), 164n (52.0 mg,
97.2 µmol), Pd(PPh3)4 (12.1 mg, 10.5 µmol) and NaBH4 (9.00 mg, 0.238 mmol), after
purification by column chromatography on silica gel (10% EtOAc in hexanes) gave 191e
(33.1 mg, 79.1 µmol, 81%) as a colourless oil; δH (400 MHz, CDCl3) 1.22 – 1.44 (8 H, m,
CH2), 1.48 – 1.62 (3 H, m, CH2), 1.65 – 1.78 (1 H, m, CH(O)CH2CH2), 2.50 – 2.62 (3 H,
m, ArCH2CH(O) + ArCH2CH2), 3.01 (1 H, dd, J 15.4, 8.9 Hz, ArCH2CH(O)), 4.62 – 4.77
(2 H, m, CH(O) + OH), 6.06 (1 H, d, J 2.3 Hz, aryl H), 6.10 (1 H, d, J 2.3 Hz, aryl H), 7.09
– 7.15 (3 H, m, aryl H), 7.17 – 7.30 (7 H, m, aryl H); δC (100 MHz, CDCl3) 25.2 (CH2),
29.2 (CH2), 29.3 (CH2), 29.4 (CH2), 31.5 (CH2), 34.3 (ArCH2CH(O)), 36.0 (ArCH2CH2),
36.1 (ArCH2CH(O)CH2), 84.6 (CH(O)), 96.6 (aryl C-H), 108.8 (aryl C-H), 120.4 (aryl Cq),
125.6 (aryl C-H), 127.3 (aryl C-H), 128.3 (aryl C-H), 128.4 (aryl C-H), 129.3 (aryl C-H),
131.2 (aryl C-H), 132.3 (aryl Cq), 134.1 (aryl Cq), 142.9 (aryl Cq), 156.4 (aryl Cq), 161.0
(aryl Cq); νmax (thin film/cm-1
) 993 (s), 1114 (vs), 1174 (w), 1220 (w), 1266 (w), 1353 (w),
1438 (s), 1477 (s), 1591 (s), 1607 (s), 2853 (m), 2927 (s), 3924 (w), 3402 (br); MS (APCI)
m/z 419 [(M+H)+]; HRMS C27H31O2S [(M+H)
+] Expected 419.2027, Found 419.2039.
6-(Allyloxy)-2-butyl-4-(phenylsulfanyl)-2,3-dihydrobenzofuran 192
As described in general procedure F, morpholine (23.0 µL, 0.263 mmol), 164k (50.0 mg,
0.112 mmol), Pd(PPh3)4 (13.9 mg, 12.0 µmol) and NaH (11.6 mg, 0.290 mmol, 60%
dispersion in mineral oil), after purification by column chromatography on silica gel (10%
EtOAc in hexanes) gave 192 (35.1 mg, 0.103 mmol, 92%) as a colourless oil; δH
(400 MHz, CDCl3) 0.92 (3 H, t, J 7.0 Hz, CH3), 1.30 - 1.48 (4 H, m, CH2), 1.59 - 1.69 (1
175
H, m, CH(O)CH2CH2), 1.73 - 1.84 (1 H, m, CH(O)CH2CH2), 2.65 (1 H, dd, J 15.4, 7.7 Hz,
ArCH2CH(O)), 3.08 (1 H, dd, J 15.4, 8.9 Hz, ArCH2CH(O)), 4.42 (2 H, dt, J 5.3, 1.5 Hz,
OCH2), 4.73 - 4.83 (1 H, m, CH(O)), 5.25 (1 H, dq, J 10.5, 1.5 Hz, CH=CH2), 5.34 (1 H,
dq, J 17.3, 1.5 Hz, CH=CH2) 5.99 (1 H, ddt, J 17.3, 10.5, 5.3 Hz, CH=CH2), 6.30 (2 H, s,
aryl H), 7.22 - 7.35 (5 H, m, aryl H); δC (100 MHz, CDCl3) 14.0 (CH3), 22.6 (CH2), 27.4
(CH2), 34.4 (ArCH2CH(O)), 35.8 (CH(O)CH2CH2), 69.1 (OCH2), 84.4 (CH(O)), 96.1 (aryl
C-H), 109.0 (aryl C-H), 117.8 (CH=CH2), 120.8 (aryl Cq), 126.9 (aryl C-H), 129.2 (aryl C-
H), 130.4 (aryl C-H), 131.6 (aryl Cq), 133.1 (CH=CH2), 134.6 (aryl Cq), 159.6 (aryl Cq),
160.9 (aryl Cq); νmax (thin film/cm-1
) 925 (m), 980 (s), 1024 (s), 1114 (s), 1181 (m), 1423
(m), 1477 (s), 1578 (s), 1606 (s), 2859 (w), 2929 (m), 2954 (m); MS (APCI) m/z 341
[(M+H)+]; HRMS C21H25O2S [(M+H)
+] Expected 341.1570, Found 341.1567.
5.10 Cross-Coupling of Dihydrobenzofurans
2-Butyl-4-(phenylsulfanyl)-2,3-dihydrobenzofuran-6-yl trifluoromethanesulfonate 193
The compound was prepared according to a literature procedure.208
Sodium tert-butoxide
(187 mg, 1.95 mmol) was added to a stirred solution of N-phenyl-
bis(trifluoromethanesulfonimide) (696 mg, 1.95 mmol) and 191b (532 mg, 1.77 mmol) in
THF (18 mL) at 0 °C. The mixture was stirred for 1 h at 0 °C, then warmed to room
temperature and stirred for a further 1 h. The mixture was then quenched with H2O (20
mL) and the aqueous layer extracted with EtOAc (3 × 30 mL). The combined organic
extracts were washed with brine (30 mL), dried with MgSO4, filtered and the solvent
removed in vacuo. The crude product was purified by column chromatography on silica gel
(10% Et2O in hexanes) to give 193 (666 mg, 1.54 mmol, 87%) as a colourless oil; δH (400
MHz, CDCl3) 0.94 (3 H, t, J 7.1 Hz, CH3), 1.31 - 1.51 (4 H, m, CH2), 1.62 - 1.74 (1 H, m,
CH(O)CH2CH2), 1.76 - 1.89 (1 H, m, CH(O)CH2CH2), 2.73 (1 H, dd, J 16.1, 7.5 Hz,
ArCH2CH(O)), 3.17 (1 H, dd, J 16.1, 9.2 Hz, ArCH2CH(O)), 4.83 - 4.93 (1 H, m, CH(O)),
6.39 (1 H, d, J 2.2 Hz, aryl H), 6.51 (1 H, d, J 2.2 Hz, aryl H), 7.35 - 7.43 (5 H, m, aryl H);
δC (100 MHz, CDCl3) 14.0 (CH3), 22.5 (CH2), 27.3 (CH2), 34.3 (ArCH2CH(O)), 35.8
176
(CH(O)CH2CH2), 85.2 (CH(O)), 101.3 (aryl C-H), 112.9 (aryl C-H), 127.1 (aryl Cq), 128.5
(aryl C-H), 129.6 (aryl C-H), 131.8 (aryl Cq), 132.5 (aryl C-H), 135.0 (aryl Cq), 149.6 (aryl
Cq), 160.6 (aryl Cq); νmax (thin film/cm-1
) 983 (s), 1092 (m), 1140 (s), 1209 (vs, C-F
stretch?),1 1420 (s), 1592 (m), 2861 (w), 2933 (w), 2957 (w); MS (ES
+) m/z 433 [(M+H)
+];
HRMS C19H20F3O4S2 [(M+H)+] Expected 433.0750, Found 433.0749.
General Procedure G – Pd-catalysed Suzuki coupling 168
Pd(PPh3)4 (11.6 mg, 10.0 µmol) and corresponding boronic acid (0.200 mmol) were added
to a microwave vial with Teflon-lined septum pre-flushed with N2. K2CO3 (2.00 M in H2O,
1 mL) and 193 (43 mg, 0.100 mmol) in 1,4-dioxane (1 mL) were then added and the
resulting mixture was heated to 135 °C and stirred for 5 h. The mixture was then cooled,
diluted with H2O (15 mL) and extracted with CH2Cl2 (3 × 15 mL). The combined organic
extracts were dried with MgSO4, filtered and the solvent removed in vacuo. The crude
product was purified by column chromatography on silica gel.
2-Butyl-4-(phenylsulfanyl)-6-(p-tolyl)-2,3-dihydrobenzofuran 194a
As described in general procedure G, 193 (44.1 mg, 0.102 mmol) and 4-
methylphenylboronic acid (27.0 mg, 0.199 mmol), after purification by column
chromatography (2% Et2O in hexanes) gave 194a (34.4 mg, 91.8 µmol, 90%) as a white
solid; m.p 59.9-61.2 °C; δH (400 MHz, CDCl3) 0.95 (3 H, t, J 6.8 Hz, CH3), 1.33 - 1.52 (4
H, m, CH2), 1.61 - 1.72 (1 H, m, (CH(O)CH2CH2)), 1.78 - 1.89 (1 H, m, (CH(O)CH2CH2)),
2.39 (3 H, s, ArCH3), 2.75 (1 H, dd, J 16.1, 7.5 Hz, ArCH2CH(O)), 3.18 (1 H, dd, J 16.1,
9.0 Hz, ArCH2CH(O)), 4.77 - 4.87 (1 H, m, CH(O)), 6.93 (1 H, d, J 1.5 Hz, aryl H), 7.03
(1 H, d, J 1.5 Hz, aryl H), 7.19 - 7.34 (7 H, m, aryl H), 7.38 - 7.43 (2 H, m, aryl H); δC (100
MHz, CDCl3) 14.0 (CH3), 21.1 (ArCH3), 22.6 (CH2), 27.4 (CH2), 34.9 (ArCH2CH(O)),
35.8 (CH(O)CH2CH2), 83.9 (CH(O)), 107.2 (aryl C-H), 122.3 (aryl C-H), 126.7 (aryl C-
H), 126.8 (aryl C-H), 127.9 (aryl Cq), 129.2 (aryl C-H), 129.4 (aryl C-H), 130.0 (aryl C-H),
131.2 (aryl Cq), 135.0 (aryl Cq), 137.2 (aryl Cq), 137.7 (aryl Cq), 142.4 (aryl Cq), 160.5
177
(aryl Cq); νmax (thin film/cm-1
) 814 (vs), 950 (m), 1206 (m), 1468 (s), 1561 (s), 1578 (s),
2858 (m), 2929 (s), 2954 (s); MS (APCI) m/z 375 [(M+H)+]; HRMS C25H27OS [(M+H)
+]
Expected 375.1777, Found 375.1775.
3-[2-Butyl-4-(phenylsulfanyl)-2,3-dihydrobenzofuran-6-yl]pyridine 194b
As described in general procedure G, 193 (43.0 mg, 99.4 µmol) and 3-pyridylboronic acid
(24.5 mg, 0.199 mmol), after purification by column chromatography (50% Et2O in
hexanes) gave 194b (25.7 mg, 71.1 µmol, 71%) as a colourless oil; δH (400 MHz, CDCl3)
0.93 (3 H, t, J 7.0 Hz, CH3), 1.33 - 1.52 (4 H, m, CH2), 1.61 - 1.73 (1 H, m,
(CH(O)CH2CH2), 1.77 - 1.90 (1 H, m, (CH(O)CH2CH2), 2.76 (1 H, dd, J 16.3, 7.5 Hz,
ArCH2CH(O)), 3.19 (1 H, dd, J 16.3, 9.0 Hz, ArCH2CH(O)), 4.79 - 4.90 (1 H, m, CH(O)),
6.88 (1 H, d, J 1.5 Hz, aryl H), 6.94 (1 H, d, J 1.5 Hz, aryl H), 7.21 - 7.40 (6 H, m, aryl H),
7.76 (1 H, dt, J 8.0, 2.0 Hz, aryl H), 8.56 (1 H, d, J 3.0 Hz, aryl H), 8.73 (1 H, br. s., aryl
H); δC (100 MHz, CDCl3) 14.0 (CH3), 22.5 (CH2), 27.3 (CH2), 34.8 (ArCH2CH(O)), 35.8
(CH(O)CH2CH2), 84.1 (CH(O)), 106.9 (aryl C-H), 121.6 (aryl C-H), 123.5 (aryl C-H),
121.2 (aryl C-H), 128.6 (aryl Cq), 129.3 (aryl C-H), 130.7 (aryl C-H), 132.4 (aryl Cq),
134.2 (aryl C-H), 136.1 (aryl Cq), 138.9 (aryl Cq), 148.1 (aryl C-H), 148.5 (aryl C-H),
160.6 (aryl Cq); νmax (thin film/cm-1
) 946 (s), 1023 (m), 1218 (s), 1293 (w), 1399 (m), 1426
(s), 1463 (m), 1577 (s), 2858 (w), 2929 (m), 2954 (m); MS (ES+) m/z 362 [(M+H)
+];
HRMS C23H24ONS [(M+H)+] Expected 362.1573, Found 362.1566.
178
2-Butyl-4-(phenylsulfanyl)-6-(2-thienyl)-2,3-dihydrobenzofuran 194c
As described in general procedure G, 193 (42.8 mg, 99.0 µmol) and 2-thienylboronic acid
(25.6 mg, 0.200 mmol), after purification by column chromatography (2% Et2O in
hexanes) gave 194c (31.2 mg, 85.1 µmol, 87%) as a colourless oil; δH (400 MHz, CDCl3)
0.93 (3 H, t, J 7.0 Hz, CH3), 1.32 - 1.50 (4 H, m, CH2), 1.60 - 1.70 (1 H, m,
(CH(O)CH2CH2), 1.75 - 1.87 (1 H, m, (CH(O)CH2CH2), 2.71 (1 H, dd, J 16.3, 7.5 Hz,
ArCH2CH(O)), 3.14 (1 H, dd, J 16.3, 9.0 Hz, ArCH2CH(O)), 4.81 (1 H, dtd, J 9.0, 7.5, 5.9
Hz, CH(O)), 6.96 (1 H, d, J 1.5 Hz, aryl H), 7.04 (1 H, dd, J 5.1, 3.6 Hz, aryl H), 7.06 (1
H, d, J 1.5 Hz, aryl H), 7.20 (1 H, dd, J 3.6, 1.1 Hz, aryl H), 7.22 - 7.34 (6 H, m, aryl H);
δC (100 MHz, CDCl3) 14.0 (CH3), 22.6 (CH2), 27.3 (CH2), 34.9 (ArCH2CH(O)), 35.8
(CH(O)CH2CH2), 84.0 (CH(O)), 106.1 (aryl C-H), 121.1 (aryl C-H), 123.2 (aryl C-H),
124.8 (aryl C-H), 126.8 (aryl C-H), 127.8 (aryl C-H), 128.4 (aryl Cq), 129.2 (aryl C-H),
130.1 (aryl C-H), 131.6 (aryl Cq), 134.7 (aryl Cq), 135.3 (aryl Cq), 143.8 (aryl Cq), 160.5
(aryl Cq); νmax (thin film/cm-1
) 932 (m), 1023 (m), 1224 (s), 1413 (m), 1476 (m), 1569 (s),
1603 (m), 2858 (w), 2930 (m), 2953 (m); MS (APCI) m/z 367 [(M+H)+]; HRMS
C22H23OS2 [(M+H)+] Expected 367.1185, Found 367.1186.
2-Butyl-6-(phenylethynyl)-4-(phenylsulfanyl)-2,3-dihydrobenzofuran 195
The compound was prepared according to a literature procedure.168
Et3N (1.13 mL, 1.00
mmol) was added to a microwave vial with Teflon-lined septum pre-flushed with N2 and
containing a stirred mixture of PdCl2(PPh3)2 (7.00 mg, 9.97 µmol), phenylacetylene (20.0
mg, 0.196 mmol) and 193 (43.8 mg, 0.101 mmol) in DMF (0.5 mL). The mixture was
heated to 90 °C and stirred for 18 h. The mixture was then cooled to room temperature and
179
diluted with H2O. The aqueous layer was extracted with Et2O (3 × 10 mL) and the
combined organic extracts were washed with 10 aq. LiCl (15 mL), dried with MgSO4,
filtered and the solvent removed in vacuo. The crude product was purified by column
chromatography on silica gel (10% CHCl3 in hexanes) to give 195 (36.2 mg, 94.1 µmol,
94%) as a pale yellow oil; δH (400 MHz, CDCl3) 0.93 (3 H, t, J 6.9 Hz, CH3), 1.32 - 1.47
(4 H, m, CH2), 1.61 - 1.69 (1 H, m, CH(O)CH2CH2), 1.76 - 1.83 (1 H, m, CH(O)CH2CH2),
2.73 (1 H, dd, J 16.4, 7.5 Hz, ArCH2CH(O)), 3.16 (1 H, dd, J 16.4, 9.1 Hz, ArCH2CH(O)),
4.76 - 4.84 (1 H, m, CH(O)), 6.83 (1 H, d, J 0.9 Hz, aryl H), 6.96 (1 H, d, J 0.9 Hz, aryl H),
7.24 - 7.39 (8 H, m, aryl H), 7.47 - 7.52 (2 H, m, aryl H); δC (125 MHz, CDCl3) 14.0
(CH3), 22.5 (CH2), 27.3 (CH2), 35.0 (ArCH2CH(O)), 35.7 (CH(O)CH2CH2), 83.9 (CH(O)),
89.0 (ArC≡CAr), 89.1 (ArC≡CAr), 111.2 (aryl C-H), 123.1 (aryl Cq), 123.6 (aryl Cq),
126.5 (aryl C-H), 127.1 (aryl C-H), 128.2 (aryl C-H), 128.3 (aryl C-H), 129.3 (aryl C-H),
129.7 (aryl Cq), 130.6 (aryl C-H), 131.6 (aryl C-H), 131.7 (aryl Cq), 134.3 (aryl Cq), 159.8
(aryl Cq); νmax (thin film/cm-1
) 755 (vs), 987 (m), 1220 (s), 1410 (m), 1562 (s), 1600 (m),
2858 (w), 2929 (m), 2955 (m); MS (ES+) m/z 385 [(M+H)
+]; HRMS C26H25OS [(M+H)
+]
Expected 385.1621, Found 385.1621.
General Procedure H – Ni-catalysed Kumada-Corriu coupling72
Ni(PPh3)2Cl2 (6.54 mg, 10 µmol) was added to a microwave vial with Teflon-lined septum
before evacuating and backfilling with Ar (3 cycles). The corresponding sulfide (0.100
mmol), benzene (1.5 mL) and Grignard reagent solution (0.300 mmol) were then added at
room temperature and the mixture was heated to 80 °C and stirred for 24 h. The reaction
mixture was then cooled to room temperature and quenched with sat. aq. NH4Cl (10 mL).
The aqueous layer was then extracted with EtOAc (3 × 10 mL) and the combined organic
extracts were dried with MgSO4, filtered and the solvent removed in vacuo. The crude
product was purified by column chromatography on silica gel.
180
2-Butyl-4-methyl-6-(p-tolyl)-2,3-dihydrobenzofuran 198a
As described in general procedure H, 194a (37.5 mg, 0.100 mmol), methylmagnesium
chloride (3 M in THF, 0.100 mL, 0.300 mmol) and Ni(PPh3)2Cl2 (6.55 mg, 10 µmol), after
column chromatography on silica gel (10% toluene in hexanes) gave 198a (20.9 mg, 74.5
µmol, 75%) as a white solid; m.p. 44.1-45.2 °C; δH (400 MHz, CDCl3) 0.96 (3 H, t, J 7.0
Hz, CH3), 1.36 - 1.59 (4 H, m, CH2), 1.66 - 1.77 (1 H, m, CH(O)CH2CH2), 1.83 - 1.95 (1
H, m, CH(O)CH2CH2), 2.29 (3 H, s, ArCH3), 2.40 (3 H, s, ArCH3), 2.80 (1 H, dd, J 15.4,
7.9 Hz, ArCH2CH(O)), 3.23 (1 H, dd, J 15.4, 8.9 Hz, ArCH2CH(O)), 4.79 – 4.89 (1 H, m,
CH(O)), 6.83 (1 H, s, aryl H), 6.89 (1 H, s, aryl H), 7.20 – 7.25 (2 H, m, aryl H), 7.44 -
7.48 (2 H, m, aryl H); δC (100 MHz, CDCl3) 14.0 (CH3), 19.1 (ArCH3), 21.1 (ArCH3), 22.6
(CH2), 27.6 (CH2), 34.3 (ArCH2CH(O)), 36.0 (CH(O)CH2CH2), 83.6 (CH(O)), 105.2 (aryl
C-H), 120.2 (aryl C-H), 124.9 (aryl Cq), 126.9 (aryl C-H), 129.3 (aryl C-H), 134.7 (aryl
Cq), 136.8 (aryl Cq), 138.6 (aryl Cq), 141.5 (aryl Cq), 159.9 (aryl Cq); νmax (thin film/cm-1
)
814 (vs), 975 (s), 1204 (m), 1479 (s), 1598 (s), 2858 (m), 2929 (s), 2954 (s), 3024 (w); MS
(APCI) m/z 281 [(M+H)+]; HRMS C20H25O [(M+H)
+] Expected 281.1900, Found
281.1893.
2-Butyl-4-(2-thienyl)-6-(p-tolyl)-2,3-dihydrobenzofuran 198b
As described in general procedure H, 194a (35.3 mg, 94.2 µmol), 2-thienylmagnesium
bromide (1 M in THF, 0.300 mL, 0.300 mmol) and Ni(PPh3)2Cl2 (6.50 mg, 10.0 µmol),
after column chromatography on silica gel (20% CHCl3 in hexanes) gave 198b (24.3 mg,
69.7 µmol, 74%) as a yellow solid; m.p. 75.1-76.4 °C; δH (500 MHz, CDCl3) 0.97 (3 H, t, J
6.9 Hz, CH3), 1.37 - 1.59 (4 H, m, CH2), 1.70 - 1.80 (1 H, m, CH(O)CH2CH2), 1.84 - 1.96
(1 H, m, CH(O)CH2CH2), 2.41 (3 H, s, ArCH3), 3.09 (1 H, dd, J 15.6, 7.6 Hz,
181
ArCH2CH(O)), 3.53 (1 H, dd, J 15.6, 9.0 Hz, ArCH2CH(O)), 4.84 - 4.92 (1 H, m, CH(O)),
6.95 (1 H, d, J 1.3 Hz, aryl H), 7.13 (1 H, dd, J 5.0, 3.5 Hz, aryl H), 7.24 - 7.28 (2 H, m,
aryl H), 7.30 - 7.34 (2 H, m, aryl H), 7.36 (1 H, dd, J 5.0, 1.1 Hz, aryl H), 7.51 (2 H, d, J
7.9 Hz, aryl H); δC (125 MHz, CDCl3) 14.0 (CH3), 21.1 (ArCH3), 22.6 (CH2), 27.6 (CH2),
36.0 (CH(O)CH2CH2), 36.2 (ArCH2CH(O)), 83.7 (CH(O)), 107.0 (aryl C-H), 118.3 (aryl
C-H), 122.7 (aryl Cq), 124.9 (aryl C-H), 125.1 (aryl C-H), 127.0 (aryl C-H), 127.6 (aryl C-
H), 129.4 (aryl C-H), 131.5 (aryl Cq), 137.2 (aryl Cq), 138.2 (aryl Cq), 142.1 (aryl Cq),
143.0 (aryl Cq), 160.9 (aryl Cq); νmax (thin film/cm-1
) 977 (s), 1045 (w), 1102 (w), 1171
(w), 1201 (s), 1218 (w), 1254 (m), 1297 (m), 1363 (w), 1400 (m), 1420 (s), 1436 (m), 1473
(m), 1516 (w), 1584 (s), 1611 (m), 2858 (w), 2928 (m), 2953 (m), 3023 (w); MS (APCI)
m/z 349 [(M+H)+]; HRMS C23H25OS [(M+H)
+] Expected 349.1621, Found 349.1606.
2-Butyl-4-(4-methoxyphenyl)-6-(p-tolyl)-2,3-dihydrobenzofuran 198c
As described in general procedure H, 194a (35.5 mg, 94.8 µmol), 4-
methoxyphenylmagnesium bromide (0.5 M in THF, 0.600 mL, 0.300 mmol) and
Ni(PPh3)2Cl2 (6.54 mg, 10 µmol), after column chromatography on silica gel (5% Et2O in
hexanes) gave 198c (22.6 mg, 60.7 µmol, 64%) as a white solid; m.p. 69.8-70.7 °C; δH
(400 MHz, CDCl3) 0.95 (3 H, t, J 7.2 Hz, CH3), 1.34 - 1.57 (4 H, m, CH2), 1.66 - 1.77 (1
H, m, CH(O)CH2CH2), 1.85 - 1.96 (1 H, m, CH(O)CH2CH2), 2.41 (3 H, s, ArCH3), 2.98 (1
H, dd, J 15.7, 8.0 Hz, ArCH2CH(O)), 3.38 (1 H, dd, J 15.7, 8.7 Hz, ArCH2CH(O)), 3.88 (3
H, s, OCH3), 4.78 - 4.88 (1 H, m, CH(O)), 6.95 - 7.03 (3 H, m, aryl H), 7.12 (1 H, d, J 1.5
Hz, aryl H), 7.25 (2 H, d, J 8.0 Hz, aryl H), 7.43 - 7.49 (2 H, m, aryl H), 7.52 (2 H, d, J 8.0
Hz, aryl H); δC (100 MHz, CDCl3) 14.0 (CH3), 21.1 (ArCH3), 22.6 (CH2), 27.6 (CH2), 35.4
(ArCH2CH(O)), 35.8 (CH(O)CH2CH2), 55.3 (OCH3), 83.8 (CH(O)), 106.5 (aryl C-H),
113.8 (aryl C-H), 119.4 (aryl C-H), 123.5 (aryl Cq), 127.0 (aryl C-H), 129.2 (aryl C-H),
129.4 (aryl C-H), 133.0 (aryl Cq), 137.0 (aryl Cq), 138.4 (aryl Cq), 138.5 (aryl Cq), 141.9
(aryl Cq), 158.8 (aryl Cq), 160.5 (aryl Cq); νmax (thin film/cm-1
) 814 (vs), 938 (m), 1034
(m), 1108 (m), 1176 (m), 1246 (s), 1290 (m), 1466 (m), 1513 (s), 1609 (m), 2835 (w),
182
2858 (w), 2929 (w), 2935 (w), 2996 (w), 3029 (w); MS (APCI) m/z 373 [(M+H)+]; HRMS
C26H29O2 [(M+H)+] Expected 373.2162, Found 373.2144.
2-Butyl-4-cyclopropyl-6-(2-thienyl)-2,3-dihydrobenzofuran 198d
As described in general procedure H, 194c (33.0 mg, 90.0 µmol), cyclopropylmagnesium
bromide (0.5 M in THF, 0.600 mL, 0.300 mmol) and Ni(PPh3)2Cl2 (6.54 mg, 10 µmol),
after column chromatography on silica gel (10% toluene in hexanes) gave 198d (19.2 mg,
64.3 µmol, 72%) as a colourless oil; δH (400 MHz, CDCl3) 0.73 - 0.79 (2 H, m,
CH(CH2)2), 0.92 - 1.00 (5 H, m, CH3 + CH(CH2)2), 1.36 - 1.55 (4 H, m, CH2), 1.66 - 1.96
(3 H, m, CH(O)CH2CH2 + CH(CH2)2), 2.90 (1 H, dd, J 15.6, 7.5 Hz, ArCH2CH(O)), 3.35
(1 H, dd, J 15.6, 8.8 Hz, ArCH2CH(O)), 4.84 (1 H, dtd, J 8.8, 7.5, 6.1 Hz, CH(O)), 6.63 (1
H, d, J 1.5 Hz, aryl H), 6.85 (1 H, d, J 1.5 Hz, aryl H), 7.02 - 7.07 (1 H, m, aryl H), 7.20 -
7.24 (2 H, m, aryl H); δC (100 MHz, CDCl3) 7.80 (CH(CH2)2), 13.1 (CH(CH2)2), 14.0
(CH3), 22.6 (CH2), 27.6 (CH2), 34.2 ((ArCH2CH(O)), 36.0 (CH(O)CH2CH2), 83.8
(CH(O)), 104.3 (aryl C-H), 113.9 (aryl C-H), 122.8 (aryl C-H), 124.2 (aryl C-H), 125.9
(aryl Cq), 127.8 (aryl C-H), 134.6 (aryl Cq), 140.6 (aryl Cq), 145.0 (aryl Cq), 159.7 (aryl
Cq); νmax (thin film/cm-1
) 823 (s), 905 (m), 992 (m), 1023 (s), 1223 (s), 1425 (s), 1432 (s),
1483 (w), 1589 (s), 1613 (m), 2858 (m), 2930 (s), 2953 (s), 3003 (w), 3081 (w); MS
(APCI) m/z 299 [(M+H)+]; HRMS C19H23OS [(M+H)
+] Expected 299.1464, Found
299.1451.
4-Benzyl-2-butyl-6-(2-thienyl)-2,3-dihydrobenzofuran 198e
As described in general procedure H, 194c (33.0 mg, 90.0 mmol), benzylmagnesium
chloride (1.82 M in THF, 0.165 mL, 0.300 mmol) and Ni(PPh3)2Cl2 (6.54 mg, 10.0 µmol),
after column chromatography on silica gel (15% toluene in hexanes) gave 198e (27.4 mg,
183
78.6 µmol, 88%) as a white solid; m.p. 35.3-36.8 °C; δH (400 MHz, CDCl3) 0.93 (3 H, t, J
7.3 Hz, CH3), 1.32 - 1.52 (4 H, m, CH2), 1.59 - 1.72 (1 H, m, CH(O)CH2CH2), 1.75 - 1.88
(1 H, m, CH(O)CH2CH2), 2.66 (1 H, dd, J 15.7, 7.7 Hz, ArCH2CH(O)), 3.10 (1 H, dd, J
15.7, 8.9 Hz, ArCH2CH(O)), 3.94 (2 H, s, ArCH2Ar), 4.78 (1 H, dtd, J 8.9, 7.7, 6.0 Hz,
CH(O)), 6.93 (1 H, d, J 1.5 Hz, aryl H), 6.97 (1 H, d, J 1.5 Hz, aryl H), 7.05 (1 H, dd, J
5.1, 3.6 Hz, aryl H), 7.17 - 7.26 (5 H, m, aryl H), 7.28 - 7.33 (2 H, m, aryl H); δC (100
MHz, CDCl3) 14.0 (CH3), 22.6 (CH2), 27.5 (CH2), 34.2 (ArCH2CH(O)), 35.9
(CH(O)CH2CH2), 39.7 (ArCH2Ar), 83.8 (CH(O)), 105.0 (aryl C-H), 119.3 (aryl C-H),
122.9 (aryl C-H), 124.3 (aryl C-H), 125.7 (aryl Cq), 126.2 (aryl C-H), 127.8 (aryl C-H),
128.5 (aryl C-H), 128.7 (aryl C-H), 134.6 (aryl Cq), 137.7 (aryl Cq), 139.6 (aryl Cq), 144.7
(aryl Cq), 160.3 (aryl Cq); νmax (thin film/cm-1
) 841 (m), 971 (w), 1030 (w), 1222 (s), 1434
(s), 1590 (s), 1614 (w), 2858 (w), 2929 (m), 2954 (m), 3026 (w), 3061 (w); MS (APCI) m/z
349 [(M+H)+]; HRMS C23H25OS [(M+H)
+] Expected 349.1621, Found 349.1605.
General Procedure I – Raney Ni desulfurisation
A solution of the corresponding sulfide (0.100 mmol) in EtOH (1 mL) was added dropwise
to a suspension of Raney Nickel in EtOH (1 mL). The reaction was stirred at room
temperature for 1 h and then filtered through Celite® 545 (Et2O eluent). The solvent was
then removed in vacuo, and the crude product was purified by column chromatography.
1-(2-Chlorohexyl)-2,4-dimethoxybenzene 182 and
1-hexyl-2,4-dimethoxybenzene 183
As described in general procedure I, 99a (40.1 mg, 0.110 mmol), Raney Nickel (700 mg of
slurry), after column chromatography on silica gel (10% CHCl3 in hexanes) gave 182 (22.8
mg, 88.8 µmol, 81%) and 183 (4.10 mg, 18.4 µmol, 11%) as colourless oils; For 182, δH
(500 MHz, CDCl3) 0.91 (3 H, t, J 7.2 Hz, CH3), 1.19 – 1.46 (3 H, m, CH2), 1.52 – 1.62 (1
H, m, CH2), 1.63 – 1.72 (1 H, m, ArCH2CH(Cl)CH2), 1.73 – 1.82 (1 H, m,
ArCH2CH(Cl)CH2), 2.93 (1 H, dd, J 13.7, 7.6 Hz, ArCH2), 3.04 (1 H, dd, 13.7, 6.3 Hz,
ArCH2), 3.81 (3 H, s, OCH3), 3.82 (3 H, s, OCH3), 4.15 – 4.22 (1 H, m, CHCl), 6.42 – 6.47
(2 H, m, aryl H), 7.08 (1 H, d, J 7.8 Hz, aryl H); δC (125 MHz, CDCl3) 14.0 (CH3), 22.2
184
(CH2), 28.6 (CH2), 37.5 (ArCH2CH(Cl)CH2), 39.4 (ArCH2), 55.2 (OCH3), 55.3 (OCH3),
63.4 (CHCl), 98.4 (aryl C-H), 103.7 (aryl C-H), 119.0 (aryl Cq), 131.6 (aryl C-H), 158.4
(aryl Cq), 159.8 (aryl Cq); νmax (thin film/cm-1
) 935 (w), 1036 (s), 1131 (m), 1155 (s), 1207
(s), 1287 (m), 1437 (w), 1464 (m), 1506 (s), 1587 (m), 1613 (m), 2836 (w), 2858 (w), 2928
(w), 2955 (w); MS (APCI) m/z 257 35
Cl, 259 37
Cl [(M+H)+]; HRMS C14H22O2Cl [(M+H)
+]
Expected 257.1303, Found 257.1299; For 183, δH (500 MHz, CDCl3) 0.89 (3 H, t, J 6.7
Hz, CH3), 1.19 – 1.37 (6 H, m, CH2), 1.49 – 1.57 (2 H, m, ArCH2CH2), 2.53 (2 H, t, J 7.6
Hz, ArCH2), 3.80 (6 H, s, OCH3), 6.40 – 6.46 (2 H, m, aryl H), 7.03 (1 H, d, J 8.2 Hz, aryl
H); δC (125 MHz, CDCl3) 13.9 (CH3), 22.4 (CH2), 29.2 (ArCH2), 29.5 (CH2), 29.8 (CH2),
31.5 (CH2), 55.0 (OCH3), 55.1 (OCH3), 98.2 (aryl C-H), 103.4 (aryl C-H), 123.5 (aryl Cq),
129.5 (aryl C-H), 158.0 (aryl Cq), 158.6 (aryl Cq); νmax (thin film/cm-1
) 923 (w), 1040 (m),
1134 (m), 1155 (s), 1207 (s), 1259 (w), 1288 (w), 1463 (m), 1505 (s), 1587 (w), 1613 (w),
2852 (w), 2921 (m), 2953 (w); MS (APCI) m/z 223 [(M+H)+]; HRMS C14H22O2 [(M+H)
+]
Expected 223.1693, Found 223.1691.
2-Butyl-2,3-dihydrobenzofuran-6-ol 196
As described by general procedure I, 191b (53.8 mg, 0.179 mmol), Raney Nickel (700 mg
of slurry), after column chromatography on silica gel (10% EtOAc in hexanes) gave 196
(33.3 mg, 0.173 mmol, 97%) as a colourless oil; δH (400 MHz, CDCl3) 0.94 (3 H, t, J 7.2
Hz, CH3), 1.33 – 1.54 (4 H, m, CH2), 1.61 – 1.73 (1 H, m, ArCH2CH(O)CH2), 1.76 – 1.91
(1 H, m, ArCH2CH(O)CH2), 2.78 (1 H, dd, J 15.1, 7.8 Hz, ArCH2), 3.19 (1 H, dd, J 15.1,
8.8 Hz, ArCH2), 4.74 – 4.84 (1 H, m, CH(O)), 4.91 (1 H, s, OH), 6.27 – 6.33 (2 H, m, aryl
H), 6.94 – 7.00 (1 H, m, aryl H); δC (100 MHz, CDCl3) 14.0 (CH3), 22.6 (CH2), 27.5
(CH2), 34.7 (ArCH2CH(O)), 35.7 (CH(O)CH2CH2), 84.6 (CH(O)), 97.5 (aryl C-H), 106.8
(aryl C-H) 119.1 (aryl Cq), 125.0 (aryl C-H), 155.9 (aryl Cq), 160.8 (aryl Cq); νmax (thin
film/cm-1
) 964 (s), 1096 (s), 1136 (s), 1186 (m), 1214 (m), 1269 (w), 1352 (w), 1458 (s),
1497 (s), 1606 (m), 1622 (m), 2859 (w), 2930 (w), 2956 (w), 3388 (br, w, O-H stretch);
MS (APCI) m/z 193 [(M+H)+]; HRMS C12H17O2 [(M+H)
+] Expected 193.1223, Found
193.1215.
185
2-Butyl-6-(p-tolyl)-2,3-dihydrobenzofuran 197
As described by general procedure I, 194a (37.0 mg, 98.8 µmol), Raney Nickel (700 mg of
slurry), after column chromatography on silica gel (10% CHCl3 in hexanes) gave 197 (23.5
mg, 88.2 µmol, 89%) as a colourless oil; δH (500 MHz, CDCl3) 0.97 (3 H, t, J 7.0 Hz,
CH2CH3), 1.37 – 1.59 (4 H, m, CH2), 1.66 – 1.78 (1 H, m, ArCH2CH(O)CH2), 1.83 – 1.95
(1 H, m, ArCH2CH(O)CH2), 2.41 (3 H, s, ArCH3), 2.91 (1 H, dd, J 15.4, 7.8 Hz, ArCH2),
3.31 (1 H, dd, J 15.4, 8.9 Hz, ArCH2), 4.78 – 4.88 (1 H, m, CH(O)), 7.00 (1 H, s, aryl H),
7.06 (1 H, d, J 7.6 Hz, aryl H), 7.20 (1 H, d, J 7.6 Hz, aryl H), 7.24 (2 H, d, J 8.1 Hz, aryl
H), 7.48 (2 H, d, J 8.1 Hz, aryl H); δC (125 MHz, CDCl3) 13.8 (CH2CH3), 20.8 (ArCH3),
22.4 (CH2), 27.4 (CH2), 35.0 (ArCH2), 35.6 (ArCH2CH(O)CH2), 83.6 (CH(O)), 107.6 (aryl
C-H), 118.8 (aryl C-H), 124.7 (aryl C-H), 125.6 (aryl Cq), 126.7 (aryl C-H), 129.1 (aryl C-
H), 136.6 (aryl Cq), 138.2 (aryl Cq), 141.3 (aryl Cq), 160.0 (aryl Cq); νmax (thin film/cm-1
)
971 (s), 1110 (w), 1166 (w), 1204 (m), 1295 (m), 1378 (w), 1431 (m), 1483 (s), 1568 (w),
1588 (w), 1618 (w), 2858 (w), 2928 (w), 2954 (w); MS (APCI) m/z 267 [(M+H)+]; HRMS
C19H23O [(M+H)+] Expected 267.1743, Found 267.1740.
5.11 Towards the Truce-Smiles Rearrangement
(2-Allylphenyl)(phenyl)sulfide 64 88c
An oven dried metal-capped microwave reactor with a Teflon-lined septum was flushed
with N2, before adding a solution containing diphenyl sulfoxide (500 mg, 2.47 mmol) in
CH2Cl2 (20 mL). Allyl TMS (1.00 mL, 6.29 mmol) and triflic anhydride (0.622 mL, 3.70
mmol) were added sequentially at room temperature and the reaction mixture was then
heated for 1 h at 60 °C in a microwave reactor. After cooling to room temperature, the
solution was quenched with sat. aq. NaHCO3 (25 mL) and the aqueous layer was extracted
186
with CH2Cl2 (2 × 10 mL). The combined organic layer was washed successively with
water (3 × 10 mL) and brine (10 mL), dried with MgSO4, filtered and concentrated in
vacuo. The crude product was purified by column chromatography on silica gel (n-hexane)
to yield 88c (339 mg, 1.50 mmol, 60% yield) as a colourless oil; δH (400 MHz, CDCl3)
3.57 (2 H, dt, J 6.6, 1.5 Hz, ArCH2), 4.93 - 5.14 (2 H, m, CH=CH2), 5.85 - 6.05 (1 H, m,
CH=CH2), 7.03 - 7.41 (9 H, m, aryl H); δC (100 MHz, CDCl3) 38.1 (ArCH2), 116.0
(CH=CH2), 126.5 (aryl C-H), 127.0 (aryl C-H), 128.1 (aryl C-H), 128.9 (aryl C-H), 129.8
(aryl C-H), 129.9 (aryl C-H), 133.5 (aryl C-H), 133.7 (aryl Cq), 136.5 (CH=CH2), 136.7
(aryl Cq), 142.0 (aryl Cq).
1-Allyl-2-(phenylsulfonyl)benzene 204
Ammonium molybdate (25.8 mg, 0.132 mmol), followed by 30% aq. H2O2 (0.794 mL,
7.04 mmol) were added to a solution of 88c (100 mg, 0.442 mmol) in MeCN (5 mL) at 0
°C. The mixture was warmed to room temperature and stirred for 16 h. The reaction was
quenched by adding Na2SO3 (901 mg, 7.15 mmol) and stirred for a further 40 min. The
solvent was then removed in vacuo, the residue dissolved in CH2Cl2 (15 mL) and sat. aq.
NH4Cl (10 mL) added. The aqueous phase was extracted with CH2Cl2 (3 × 15 mL) and the
combined organic layers were dried over MgSO4, filtered and solvent removed in vacuo.
The crude product was purified by column chromatography on silica gel (10% EtOAc in
hexanes) to give 204 (66 mg, 0.255 mmol, 58%) as a white solid; m.p. 51.2 – 52.5 °C; δH
(400 MHz, CDCl3) 3.65 (2 H, dt, J 6.6, 1.5 Hz, ArCH2), 4.91 (1 H, dq, J 16.9, 1.5 Hz,
CH=CH2), 4.97 (1 H, dq, J 10.1, 1.5 Hz, CH=CH2), 5.69 (1 H, ddt, J 16.9, 10.1, 6.6 Hz,
CH=CH2), 7.32 (1 H, dd, J 7.6, 0.8 Hz, aryl H), 7.43 (1 H, td, J 7.6, 1.3 Hz, aryl H), 7.47 -
7.61 (4 H, m, aryl H), 7.83 - 7.90 (2 H, m, aryl H), 8.24 (1 H, dd, J 7.9, 1.4 Hz, aryl H); δC
(100 MHz, CDCl3) 36.4 (ArCH2), 116.9 (CH=CH2), 126.7 (aryl C-H), 127.5 (aryl C-H),
129.1 (aryl C-H), 129.5 (aryl C-H), 131.7 (aryl C-H), 133.0 (aryl C-H), 133.6 (aryl C-H),
135.5 (CH=CH2), 138.6 (aryl Cq), 139.9 (aryl Cq), 141.7 (aryl Cq); νmax (thin film/cm-1
)
1153 (vs, S=O sym), 1306 (s, S=O asym), 1446 (m), 2979 (vw), 3063 (vw); MS (ES+) m/z
259 [(M+H)+]; HRMS C15H15O2S [(M+H)
+] Expected 259.0793, Found 259.0801.
187
1-(Methylsulfonyl)-2-(1-phenylallyl)benzene 207
A solution of 204 (50.0 mg, 0.194 mmol) in THF (1.5 mL) was added dropwise to a
mixture of n-BuLi (1.60 M in hexanes, 0.150 mL, 0.240 mmol) in THF (0.5 mL) at −78
°C. The resulting mixture was warmed to room temperature, with stirring, and then heated
to 60 °C and stirred for 16 h. The mixture was cooled to room temperature, MeI (24.2 µL,
0.388 mmol) added, reheated to 60 °C and stirred for a further 5 h. The solution was then
cooled to room temperature, quenched with sat. aq. NH4Cl (10 mL) and EtOAc added (15
mL). The aqueous layer was extracted with EtOAc (3 × 15 mL) and the combined organic
extracts were dried with MgSO4, filtered and solvent removed in vacuo. The crude product
was purified by column chromatography (10% EtOAc in hexanes) to give 207 (36.0 mg,
0.132 mmol, 70%) as a colourless oil; δH (400 MHz, CDCl3) 2.85 (3 H, s, SO2CH3), 4.90
(1 H, dt, J 17.2, 1.4 Hz, CH=CH2), 5.35 (1 H, dt, J 10.3, 1.4 Hz, CH=CH2), 6.13 (1 H, dt, J
6.1, 1.4 Hz, (Ar)2CH), 6.33 (1 H, ddd, J 17.2, 10.3, 6.1 Hz, CH=CH2), 7.20 - 7.26 (3 H, m,
aryl H), 7.28 - 7.35 (2 H, m, aryl H), 7.39 - 7.46 (2 H, m, aryl H), 7.59 (1 H, td, J 7.5, 1.5
Hz, aryl H), 8.14 (1 H, dd, J 7.9, 1.3 Hz, aryl H); δC (100 MHz, CDCl3) 44.8 (SO2CH3),
48.1 ((Ar2)CH), 117.9 (CH=CH2), 126.8 (aryl C-H), 127.2 (aryl C-H), 128.6 (aryl C-H),
128.9 (aryl C-H), 129.8 (aryl C-H), 131.9 (aryl C-H), 133.7 (aryl C-H), 138.7 (aryl Cq),
140.2 (CH=CH2), 142.0 (aryl Cq), 142.7 (aryl Cq); νmax (thin film/cm-1
) 1147 (vs, S=O
sym), 1305 (s, S=O asym), 2927 (w), 3027 (w), 3061 (w); MS (ES+) m/z 273 [(M+H)
+];
HRMS C16H17O2S [(M+H)+] Expected 273.0949, Found 273.0945.
(E)-1-(Phenylsulfonyl)-2-(prop-1-en-1-yl)benzene 208
A solution of 204 (50 mg, 0.194 mmol) in THF (1.5 mL) was added dropwise to a mixture
of NaNH2 (9.00 mg, 0.231 mmol) in THF (0.5 mL) at −78 °C. The resulting mixture was
warmed to room temperature, with stirring, and then heated to 60 °C and stirred for 16 h.
188
The mixture was then cooled to room temperature, quenched with sat. aq. NH4Cl (10 mL)
and EtOAc added (15 mL). The aqueous layer was extracted with EtOAc (3 × 15 mL) and
the combined organic extracts were dried with MgSO4, filtered and solvent removed in
vacuo. The crude product was purified by column chromatography (10% EtOAc in
hexanes) to give 208 (42 mg, 0.163 mmol, 86%) as a white solid; m.p. 91.1 – 92.7 °C; δH
(400 MHz, CDCl3) 1.83 (3 H, dd, J 6.5, 1.5 Hz, CH3), 5.93 (1 H, dq, J 15.6, 6.5 Hz,
CH=CHCH3), 7.16 (1 H, dq, J 15.6, 1.5 Hz, ArCH=CH), 7.38 - 7.60 (6 H, m, aryl H), 7.83
- 7.89 (2 H, m, aryl H), 8.22 (1 H, dd, J 7.9, 1.1 Hz, aryl H); δC (100 MHz, CDCl3) 18.7
(CH3), 124.4 (aryl C-H), 127.0 (aryl C-H), 127.3 (ArCH=CH), 127.7 (aryl C-H), 128.4
(aryl C-H), 128.8 (aryl C-H), 131.2 (CH=CHCH3), 133.0 (aryl C-H), 133.7 (aryl C-H),
136.9 (aryl Cq), 138.3 (aryl Cq), 141.6 (aryl Cq); νmax (thin film/cm-1
) 1150 (vs, S=O, sym),
1303 (s, S=O asym), 2852 (vw), 2912 (vw), 3061 (vw); MS (ES+) m/z 259 [(M+H)
+];
HRMS C15H15O2S [(M+H)+] Expected 259.0793, Found 259.0794.
189
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