Sulfoxide-Directed Metal-Free Aromatic CH Functionalisation

189 Pages·2017·5.01 MB·English

by  Harry Shrives

Sulfoxide-Directed Metal-Free Aromatic C-H Functionalisation:
Application to Heterocycle Synthesis and Derivatisation.

A thesis submitted to the University of Manchester for the degree of Doctor of
Philosophy in the Faculty of Science and Engineering

2017

Harry J. Shrives

School of Chemistry
Harry J. Shrives Ph.D Thesis
Contents
List of Abbreviations 4
Abstract. 7
Declaration 8
Copyright Statement 9
Acknowledgments 10
Chapter 1: Introduction 12
1.1 Pummerer and Pummerer-type Reactions 12
1.1.1 The Classical Pummerer Rearrangement 12
1.1.2 Additive and Vinylogous Pummerer Reactions 14
1.1.3 Aromatic and Hetero-aromatic Pummerer-type Reactions 20
1.1.4 Interrupted Pummerer Reactions 29
1.2 Functionalisation of Aromatics Through Charge Accelerated Rearrangements 32
1.2.1 Charge Accelerated [3,3]-Sigmatropic Rearrangments 32
1.2.2 Ortho Alkylations of Aromatic and Heteroaromatic Systems 39
1.3 Proposed Work 46
Chapter 2: Results and Discussion 49
2.1 Propargylations with Branched Propargyl Silanes 49
2.2 Synthesis of Benzothiophenes 58
2.2.1 Acid-Mediated Cyclisations to Give Alkyl Benzothiophenes 59
2.2.2 Iodine-Mediated Cyclisations to Give Carbonyl-Substituted Benzothiophenes 60
2.2.3 Iodine-Mediated Cyclisations to Give Alkyl-Substituted Benzothiophenes 62
2.2.4 Iodine-Mediated Cyclisations to Give Alkenes 64
2.2.5 Cyclisations to Give Highly Conjugated Benzothiophene-Containing Scaffolds 67
2.2.6 Iodine-Mediated Cyclisations: Mechanisms 71
2.2.7 Access to Benzodithiophene Scaffolds: A Novel Dimerisation 72
2.3 Selective Functionalisation of Benzothiophenes 80
2.3.1 Benzothiophene S-Oxides: Synthesis and Reactivity 81
2.3.2 Selective Arylation of Benzothiophenes Using Phenols 82
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Harry J. Shrives Ph.D Thesis
2.3.3 Selective Alkylation of Benzothiophenes 89
2.3.4 Conclusion and Future Work 96
Chapter 3: Experimental 102
3.1 General Eperimental 102
3.2 Experimental Data 103
3.2.1 General Procedure A: Preparation of 1,3-Bispropargyl Silanes 103
3.2.2 General Procedure B: Propargylation of Aryl Sulfoxides 104
3.2.3 General Procedure C: Preparation of Propargyl Silanes 106
3.2.4 General Procedure D: Propargylation of Heterocycles 110
3.2.5 Gerenal Procedure E: Acid-Mediated Cyclisations 114
3.2.6 General Procedure F: Deprotections 116
3.2.7 General Procedure G: Iodine-Mediated Cyclisations to Give Alkyl Subsitution 118
3.2.8 General Procedure H: Iodine-Mediated Cyclisations to Give Alkenes 121
3.2.9 General Procedure I: Two-Directional Propargylations 126
3.2.10 General Procedure J: Oxidation to bis-sulfoxide 128
3.2.11 General procedure K: Bis-sulfide Formation 129
3.2.12 General Procedure L: Two-Directional Eliminative Cyclisation 130
3.2.13 General Procedure M: Iodine-Mediated Dimerisations 132
3.2.14 General Procedure N: Oxidation of Benzothiophenes 136
3.2.15 General Procedure O: Arylation of Benzothiophene S-Oxides 141
3.2.16 General Procedure P: Arylation of Benzothiophenes with in-situ Oxidation 146
3.2.17 General Procedure Q: Propargylation/Allyation of Benzothiophene S-Oxides 153
3.2.18 General Procedure R: Propargylation of Benzothiophenes with in-situ Oxidation 162
3.2.19 General Procedure S: C2 Propargylation of Benzothiophene S-Oxides 170
3.2.20 General Procedure T: C2 Allylations of Benzothiophene S-Oxides 172
3.3 Appendix: X-Ray Crystal Structures 179
Chapter 4: References 186

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Harry J. Shrives Ph.D Thesis
List of Abbreviations
Ac acyl
AIBN 2,2’-azo bisisobutyronitrile
aq. aqueous
Ar aryl
BDT benzodithiophene
BINAP 2,2’-bis(diphenylphosphino-1,1’-binaphthyl)
Bn benzyl
Boc t-butoxycarbonyl
br. broad (NMR)
Bu butyl
Bz benzoyl
CAN cerium(IV) ammonium nitrate
cat. catalytic
CI chemical ionisation
C celsius
Cy cyclohexyl
d doublet (NMR)
δ chemical shift (NMR)
DCE 1,2-dichloroethane
DDQ 2,3-dichloro-5,6-dicyano-p-benzoquinone
DMF N,N-dimethylformamide
DMSO dimethylsulfoxide
DMTSF dimethyl(methylthio)sulfonium tetrafluoroborate
DPPE ethylenebis(diphenylphosphine)
dr diasteroisomeric ratio
DTBP di-tert-butylpyridine
E electrophile
ee enantiomeric excess
EDG electron donating group
EG ethylene glycol
EI electron ionisation
equiv equivalent
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Harry J. Shrives Ph.D Thesis
ES+/ES- positive/negative ion electrospray (MS)
Et ethyl
EWG electron withdrawing group
FSPE fluorous solid phase extraction
g gram
h hour
HFIP 1,1,1,3,3,3-hexafluoroisopropanol
HMPA hexamethylphosphoramide
HRMS high resolution mass spectrometry
Hz hertz
IBX o-iodoxybenzoic acid
i-Pr isopropyl
IR infrared
J coupling constant (NMR)
μ electron mobility
M Molar
m multiplet (NMR)
m-CPBA m-chloroperbenzoic acid
Me methyl
mg miligram
MHz megahertz
min minutes
ml millilitre
mmol millimole
MOM methoxymethyl
mp melting point
MS mass spectrum
MW micro wave
m/z mass/charge ratio (MS)
NDT naphthodithiophene
NCS N-chlorosuccinimide
Nf nonafluorobutanesulfonic
NMR nuclear magnetic resonance
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Harry J. Shrives Ph.D Thesis
Nu nucleophile
PCE Power Conversion Efficiency
Ph phenyl
PIFA iodobenzene-I,I-bis(trifluoroacetate)
PMB p-methoxybenzyl
ppm parts per million
Pr propyl
PTSA p-toluenesulfonic acid
Pyr. pyridine
q quartet (NMR)
quin quintet (NMR)
RF perfluoroalkyl
rt room temperature
s singlet (NMR)
sxt sextet (NMR)
SEM 2-(trimethylsilyl)ethoxymethyl
t triplet (NMR)
TBAF tetrabutylammonium fluoride
TBS tert-butyldimethylsilyl
TFA trifluoroacetic acid
TFAA trifluoroacetic anhydride
Tf trifluoromethanesulfonic
THF tetrahydrofuran
TIPS triisopropylsilyl
TMEDA N,N,N’,N’-tetramethylethylenediamine
TMS trimethylsilyl
Tol tolyl
Ts tosyl

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Harry J. Shrives Ph.D Thesis
Abstract.
University of Manchester
Harry J. Shrives
Degree of Doctor of Philosophy.
Sulfoxide-Directed Metal-Free Aromatic C-H Functionalisation: Application to
Heterocycle Synthesis and Derivatisation.
March 2017.

Selective metal-free functionalisation of aromatic C-H bonds is a valuable goal in
organic synthetic chemistry. Recently it has been shown that Pummerer-type reactions,
for example interrupted Pummerer reactions, can be used to trap nucleophiles and
deliver them selectively to aromatic rings via [3,3]-sigmatropic rearrangements.
This thesis investigates the utility of sulfoxide-directed metal-free C-H
functionalisations in the synthesis and derivatisation of a range of benzothiophene
scaffolds. Through a sequence involving metal-free aromatic propargylation reactions
and novel, diversity introducing heterocyclisations, benzothiophenes possessing a range
of functionality, namely ketone, alkane or alkene substituents, can be synthesised. The
value of this new cyclisation protocol is demonstrated through the sysnthesis of
different highly conjugated benzothiophene motifs, molecules of particular interest in
organic electronics. Using alkene substituted benzothiophenes; a new, iodine-mediated
route to highly conjugated benzodithiophene cores is reported along with the
application of two-directional heterocyclisations allowing the synthesis of
naphthodithiophene scaffolds.
Finally, selective C3 arylation and alkylation of benzothiophenes is reported
through the use of benzothiophene S-oxides, an underexplored class of organic
compound. Oxidation of the sulfur atom intrinsic to benzothiophene molecules allows
the capture of phenol, propargyl silane and allyl silane coupling partners, which are
delivered with complete regio-selectivity to the C3 position of the benzothiophene.

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Harry J. Shrives Ph.D Thesis
Declaration
No portion of the work referred to in the 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.
Portions of the work refered to in this thesis have been published in:
Eberhart, A. J.; Shrives, H. J.; Álvarez, E.; Carrër, A.; Zhang, Y.; Procter, D. J. Chem. -Eur.
J., 2015, 21, 7428.

Eberhart, A. J.; Shrives, H.; Zhang, Y.; Carrër, A.; Parry, A. V. S.; Tate, D. J.; Turner, M. L.;
Procter, D. J. Chem. Sci., 2016, 7, 1281.

Shrives, H. J.; Fernández-Salas, J. A.; Hedtke, C; Pulis, A. P.; Procter, D. J. Nat. Commun.,
2017, 8, 14801, doi: 10.1038/ncomms14801

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Harry J. Shrives Ph.D Thesis
Copyright Statement

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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.

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intellectual property (the “Intellectual Property”) and any reproductions of
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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.

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any relevant Thesis restriction declarations deposited in the University Library,
The University Library’s regulations (see
http://www.manchester.ac.uk/library/aboutus/regulations) and in The
University’s policy on Presentation of Theses

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Harry J. Shrives Ph.D Thesis
Acknowledgments
I would like to thank, first and foremost, my supervisor Professor David J. Procter
for the invaluable continued support and mentoring he has provided over the last four
years. The chance to contribute to the chemistry going on in his group has been an
irreplaceable experience in which I have learnt in incredible amount. Also, I must thank
Novartis for funding my Ph.D studentship.
Thanks must also go to all the current and past members of the Procter group
who have made my time so enjoyable; Craig, Irem, Miles, Matezeus, Nico, Becky,
Huanming, Kay, Charlotte and the many others that have been a pleasure to work with.
Special thanks should be given Andrew, Yuntong, Jose and Kristen all of whom, at one
point or another, have been involved in my project and have therefore played a
significant role in my development as a researcher, chemist and individual.
I would like to dedicate this thesis to my mother, Liz, for her unwavering support
and encouragement throughout the duration of my undergraduate and Ph.D. studies,
her experience and guidance has been unbelievably helpful over the years. Last, but not
least, I would like to thank Amy for putting up with me day-to-day and for keeping me
sane, happy and motivated throughout my studies.

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