Gold(I)-catalysed Synthesis of Cyclic Sulfamidates by Intramolecular Allene Hydroamination

206 Pages·2014·3.63 MB·English

Gold(I)-catalysed Synthesis of Cyclic
Sulfamidates by Intramolecular Allene
Hydroamination

Mari C. M Higginbotham
Submitted for the degree of Doctor of Philosophy

Heriot-Watt University
School of Engineering and Physical Sciences
June 2014

The copyright in this thesis is owned by the author. Any quotation from the
thesis or use of any information contained in it must acknowledge this
thesis as the source of the quotation or information.
1. Abstract

The work reported in this thesis outlines the gold(I)-catalysed synthesis of cyclic
sulfamidates by intramolecular allene hydroamination. Work carried out in an attempt to
prepare a novel acyl anion equivalent is also included but endeavours were halted after
one year of study. The thesis is divided into six chapters:

Chapter one provides an introduction to the reactivity of gold, current metal-catalysed
hydroamination reactions and allene structure, synthesis and reactivity. The current
synthetic methods for the preparation of sulfamidates and their uses is also covered.

Chapter two outlines the attempted use of the Burgess reagent to prepare olefinically
substituted sulfamidates and the attempts to reverse regioselectivity in sulfamidate
synthesis.

Chapter three includes an initial proof of concept in gold(I) catalysis and an account of
substrate synthesis. Allenes were synthesised by Crabbé homologation or Johnson-
Claisen rearrangement reactions. The allenes were then converted to the corresponding
sulfamates.

Chapter four outlines our studies of gold(I)-catalysed hydroamination. This includes
optimisation of catalyst and the effects of substitution on reaction rate and
stereochemical hypothesis. The current scope and limitations of this chemistry is also
discussed.

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Chapter five outlines the research work attempted within the first year of study. The
work focussed on the attempted preparation of a thermally unmasked acyl anion
equivalent.

Chapter six provides a formal report of the experimental procedures.

Stereochemical abstract: All compounds with stereogenic centres were prepared as
racemic mixtures but only one enantiomer is represented in the schemes.

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2. Acknowledgements

Firstly, I would like to express my sincere gratitude to Dr Magnus Bebbington for
providing me with the opportunity to work under his supervision. I will be eternally
grateful for his relentless patience, guidance and encouragement during my studies.

Thanks to everyone who has passed through the doors of the Bebbington Lab,
especially Robert for his friendship and strong opinions.

Thanks go to the EPSRC for providing the funding for this project.

I am grateful to Pauline for dragging me out of the lab for the odd coffee and natter. I
must thank James for providing me with access to his glassware stash even if it wasn’t
always clean!

I would like to thank Toria for her unfaltering friendship through the years and for
listening to me harp on about organic chemistry and feining interest accordingly.

To my parents, I owe a lot, and appreciate your enthusiasm and support during my
studies.

Finally, I must thank Gary for being my lighthouse in stormy seas. Maybe now we can
finally set a date…

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ACADEMIC REGISTRY
Research Thesis Submission

Name: Mari Campbell Muir Higginbotham
School/PGI: EPS/CHEMISTRY
Version: (i.e. First, Final Degree Sought PhD/Chemistry
Resubmission, Final) (Award and
Subject area)

Declaration

In accordance with the appropriate regulations I hereby submit my thesis and I declare that:

1) the thesis embodies the results of my own work and has been composed by myself
2) where appropriate, I have made acknowledgement of the work of others and have made
reference to work carried out in collaboration with other persons
3) the thesis is the correct version of the thesis for submission and is the same version as
any electronic versions submitted*.
4) my thesis for the award referred to, deposited in the Heriot-Watt University Library, should
be made available for loan or photocopying and be available via the Institutional
Repository, subject to such conditions as the Librarian may require
5) I understand that as a student of the University I am required to abide by the Regulations
of the University and to conform to its discipline.

* Please note that it is the responsibility of the candidate to ensure that the correct version
of the thesis is submitted.

Signature of Date:
Candidate:

Submission

Submitted By (name in capitals):

Signature of Individual Submitting:

Date Submitted:

For Completion in the Student Service Centre (SSC)

Received in the SSC by (name in
capitals):
Method of Submission
(Handed in to SSC; posted through
internal/external mail):
E-thesis Submitted (mandatory for
final theses)
Signature: Date:

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3. Contents

Chapter 1: Introduction 1
1.1 Gold - the element 2
1.1.1 Reactivity of gold 3
1.1.2 Gold catalysis 7
1.2 Hydroamination 11
1.2.1 Hydroamination of alkynes 12
1.2.2 Hydroamination of alkenes 16
1.2.3 Hydroamination of allenes 19
1.3 Structure, synthesis and reactivity of allenes 21
1.3.1 Structure and bonding of allenes 21
1.3.2 Synthesis of allenes 22
1.4 Sulfamidate chemistry 26
1.4.1 Synthesis of sulfamidates 27
1.4.2 Reactivity of sulfamidates 34
1.4.3 Sulfamidates in target synthesis 36

Chapter 2: Attempted reversal of the regioselectivity in the Burgess-
Reagent mediated sulfamidate synthesis 40
2.1 Initial attempts at vinyl sulfamidate synthesis 42
2.2 Initial investigations in regioselectivity switching 44
2.3 More general attempts at regioselectivity switching 47

Chapter 3: Preparation of Substrates for allene hydroamination and
proof of principle for gold(I)-catalysis 49
3.1 The Crabbé approach 51
3.1.1 Preparation of homopropargyl alcohols 51
3.2 The Johnson-Claisen approach 55
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3.3 Sulfamate formation 58

Chapter 4: Sulfamidate synthesis by gold(I) catalysed hydroamination -
optimisation and controls 65
4.1 Initial investigations into allene hydroamination 66
4.2 Preparation of quaternary-centred sulfamidates 70
4.3 Sulfamidate reactivity 72
4.4 Possible stereochemical rationale 74
4.5 Unsuccessful substrates 76
4.6 Future Work 77

Chapter 5: Earlier Work: Attempts to prepare a thermally unmasked
acyl anion equivalent 78
5.1 Acyl anion equivalent methodology 79
5.2 Current approaches to the preparation of acyl anion equivalents 82
5.2.1 Use of metallated enol ethers 85
5.2.2 Other α,β-unsaturated acyl anion equivalents 89
5.3 Uses of 4H-1,3-Dioxins in synthesis 90
5.4 Applications of Meldrum’s Acid to facilitate lactone formation 92
5.5 Cyclic ketones as a potential route to metallated dioxins 94
5.5.1 Dioxene chemistry 96
5.6 Unsaturated cyclic acetal formation 98
5.6.1 Lactone formation from furanones 99
5.6.2 Attempted preparation of an acyl anion equivalent from
commercially available 2,2,6-trimethyl-1,3-dioxin-4-one 100
5.6.3 Preparation of Dioxinones to test Dioxin Formation
Methodology 102
5.7 Conclusions and possible avenues for future investigation 105
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Chapter 6: Experimental 106
6.1 General procedures 107
6.1.1. Experimental for chapter 2 108
6.1.2. Experimental for chapter 3 111
6.1.3 Experimental for chapter 4 145
6.1.4 Experimental for chapter 5 159

Appendix A: 172
X-ray data for cis-6-cyclohexyl-4-vinyl-1,2,3-oxathiazinane 2,2-dioxide (217)

Appendix B: 180
X-ray data for (4S,5R)-5-methyl-4-vinyl-1,2,3-oxathiazinane 2,2-dioxide (300)

Appendix C: Published Paper 185
Gold(I)-catalysed synthesis of cyclic sulfamidates by intramolecular allene
hydroamination, Chem. Comm., 2012, 48, 7565.

References 189

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4. Abbreviations

d NMR chemical shift
n wavenumber
Å Angstrøm
Ac acetyl
aq. aqueous
atm. atmosphere
Bn benzyl
Boc tert-butyloxycarbonyl
b.p. boiling point
br. broad
cat. catalyst
cm-1 wavenumbers
d doublet
DCM dichloromethane
d.e. diastereomeric excess
°C degrees Celsius
DEPT distortionless enhancement by polarisation transfer
DMA dimethylacetamide
DMAP 4-(dimethylamino)pyridine
DMDO dimethyldioxirane
DMF N,N dimethylformamide
DMSO dimethylsulfoxide
E electrophile
ee enantiomeric excess
eq. equivalents
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ESI electrospray ionisation
eV electronvolt
FTIR Fourier transform infra-red
GC gas chromatography
lit. literature
HRMS high resolution mass spectrometry
IR infra-red
J NMR coupling constant
LDA lithium diisopropylamide
M molar (mol/litre)
m multiplet
Mbs p-methoxybenzenesulfonyl
m-CPBA meta-chloroperoxybenzoic acid
MHz mega Hertz
min(s) minute(s)
m.p. melting point
MS molecular sieves
m/z mass/charge ratio
NBS N-bromosuccinimide
NCS N-chlorosuccinimide
NMR nuclear magnetic resonance
Nu nucleophile
o/n overnight
OTf trifluoromethanesulfonate
p para
PCC pyridiniumchlorochromate
Pd/C palladium on activated charcoal
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