novel iron-pybisulidine catalysts for the selective aerobic oxidation and co/cc cleavage of organic

482 Pages·2014·20.82 MB·English

NOVEL IRON-PYBISULIDINE CATALYSTS FOR THE
SELECTIVE AEROBIC OXIDATION AND C-O/C-C
CLEAVAGE OF ORGANIC SUBSTRATES
Thesis submitted in accordance with the requirements of
the University of Liverpool for the degree of Doctor in
Philosophy
by
Angela Gonzalez de Castro
January 2014
“Do not go where the path may lead;
Go instead where there is no path and leave a trail”
(Anonymous)

“Logic will take you from A to B;
Imagination will take you everywhere”
(Albert Einstein)
ACKNOWLEDGEMENTS

I would like to take this opportunity to express my gratitude to all the people that have
contributed to make this Thesis possible. Firstly, I would like to show my gratitude to my
supervisor Prof Jianliang Xiao for giving me the opportunity to join his research group as a
Ph D student. I would like to thank Jianliang for all his help and supervision during my 4
years in his group. His encouragement and passion for chemistry have been an angular
support and source of motivation throughout my Ph D. I also want to thank all the freedom I
have received from him for the exploration of a completely new area of research in his group
and his encouragement to follow my own thinking and instinct in investigating and
interpreting interesting results.
I will like to thank Dr Craig Robertson for his help and valuable lessons in X-ray diffraction
experiment and analyses. He has shown great enthusiasm in the project and provided high-
quality X ray diffraction analyses at lightning speed. My thanks also go to Dr. John Bacsa
who provided X-ray analyses for compounds shown in Chapter 2 and taught me a lot about
X ray techniques. Thanks also go to Dr Konstantin Luzyanin and Dr Jon Iggo for his
suggestions and discussions in NMR experiments and for his help with the NMR facilities of
the department. I will like to show gratitude to the Analytical staff of the Chemistry
department and the members of the MS service of the University of Swansea for all the
analytical data they have provided and their help.
Many thanks go to the past and present members of the Xiao group, who have helped me
during my time in Liverpool. I am particularly grateful to Dinesh, whose advice and
suggestions have contributed to improve the chemistry presented in this thesis and who gave
me a hand in synthesising some of the isochromans shown in Chapter 5. I also want to thank
him for his help in many aspects of my life, for his unconditional friendship and for our four
hours long debates in Bold St. cafes. I would like to thank Weijun for his support and
friendship and all the questions he has helped me answering. I really miss our debates about
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Chemistry, food and life. My thanks go to Jianjun and Steven for their support, enthusiasm
and participation in our daily discussions. I would like to thank the ladies of the Xiao group:
Zhijun, Jen and Barbara who have contributed to make my time in this group more
enjoyable. I additionally want to thank Noemi, Antonio, Ed, John Li, Xiaofeng, Yi, Felix,
Ory, Sergio, Maria, Carlos and Susanna for their help and friendship through all these years.
Many thanks go to my “scouse” family: Marta, Ben, Gita, Naser, Natalia, Alejandro,
Angela, Paula, Rocio and Barbara-Gisela. You have truly made me feel at home and you are
the best friends anyone could ask for. A special mention goes to the “gastro-club” meetings
in the Kazimier Garden on Thursdays which have made my time in Liverpool truly
enjoyable. I also want to thank my friends from Spain, especially Nuria, Rafa, Marta C.,
Agueda, Maria T. and Martita among others for their support and love no matter the distance
between us.
Finally, I will like to thank everyone who has helped me to get where I am now. My thanks
go to Prof. Jose M. Gonzalez from the University of Oviedo for his valuable lessons in
Organic Chemistry and for sparking my interest in research and Organic Chemistry. I will
also want to thank Dr. Maria Jesus Gonzalez Castanon and Prof. Alfredo Sanz Medel for
their lessons in Analytical Chemistry. I want to express my gratitude to Dr. Juan Felix
Espinosa and Dr. Paloma Vidal from Lilly Laboratories in Alcobendas for all their help and
lessons in advance NMR spectroscopy and in chemical research in general. Finally, I would
like to give my deepest thanks to my ever-loving parents and sister for their huge emotional
and economical support. You have always had a strong faith in my capabilities and have
helped me in very difficult moments. You have shown me unconditional support in
everything I do and provided great advice and guidance. Such support has been my biggest
source of inspiration for making possible the chemistry that is presented in this Thesis and
therefore, it is to you I dedicate this Thesis.

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ABSTRACT

The selective oxidation of organic compounds is one of the most attractive transformations
for both, industry and academia. Industrial interest stems from the potential application of
such oxidation methodologies in the economic, greener synthesis of valuable products,
whereas academic research is challenged by the difficulties in achieving specific, direct
functionalisation of the “inert” CH bonds in complex molecules. In this Ph. D. thesis, our
contribution to the selective oxidation of organic substrates using a novel class of iron
catalysts is presented.
A general introduction covering the major challenges in the area of iron-catalysed selective
oxidation of organic compounds is described in Chapter 1. Chapter 2 covers the design,
synthesis and coordination properties of the novel PyBisulidine type ligands, which we have
conceived for their potential use in selective oxidation, attempting to overcome some of the
limitations of current methods.
The efficiency of such PyBisulidine ligands is demonstrated in Chapter 3, where iron-
PyBisulidine complexes are used for catalysing the aerobic α-oxidation of functionalised
ethers. High catalytic efficiency, very good mass balance and excellent functional group
tolerance were achieved with these catalysts under mild conditions. Such advantages stem
from an unconventional reaction mechanism, involving the dehydrogenative oxygenation of
the ether substrate to give a peroxobisether, followed by the cleavage of the peroxy bond to
form two ester molecules. Unlike metalloenzymes and biomimetic iron complexes, H is
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released as the sole byproduct during the catalytic cycle. The oxidation mechanism is
discussed in Chapter 4.
Like natural dioxygenases, iron-PyBisulidine catalysts were found capable of promoting the
aerobic cleavage of aliphatic C-C and C-O bonds. Even though biomimetic complexes are
often seen as simplified models to study enzymatic processes, a more synthetic perspective
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of the selective aerobic cleavage of ethereal C-C and C-O bonds is described in Chapter
5.The great potential of such cleavages in organic synthesis is well exemplified in the iron-
PyBisulidine catalysed direct conversion of natural isochromans into biologically active
isochromanones with excellent selectivity.
The ability of the iron-PyBisulidine complexes in catalysing aerobic C-C cleavages is
further expanded in Chapter 6, where the oxidative cleavage of olefinic C=C bonds to
carbonyl compounds is demonstrated. The catalytic reactions proceeded efficiently, showing
a broad scope and a mechanism that involves the formation of dioxetane intermediates is
postulated. Chapter 7 is an extension of Chapter 6, in which iron-PyBisulidine complexes
were found to catalyse α-methylstyrene linear dimerisation under an inert atmosphere.
Moreover, control in the regioselectivity of the double bond in the dimers can be achieved
by modifications in the PyBisulidine ligands.
Final conclusions and a perspective of the research covered in this Ph.D. thesis are provided
in Chapter 8.

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ABBREVIATIONS

α alpha
δ chemical shift
Å amstrong
AcOEt ethyl acetate
AcOH acetic acid
Ar aryl
atm atmosphere
°C Celsius degree
13C carbon 13
CI chemical ionisation
circa approximately
DCM dichloromethane
DCE 1,2-dichloroethane
FAB fast atom bombardment
EI ionisation potential
equiv. equivalent
ESI electrospray ionisation
V
Et O diethyl ether
2
g gram(s)
GC gas chromatography
h hour
1H proton
H molecular hydrogen
2
HRMS high resolution mass spectroscopy
HOMO highest occupied molecular orbital
Hz hertz
i.e. id est (that is to say)
IR infrared spectrometry
J coupling constant value
LUMO lowest occupied molecular orbital
MeCN acetonitrile
MEMCl 2-methoxyethoxymethyl chloride
mg milligram(s)
min minute(s)
mL millilitre
mmol milimole(s)
VI
MS mass spectrometry
NEt triethylamine
3
NMR nuclear magnetic resonance
O molecular oxygen
2
Ph-H benzene
Ph-Me toluene
ppm parts per million
rsm recovered starting material
r.t. room temperature
S/C substrate to catalyst ratio
THF tetrahydrofuran
THP tetrahydropyran
TMS tetramethylsilane
TON turnover number
t retention time
R
vide infra see below
vide supra see above
vs versus

VII
CONTENTS
ACKNOWLEDGEMENTS…………………………………………………………. I

ABSTRACT…………………………………………………………………………... III

ABBREVIATIONS…………………………………………………………………... V

CONTENTS…………………………………………………………………………... VIII

CHAPTER 1: INTRODUCTION…………………………………………………… 1
1.1. Iron: metal of the past, metal for the future……………………………………... 2
1.2. Iron catalysed selective oxidation of organic compounds………………………. 5
1.3. Major challenges in iron-catalysed selective oxidations………………………… 8
1.3.1. Alternatives to tetradentate ligands………………………………………... 8
1.3.2. Use of molecular oxygen as oxidant………………………………………. 11
1.3.3. Electron-rich substrates: aerobic oxidation of ethers……………………… 24
1.3.4. Aerobic C-C cleavage of organic substrates……………………………… 32
1.4. Aims of the thesis………………………………………………………………. 44
1.5. References………………………………………………………………………. 46

CHAPTER 2: DESIGN, SYNTHESIS AND PROPERTIES OF NOVEL
PYBISULIDINE TYPE LIGANDS…………………………………………………. 53
2.1. Introduction……………………………………………………………………… 54
2.1.1. Ligand design in homogeneous iron catalysis…………………………….. 54
2.1.2. PyBox ligands: successes and challenges…………………………………. 56
2.2. Aims of the chapter……………………………………………………………… 58
2.3. Results and discussion…………………………………………………………... 58
2.3.1. Pentacoordianted designs………………………………………………….. 58
2.3.2. Tridentate ligands………………………………………………………….. 62
2.3.2.1. Design and synthesis of PyBisulidines……………………………... 62
2.3.2.2. Coordiantion properties of PyBisulidines………………………….. 64
2.3.2.3. Ligand library………………………………………………………. 68
2.3.2.3.1. Sulfonamide substitution…………………………………………. 68
2.3.2.3.2. Amino substitution……………………………………………….. 70
2.3.2.3.3. Pyridine substitution……………………………………………… 74
2.3.2.3.4. Bidentate designs………………………………………………… 76
2.3.2.3.5. Asymmetric versions…………………………………………….. 78
2.4. Conclusions……………………………………………………………………… 79
2.5. Experimental section……………………………………………………………. 80
2.6. References………………………………………………………………………. 97

CHAPTER 3: DISCOVERY, OPTIMISATION AND SCOPE OF THE
Fe(OTf) -PYBISULIDINE CATALYSED AEROBIC α-OXIDATION OF
2
ETHERS…………………………………………………………………………….. 100
3.1. Introduction……………………………………………………………………… 101
3.1.1. Organic esters……………………………………………………………… 101
3.1.2. Methods for ester syntheses………………………………………………. 104
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