NEW ASPECTS OF ACID-CATALYSED CYCLISATIONS ABDUL HADI ALDMAIRI A Thesis ...

309 Pages·2015·16.08 MB·German

NEW ASPECTS OF ACID-CATALYSED

CYCLISATIONS

ABDUL HADI ALDMAIRI

A Thesis Submitted for the
Degree of Doctor of Philosophy

At
Cardiff University

2014
Declaration
This work has not previously been accepted in substance for any degree and is not being
concurrently submitted for candidature for any degree.

Signed ………………………………………………… (Abdul Hadi Admairi)
Date……………………………………………………

STATEMENT 1
This thesis is the result of my own investigations, except where otherwise stated. Other sources
are acknowledged by footnotes giving explicit references. A bibliography is appended.

Signed ………………………………………………… (Abdul Hadi Admairi)
Date……………………………………………………

STATEMENT 2
I hereby give consent for my thesis, if accepted, to be available for photocopying and for inter-
library loan, and for the title and summary to be made available to outside organisations.

Signed ………………………………………………… (Abdul Hadi Admairi)
Date……………………………………………………

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Abstract
This thesis describes the use of both sulfuric acid and triflic acid, to promote
hydroamination and hydroalkoxylation cyclisations for the formation of N- and O-
heterocycles.
Chapter 2 describes the synthesis of 2,2,6-trisubstetuted piperidine. A wide range of
protecting groups has been employed in the cyclisation. A new, general and flexible
method for the highly enantioselective synthesis of chiral piperidine and spiro-
piperidine has been developed. The main advantages of this synthetic method lie in
the readily availability of the precursors. There is no reason why this reaction cannot
find further application in natural product synthesis.
Chapter 3 describes a miscellany of cascade and transannular cyclizations.
The hydroamination has also been used to form the sterically crowded bridged
isoquinuclidines through a transannular cyclisation, which would have rearranged to
the less hindered products.
We have also applied acid-catalyzed intramolecular cascade methodology to the
synthesis of polycyclic hydroquinolines.
Oxygen-centered transannular cyclisation has been compared with nitrogen-based
examples, by acid-catalyzed hydroalkoxylation cyclisation to give only the sterically
crowded bridged cineoles.
Chapter 4 describes a new discovery of a novel N-to-O transfer reaction.
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Acknowledgements

I would like to thank ‘my Boss’ Professor David W Knight for his great support and
wisdom throughout my studies at Cardiff University. I have ever never seen like his
beautiful mind.

I would like to thank Damascaus University for financial support.

I would also like to thank my wonderful lab friends Dr. Jessica Hatherley, Dr. Andy
Smith, Dr. Ian King, Dr. Laura Henderson and Piotr Rutkowski.

I must also acknowledge all the analytical and technical staff especially Dr Rob
Jenkins, Robin, Dave, Gaz and Jamie for their hard work and help. Thanks to Dr.
Kariuk for the X-ray crystal structures.

I would also like to say a BIG thank you to my wife FATMA and my son ZIAD for
their love and support throughout my life.

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Table of Contents
DECLARATION......................................................................................................................... ii
ABSTRACT.................................................................................................................................iii
ACKNOWLEDGEMENTS........................................................................................................iv
TABLE OF CONTENT............................................................................................................. v
ABBREVIATIONS AND ACRONYMS................................................................................ vii
CHAPTER 1: GENERAL INTRODUCTION..........................................................................1
Introduction…………….......................................................................................................1
Carbon-nitrogen bond synthesis...........................................................................................6
Intermolecular acid-catalyzed hydroamination of alkenes..................................................11
Intramolecular acid-catalyzed hydroamination of alkenes… .……………………………14
Acid-catalysed hydroamination reactions in the Knight group … .……………………16
Conclusion…………………………………………………………………………..……..22
References ……………………………………………………………………….………...23
CHAPTER 2: Acid-catalysed synthesis of piperidines . ……………................ …. 26
Piperdine synthesis .............................................................................................................26
How to make hindered piperidines .............................................................................. …..34
Spiro-piperidine................................................... ……………………………… …..64
Asymmetric synthesis of 2,2,6-trimethylpiperidine ................................................... …..66
Conclusion..........................................................................................................................70
References ………………… ………………………………………………….………..71
CHAPTER 3: Acid-catalyzed cyclisations in synthesis . .............................................. … 76
Introduction …………......................................................................................................76
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Cascade cyclisations..........................................................................................................76
Transannular cyclisations.................................................................................................87
Cyclisations of highly methylated cyclopentenyl carbamates and sulphonamides … …99
Acid-catalysed Hydroalkoxylation Cyclisations……………… .……………………..105
Conclusion.......................................................................................................................109
References …………………………………………………………...……..….…… 110
CHAPTER 4: A Novel N-to-O Rearrangement ................................... ........................... 113
CHAPTER 5: EXPERIMENTAL....................................................................................... 154
General experimental details......................................................................................... 154
General Procedures...........................................................................................................156
APPENDICES ................................................................................................................ 278
Appendix 1: 1-Toluenesulfonyl-2,2,6-trimethylpiperidine 237 ……………….………….. 279
Appendix 2: 2,2-Dimethyl-1-tosylpiperidine 250 ………………………………….…….. 281
Appendix 3: 1-(4-Nitrophenylsulfonyl)-2,2,6-trimethyl piperidine 261 ………………….. 283
Appendix 4: 1,3-Dimethyl-2-tosyl-2-azabicyclo[2.2.2]octane 420……………………….. 285
Appendix 5: 4,7-Dimethyl-6-((4-nitrophenyl)sulfonyl)-6-azabicyclo[3.2.1]octane 424…….287
Appendix 6: 1-Methyl-2-tosyl-2-azabicyclo[2.2.2]octane 430………………………...….. 289
Appendix 7: 4-Iodo-6-tosyl-6-azabicyclo[3.2.1]octane 436………………….. ……………291
Appendix 8: Methyl (1-methyl-2-oxabicyclo[2.2.2]octan-4-yl)methyl)carbamate 597……..293

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Abbreviations and acronyms
Ac acetyl
app. apparent
aq. aqueous
Ar aromatic
Bn benzyl
b.p. boiling point
br broad
Bu butyl
COSY correlation spectroscopy
CI chemical ionisation
d doublet
DCM dichloromethane
dd double doublet
dt double triplet
DEPT Distortionless Enhancement by Polarization Transfer
DMF dimethylformamide
DMSO dimethylsulfoxide
e.e. enantiomeric excess
EI electron ionisation
eq. equivalent(s)
ES electrospray
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ether diethyl ether
Et ethyl
∆ heat
h hour(s)
HRMS high resolution mass spectrometry
Hz hertz
IR infra-red
J coupling constant
m multiplet
M molar
Me methyl
MHz megahertz
 mol micromole(s)
ml millilitre(s)
mmol millimole(s)
m.p. melting point
MS mass spectrometry
Ms methane sulfonyl
NMR nuclear magnetic resonance
NOSEY nuclear Overhauser enhancement spectroscopy
Ns or nosyl p-nitrobenzenesulphonyl
o ortho
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p. page
p para
Ph phenyl
q quartet
r.t. room temperature
s singlet
t triplet
td triple doublet
THF tetrahydrofuran
TfOH/triflic acid trifluoromethanesulfonic acid
TLC thin layer chromatography
Ts toluenesulfonyl
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Chapter 1

Introduction