A novel approach to 4-functionalized imidazolidin-2-ones, {α-hydroxyhydroxamic [alpha-hydroxyhydroxamic] acids and {α-hydroxyamidoximes [alpha-hydroxyamidoximes] [Elektronische Ressource] / by Khalid Widyan
166 Pages
English
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A novel approach to 4-functionalized imidazolidin-2-ones, {α-hydroxyhydroxamic [alpha-hydroxyhydroxamic] acids and {α-hydroxyamidoximes [alpha-hydroxyamidoximes] [Elektronische Ressource] / by Khalid Widyan

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166 Pages
English

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Published 01 January 2005
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University of Hamburg
Faculty of Chemistry




A Novel Approach to 4-Functionalized Imidazolidin-
2-ones, α-Ηydroxyhydroxamic Acids and
α-Hydroxyamidoximes


Dissertation submitted in partial satisfaction of the requirements for the
degree Doctor of Philosophy in pharmaceutical chemistry



by

Khalid Widyan
from
Al-Kharaj-Jordan


Committee in charge:
Prof. Detlef Geffken
Dr. Thomas Kurz
Prof. Wittko Francke




Hamburg 2005






























Referees: Prof. Dr. D. Geffken
Prof. Dr. H.-J. Duchstein


Defense of doctoral thesis: 23.05.2005

















To My Parents


















Acknowledgements


First Of all, All praise and thanks be to Allah, God the Almighty, most
beneficent and most merciful.

This work was carried out at the Institute of Pharmacy, Department of
Chemistry, University of Hamburg, during the years 2002-2005.

Looking back over two years of doing research, I find it difficult to capture
the influence that the experience has had on me in a few words. The duration
of my studies here contained both instances of despondency as well as
moment of great personal triumph. I find myself both sad that my stay here
has finished and relieved that it is finally over.

Many people have contributed to my education. I consider myself
exceedingly fortunate to have had Prof. D. Geffken and Dr. T. Kurz thesis
advisors. Their enthusiasm for chemistry is both genuine and contagious.
The perspective and approach they bring towards research have had a deep
and beneficial influence on me.

I would like to thank Prof. J. Kopf for his valuable help in the preparation of
the X-ray crystal structure.

Sincere thanks are also due to Prof. Dr. P. Heisig and Ms. Tatjana Claussen
for providing all the required facilities for carrying out the tests for
antibacterial activity.

I wish to express my gratitude to Prof. Dr. H.-J. Duchstein for his excellent
editorial revision of my thesis.

Many thanks are also due to Prof. Dr. W. Francke for having chaired the
examination committee.

I am deeply indebted to Ms. Katrin Schlüter for being willing to help, for
keeping my social life alive in the lab and for her careful reading of my
manuscript and revising the language of my thesis.

Special thanks to Dr. W. Thimann for his valuable help during the
preparation of the manuscript and for revising the language of my thesis.

My warmest thanks go to Mr. Mehdi Khankischpur for his help in writting
the summary in German.

The encouragement of the whole pharmaceutical chemistry group in the
department, students as well as faculty members, was greatly beneficial for
keeping me in touch with the lighter aspects of life, particularly when the
work was getting serious.

Finally I wish to thank my family. My brothers and sisters were always
heartening and encouraging. Most of all, I am grateful to my parents who
introduced me to science, taught me the value of hard work, and gave me
endless support along the way.




Hamburg, April 2005 Khalid Widyan












Papers Discussed:

This dissertation is based on the following publications:

I: Kurz, Thomas; Geffken, Detlef; Widyan, Khalid. Synthesis and reactivity
of 3-aralkoxy-4-imino-imidazolidin-2-ones: a novel class of 4-imino-
hydantoins. Tetrahedron (2004), 60 (10), 2409-2416.

II: Kurz, Thomas; Widyan, Khalid. A convenient synthesis of 3-amino-4-
imino(thioxo)-imidazolidin-2-ones. Tetrahedron Letters (2004), 45 (38),
7049-7051.

III: Kurz, Thomas; Widyan, Khalid. O-Protected 3-hydroxyoxazolidin-2,4-
diones: novel precursors in the synthesis of α-hydroxyhydroxamic acids.
Organic and Biomolecular Chemistry (2004), 2 (14), 2023-2027.

IV: Kurz, Thomas; Widyan, Khalid. Efficient conversion of O-substituted 3-
hydroxy-4-imino-oxazolidin-2-ones into O-substituted α-hydroxy-
amidoximes. Organic Letters (2004), 6 (24), 4403-4405.

V: Widyan, Khalid; Kurz, Thomas; Synthesis of novel 4-functionalised
oxazolidin-2-ones. Synthesis, accepted.

Offprints were made available with permission from the publisher.













Standard Abbreviations and Acronyms

aq aqueous
Ar aryl
aromat aromatic
Bn benzyl
br broad (spectral)
t-Bu tert-butyl
Bz benzoyl (not benzyl)
°C degrees Celsius
calcd. calculated
-1cm wavenumber(s)
∆ reflux
δ chemical shift in parts per million downfield from
tetramethylsilane
d day(s); doublet (spectral)
DCC N,N′-dicyclohexylcarbodiimide
2-DCP di-2-pyridyl carbonate
DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
CDCl chloroform-deuterated 3
CDI 1,1‘-carbonyldiimidazole
CDT 1,1‘-carbonyldi-(1,2,4-triazole)
CH Cl dichloromethane 2 2
DMSO-d dimethylsulfoxide-deuterated 6
e.g for example (latin: exempli gratia)
equiv equivalent(s)
EtN triethylamine 3
EtO diethyl ether 2
EtOAc ethyl acetate
EtOH ethanol
FAB fast atom bombardment
g gram(s)
h hour(s)
HCl hydrochloric acid
HOBT hydroxybenzotriazole
Hz hertz
ie that is (latin: id est)
IR infrared
J coupling constant (in NMR spectrometry)
K CO potassium carbonate 2 3
L liter(s)
lit. literature (abbreviation used with period)
m meta
m multiplet (spectral)
+M parent molecular ion
Me methyl
MeOH methanol
MgSO magnesium sulfate 4
min minute(s)
mmol millimole(s)
mp melting point
MS mass spectrometry
MW molecular weight
m/z mass-to-charge ratio
NaOMe sodium methoxide
NMR nuclear magnetic resonance
p para
Ph phenyl
ppm part(s) per million
i-Pr isopropyl
q quartet (spectral)
rt room temperature
s singlet (spectral); second(s)
t triplet (spectral)
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin-layer chromatography
TMS trimethylsilyl; tetramethylsilane
TMSBr bromotrimethylsilane
TMSCN trimethylsilylcyanide 9
Table of contents

Chapter 1
Synthesis of Novel 4-Functionalized Imidazolidin-2-ones: Dimroth
Rearrangement of an Intermediate

1 Introduction...........................................................................................13
1.1 Preface...................................................................................................................13
1.2 Methods of hydantoin synthesis ............................................................................ 14
1.2.1 Synthesis of 3-unsubstituted hydantoins ....................................................... 14
1.2.2 3-substituted hydantoins ........................................................... 15
1.3 Synthetic plan........................................................................................................16
2 Synthesis.................................................................................................18
2.1 Synthesis of diethylphosphonoalkyl α-aminonitriles ............................................ 18
2.2 4-functionalized imidazolidin-2-ones ............................................... 19
2.2.1 Synthesis of 3-alkoxy(aralkoxy)-4-imino-imidazolidin-2-ones and
4-alkoxy(aralkoxy)imino-im.......................................................... 19
2.2.2 3-phenylethoxy-imidazolidin-2,4-dione .................................. 27
2.2.3 Synthesis of 3-phenylethoxy-4-thioxo-imidazolidin-2-one ..........................27
2.2.4 Synthesis of 3-aralkoxy-4-substituted imino-imidazolidin-2-ones .............. 28
2.3 3-amino-4-imino-imidazolidin-2-ones.............................................. 29
2.4 Synthesis of phosphonic acids............................................................................... 34
3 Biological Studies ..................................................................................36
4 Conclusions............................................................................................37
5 Experimental Part.................................................................................38
6 References..............................................................................................68

Chapter 2
Efficient Conversion of α-Hydroxynitriles into O-Substituted
α-Hydroxyhydroxamic Acids and O-Substituted α-Hydroxyamidoximes

7 Introduction...........................................................................................71
7.1 Preface...................................................................................................................71
7.2 Methods of synthesis of O-substituted α-hydroxy-hydroxamic acids................... 74
7.3 Methods of synthesis of α-hydroxyamidoximes ................................................... 75
7.3.1 Synthesis of O-unsubstituted α-hydroxyamidoximes ................................... 75
7.3.2 O-substituted αidoximes ....................................... 75
7.4 Synthetic plan........................................................................................................76
8 Synthesis.................................................................................................78
8.1 Synthesis of cyanohydrins ..................................................................................... 78
8.2 functionalized oxazolidin-2-ones...................................................... 78
8.2.1 Synthesis of O-substituted 3-hydroxy-4-imino-oxazolidin-2-ones ............... 78
8.2.2 O-substituted 3-hydroxy-oxazolidin-2,4-diones ....................... 81
8.3 Synthesis of α-hydroxyhydroxamic acids ............................................................. 82
8.3.1 Synthesis ofα-hydroxyhydroxamic acids............................... 82
8.3.2 O-unsubstituted αic acids........................... 85
8.4 Synthesis of α-hydroxyamidoximes...................................................................... 86 10
8.4.1 Synthesis of O-substituted α-hydroxyamidoximes........................................86
8.4.2 3-hydroxy-4-imino-oxazolidin-2-ones .....................................88
8.4.3 O-unsubstituted α-hydroxyamidoximes....................................88
8.5 Towards the synthesis of α-hydroxythiohydroxamic acids and N,O-substituted α-
hydroxyamidoximes.......................................................................................................89
8.5.1 Synthesis of substituted 3-hydroxy-4-thioxo-oxazolidin-2-ones ...................90
8.5.2 4-substituted imino-oxazolidin-2-ones .....................................92
8.5.3 substituted 4-hydroxyimino-oxazolidin-2-ones.........................93
9 Biological Studies...................................................................................95
10 Conclusions ............................................................................................95
11 Experimental part .................................................................................96
12 References...........................................................................................141
13 Summary.............................................................................................145
14 Zusammenfassung.............................................................................. 153