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Synthesis of carba- and heterocycles based on novel one-pot cyclization of 1,1-bis(trimethylsilyloxy)ketene acetals and 1,3-bis(silyl enol ethers) [Elektronische Ressource] / vorgelegt von Ehsan Ullah

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Synthesis of Carba- and Heterocycles based on novel One-Pot Cyclizationof 1,1-Bis(trimethylsilyloxy)ketene Acetals and 1,3-Bis(Silyl Enol Ethers) I n a u g u r a l d i s s e r t a t i o n zurErlangung des akademischen Grades doctor rerum naturalium (Dr. rer. nat.) an der Mathematisch-Naturwissenschaftlichen Fakultät derErnst-Moritz-Arndt-Universität Greifswald vorgelegt von Ehsan Ullah geboren am 01-01-1977 in Rawalpindi, Pakistan Greifswald, 28-08-2006 Dekan: .................................................................................................................... 1. Gutachter : ......................................................................................................... 2. Gutachter: Tag der Promotion: ................................................................................................
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Synthesis of Carba- and Heterocycles based on novel One-Pot Cyclization
of 1,1-Bis(trimethylsilyloxy)ketene Acetals and 1,3-Bis(Silyl Enol Ethers)
I n a u g u r a l d i s s e r t a t i o n
zur
Erlangung des akademischen Grades
doctor rerum naturalium (Dr. rer. nat.)
an der Mathematisch-Naturwissenschaftlichen Fakultät
der
Ernst-Moritz-Arndt-Universität Greifswald


vorgelegt von
Ehsan Ullah
geboren am 01-01-1977
in Rawalpindi, Pakistan
Greifswald, 28-08-2006 Dekan:
....................................................................................................................
1. Gutachter : .........................................................................................................
2. Gutachter:
Tag der Promotion: ................................................................................................ “Dedicated to Mama and Papa,
my beloved brothers and sisters to whom I owe everything” Contents
Acknowledgement
Abbreviations I
Introduction II
Publication 1 III
Publication 2 IV
Publication 3 V
Publication 4 VI
Publication 5 VII
Publication 6 VIII
Publication 7 IX
Publication 8 X
Publication 9 XI
Publication 10 XII
Manuscript in preparation XIII
X-ray crystal data XIV
Curriculum Vitae XV
Declaration/Erklärung XVIAcknowledgements
Acknowledging people who in one way or the other have contributed to my life and
achievements, if there are any, is always most difficult task encountered. Writing this page is
much more difficult for me than writing the whole thesis because I don’t find any words,
infact there are no such words that can justify their contributions and encouragements.
So then let me take pride in acknowledging Prof. Dr. Peter Langer, my supervisor, for his
guidance, support, patience and encouragement. Without all these favours from him,
accomplishment of this work would have been extremely difficult.
My thanks are due to our former group fellow, Dr. Gopal Bose, who was always there
whenever I needed his help. I owe him a lot and was lucky to have such a great helping hand
next door.
This acknowledgment can’t be complete without thanking Dr. Bettina Appel and Mrs.
Schröeder whose scientific and personal help and advices will always keep me indebted to
them.
I am thankful to all my past and present lab fellows, Christian, Katrin Harder, Andreas,
Phoung, Mrs. Turski, Steffi and Dr. Essen for providing a friendly working environment.
Dr. Heim, Dr. Uwe, Simon, Dr. Anja, Dr. Van, Tuan, Gerson, Rahn, Rüdiger, Steffi, Nicole,
Jope and all others whom I have missed here do deserve equal credit.
I feel greatly indebted to my friends Zafar, Mukhtar, Sven, Sher and Dr. Shyjoumon Kutty for
their affection, love, care and permanent encouragement during rough times.
Thanks also go to the members of the technical sections (NMR, IR, MS and X-Ray etc) of
Universities of Greifswald and Rostock and Leibniz Institute for Catalysis.
My special thanks go to Zulfiqar Ahmed and Maimoon Jaffery for their help in the days of
trouble.
At last but not at least to my family for their support, encouragement and understanding. I
find no words to express their love. Thanks for all their love and support. Their contribution
in my life is far beyond from explanation. I love them all and forever. Abbreviations
Ar Aromatic
APT Attached Proton Test
nBuLi n-Butyllithium
DEPT Distortionless Enhancement by Polarisation
Trasfer
EI Electronic Ionization
ESI Electronspray Ionization
EtOAc Ethylacetate
HRMS High Resolution Mass Spectroscopy
IR Infrared Spectroscopy
LDA Lithium diisopropylamine
HMDS Hexamethyldisilazine
MS Mass Spectrometry
Ph Phenyl
Et N Triethylamine 3
NMR Nuclear Magnetic Resonance
NOESY Nuclear Overhause and Exchange SpectroscopY
Me SiOTf Trimethylsilyl trifluoro methanesulfonate 3
Me SiCl Trimethylsilylchloride 3
mp. Melting point
TBAI Tetrabutyl ammonium iodide
TFA Trifluoroacetic acid
THF Tetrahedrofuran
TLC Thin Layer Chromatography
TMS Trimethylsilane
UV Ultraviolet Spectroscopy
EXSY EXchange SpectroscopY
HMBC Heteronuclear Multiple Quantum Coherence
HSQC Heteronuclear Single Quantum Coherence
Oct Octyl
Pent Pentyl
Bu Butyl
MTO Methyltrioxorhenium
IINTRODUCTION
IIOne-Pot Cyclization Reactions of 1,1-Bis(trimethylsilyloxy)ketene acetals
1,1-Bis(trimethylsilyloxy)ketene acetals represent useful synthetic building blocks which can
be regarded as masked carboxylic acid dianions. In recent years, a number of cyclization
reactions of 1,1-bis(trimethylsilyloxy)ketene acetals have been reported.
The palladium(0) catalysed reaction of 1,1-bis(trimethylsilyloxy)ketene acetals, such as 1,
with allyl acetates, such as 2, has been reported to give -unsaturated carboxylic acids which
were transformed into 5-(hydroxymethyl)- -lactones (e. g. 3) by addition of H O in the 2 2
1presence of catalytic amounts of methyltrioxorhenium (MTO) (Scheme 1).
Ph
Ph
OSiMe
Ph
3 i Ph
+
Ph
OH
OAc
OSiMe
O
3 ii
O
Ph
1 2 3 (65%)
Scheme 1. Synthesis of 3: i, 1 (1.1 equiv.), 2 (1.0 equiv.), THF, Pd(PPh ) (0.02 equiv., 2%), 3 4
24 , reflux; ii, MTO (5%), 30% H O (1.1 equiv.), 72 h 2 2
O
CO H
2
OMe
O
OSiMe
3
H
Hi, ii, iii
+
+
OSiMe
3
MeO
Cr(CO)
3
O
1a 4 5 (41%) 6 (23%)
Scheme 2. Synthesis of 5, 6: i, 1a (1.5 equiv.), 4 (1.0 equiv.), THF, -78 °C, t-BuOK (1M)
in THF, HMPA (6 mL), 1.5 h stirring; ii, I (5.0 equiv.) in THF, 20 °C; iii, H O2 2
3-Hydroxymaleic anhydrides, such as 8, have been prepared by cyclization of 1,1-
5bis(trimethylsilyloxy)ketene acetals with oxalyl chloride (7) (Scheme 3).
1
::JJOSiMe
3
O
Ph
OSiMe
3
Ph
i1b O
O Cl
ii
HO
O
+
Cl O 8 (70%)
7
_
Me SiCl
3
Me SiOTf
3
OSiMe
_
3
_
Me SiOTf
Me SiCl
3
3
Ph
O
Cl
O
_ +
O
OTf
SiMe
3
A
Scheme 3. Synthesis of 8: i, 1b (1.0 equiv.), CH Cl , 78 °C, 7 (1.3 equiv.), Me SiOTf2 2 3
(0.5equiv.); ii, 78 20 °C, 12 h, then 20 °C, 3 h
OSiMe
3
HO O
OSiMe
ii
3
O
i1c
O
+
O OSiMe
3
O
9 10 (47%) 11 (72%)
Scheme 4. Synthesis of 11: i, 1c (1.0 equiv.), 9 (1.0 equiv.), Me SiOTf (0.5 equiv.), CH Cl , –3 2 2
78 20 °C, 12 h, 20 °, 3 h, 2) H O; ii, TFA, CH Cl , 20 °C, 72 h 2 2 2
The MeSiOTf mediated reaction of 1,1-bis(trimethylsilyloxy)ketene acetals with 3-3
6
silyloxyalk-2-en-1-ones, such as 9, afforded 5-ketoacids, such as 10. Treatment of the latter
6with TFA in CH Cl afforded pyran-2-ones, such as 11 (Scheme 4).2 2
2
:oVery recently, Rudler et al. have reported the two-step cyclocondensation of silyl ketene
7
acetals, such as 1d, with pyridinium salt 12 to give open-chained products (13). The latter
were transformed into bicyclic products, such as 14, by treatment with mCPBA (Scheme 5).
O
OH
OSiMe
3
i
+
OSiMe
3
N
N
CO Me
2
(70%)1d 12 13
ii
O
HO O
N
CO Me
2
14 (75%)
Scheme 5. Synthesis of hydroxylactone 14. i, 1d (1.4 equiv.), 12 (1.0 equiv.), CH Cl ,2 2
ClCO Me (2.0 equiv.), 2 h; ii, 13 (1.0 equiv.), MCPBA (1.4 equiv.), 2 h, NaOH, H O.2 2
The iodolactonization of the open-chained products again resulted in the formation of bicyclic
7
products, such as 15 (Scheme 6).
3

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