Download towards the synthesis of functionalised macrocyclic receptors

TOWARDS THE SYNTHESIS OF
FUNCTIONALISED
MACROCYCLIC RECEPTORS
A dissertation submitted to the University of Manchester for the degree of
Master of Science by Research
in the Faculty of Engineering and Physical Sciences
2012
IMAN RAJABI
SCHOOL OF CHEMISTRY
1
Table of Contents
Abstract.................................................................................................. 4
Declaration ............................................................................................ 5
Copyright statement ............................................................................. 5
Acknowledgements ............................................................................... 6
List abbreviations ................................................................................. 7
INTRODUCTION ................................................................................ 8
1
Introduction.................................................................................... 9
1.1
Supramolecular chemistry ......................................................... 9
1.1.1
Host-Guest Chemistry ........................................................................................................... 9
1.2
Macrocycles ............................................................................... 10
1.2.1
Crown Ethers ...................................................................................................................... 12
1.2.1.1
Synthesis of crown ether .................................................................................................. 14
1.3
Mixed-donor Macrocycles ....................................................... 15
1.3.1
Templating Effects .............................................................................................................. 17
1.3.2
The Caesium Effect ............................................................................................................. 19
1.4
Macrocycles as Catalysts.......................................................... 20
1.4.1
Application of crown ethers (single/mixed donor) .............................................................. 24
1.4.1.1
Miscellaneous applications of crown ethers in synthesis ................................................. 25
2
Results and Discussion ................................................................ 28
2.1
Pyridine-based Macrocycles .................................................... 28
2.1.1
Introduction......................................................................................................................... 28
2.1.2
Aims and Objectives ............................................................................................................ 31
2.2
Discussion of Results................................................................. 32
2.2.1
Preparation of Bromo-ditosylate ........................................................................................ 33
2.2.1.1
Esterification of chelidamic acid ...................................................................................... 36
2.2.1.2
Preparation of bromide 78 ................................................................................................ 36
2.2.1.3
Reduction of bromo-diester ............................................................................................. 38
2.2.2
Preparation of macrocycle 82 ............................................................................................. 40
2
2.2.2.1
Attempted synthesis of macrocycles using different spacers ............................................ 41
2.2.3
Oxidation of Macrocycle ..................................................................................................... 42
2.2.4
Oxidation of bromo-ditosylate 81 and the synthesis of a crown-N-oxide ............................. 43
2.2.4
Attempted Pd-Coupling reaction......................................................................................... 45
3.
Conclusion ................................................................................... 45
3.1 Future Work................................................................................ 46
EXPERIMETAL................................................................................. 47
4
Experimental ................................................................................ 48
4.1
General Experimental .............................................................. 48
4.2
Cross-linkers ............................................................................. 49
4.3
Macrocycles ............................................................................... 56
4.4 Unsuccessful attempts at the synthesis of three further
macrocycles.......................................................................................... 58
5. References ....................................................................................... 61
Appendix .............................................................................................. 63
3
Abstract
A practical route to the synthesis of two new macrocyclic thio-crown ethers, 13bromo-3,6,9-trithia-15-azabicyclo[9.3.1]pentadeca-1(15),11,13-triene, 82, and 13bromo-3,6,9-trithia-15-azabicyclo[9.3.1]pentadeca-1(15),11,13-triene-15-oxide,
84, is described. Both macrocycles were fully characterised using elemental
analysis, 1H NMR, 13C NMR, and mass spectroscopy. The solid-state structure of
82 was also determined using X-ray crystallography. During these investigations it
was shown that Cs+ can be replaced by K+ as an effective template in the pivotal
macrocyclisation reaction.
An
operationally
simple
route
to
the
synthesis
of
4-bromo-2,6-
bis((tosyloxy)methyl)pyridine 81, the key intermediate to both macrocycles,
starting from chelidamic acid 75 has also been developed which will facilitate the
synthesis of other macrocycles using this scaffold. The attempted functionalisation
of 82 using a Heck reaction is described.
4
Declaration
No portion of the work referred to in the dissertation has been submitted in support
of an application for another degree or qualification of this or any other university
or other institute of learning.
Copyright statement
i. The author of this dissertation (including any appendices and/or schedules to
this dissertation) owns any copyright in it (the “Copyright”) and s/he has given The
University of Manchester the right to use such Copyright for any administrative,
promotional, educational and/or teaching purposes.
ii. Copies of this dissertation, either in full or in extracts, may be made only in
accordance with the regulations of the John Rylands University Library of
Manchester. Details of these regulations may be obtained from the Librarian. This
page must form part of any such copies made.
iii. The ownership of any patents, designs, trade marks and any and all other
intellectual property rights except for the Copyright (the “Intellectual Property
Rights”) and any reproductions of copyright works, for example graphs and tables
(“Reproductions”), which may be described in this dissertation, may not be owned
by the author and may be owned by third parties. Such Intellectual Property Rights
and Reproductions cannot and must not be made available for use without the prior
written permission of the owner(s) of the relevant Intellectual Property Rights
and/or Reproductions.
iv. Further information on the conditions under which disclosure, publication and
exploitation of this dissertation, the Copyright and any Intellectual Property Rights
and/or Reproductions described in it may take place is available from the Head of
School of Chemistry.
5
Acknowledgements
I’ll like to take this opportunity to express my appreciation to the people who have
been influential in successful completion of this project.
I would like to show my gratitude to my supervisor and mentor, Dr. Peter Quayle
for giving me the opportunity to be part of the Quayle group and for his endless
support and valuable advice through out the past year. It was a pleasure to learn
from him and to work in his group.
I would like to thank every single member of the Quayle group for their help and
assistance. Especially, Omer Rasheed, Mark Little and Andreas Economou.
My appreciation also goes to all technical and administrative staff from the
Chemistry Department.
Last but not least, I would also like to thank my dear parents, brothers and lovely
fiancée for encouraging me to study harder and supporting me through out.
6
List abbreviations
br.s
Broad singlet
mCPBA
3-Chloroperoxybenzoic acid
d
doublet
DCM
Dichloromethane
DMAP
4-(Dimethylamino)pyridine
DMF
N,N-Dimethylformamide
EtOAc
Ethyl acetate
HPLC
High pressure liquid chromatography
HRMS
High resolution mass spectrometry
IR
Infrared spectroscopy
m
multiplet
MeOH
Methanol
MS
Mass spectrometry
NMR
Nuclear magnetic resonance
NRO
Nucleophilic ring opening
q
quartet
quin.
quintet
RuAAC
Ruthenium mediated azide-alkyne cyclisation
s
singlet
t
triplet
TBAB
Tetrabutylammonium bromide
TEA
Triethylamine
THF
Tetrahydrofuran
TLC
Thin layer chromatography
TsCl
Tosyl chloride
7
INTRODUCTION
8
1
Introduction
1.1
Supramolecular chemistry
Jean-Marie Lehn described supramolecular chemistry as an interdisciplinary field
of science covering the chemical, physical and biological features of highly
complex chemical species involving two or more molecules held together by noncovalent interactions.1 Therefore, two factors which are important in determining
the use of this chemistry are the nature of the molecular components and types of
interactions which hold them together. These interactions include; Van der Waals
forces, hydrogen bonding, metal ion coordination, electrostatic, - interactions
and hydrophobic forces.2 Non-covalent interactions play a key role in a lot of
biological processes, such as protein folding and substrate binding by enzymes or
receptors.3
Supramolecular chemistry impinges on numerous, cognate, areas of research
although those which are most germane to this discussion are host-guest chemistry
and self-assembly.
1.1.1
Host-Guest Chemistry
Host-guest chemistry is related to complexes that are made up of two or more
molecules or ions held together by interactions other that full covalent bonds. To
form a complex, the host compound identifies and incorporates the guest into the
molecules. In this case the guest can be a specific molecule, atom or ions. 4-7
Different types of interactions are involved in formation of these complexes. They
includes; hydrogen bonding, hydrophobic interactions, ion-dipole, , and ionion. According to Cram the host compound is a molecule or ion whose binding
sites converge in the complex and the guest compound is any molecule or ion
whose binding sites diverge in the complex.5
9
Figure 1-1. Examples of two typical host-guest complexes.
One classic example of host-guest chemistry is enzyme-substrate interaction. The
chemical reaction starts with the binding of the substrate to the active site on the
enzyme which is specific to that substrate. In 1894, Emil Fischer postulated the
lock and key analogy for the active site and enzyme. In this analogy the lock is the
enzyme (host) and the key is the substrate (guest).6
Figure 1-2. Lock and key analogy
1.2
Macrocycles
The synthesis of the first macrocycle dates back to mid 1930s were the synthesis of
1,4,8,11-tetraazacyclotetradecane was reported.8 However, in early 1960s the field
began to develop through the work of Busch and Curtis.9 The first macrocycles
were synthesised to copy biologically occurring macrocycles such as chlorins,
corrins and corphins. By the late 1960s another area of macrocyclic synthesis was
developed. This time the initial idea was towards modelling biological processes
such as ion transport.10
10
Petersons’ oxygen-based crown ethers and the mixed oxygen-nitrogen bicyclic
cryptands of Lehn were among the first10,11 synthetic macrocycles to exhibit high
selectivity towards alkali and alkaline earth metal ions.
The macrocyclic ring structure allows the host molecule to achieve a degree of
structural pre-organisation.12 This enables key functional groups to interact with a
host within the binding sites thereby minimising entropic loss. Overall these
properties can result in certain macrocycles having both a high binding affinity as
well as high selectivity for specific guest species.13 Macrocycles are not rigid
molecules: they can reorganise in a way to hold their structural pre-organisation
and at the same time have adequate flexibility to stitch to a target surface and
increase binding interactions. This can result in high affinity and selectivity for
targets, while keeping enough bioavailability to reach intracellular locations.12-13
Despite all these benefits, applications as drug candidates stemming from the
pharmaceutical and drug discovery sectors have been somewhat limited, although
there are specific exceptions as illustrated below (Figure 1-3).
11
1.2.1
Crown Ethers
In 1967 Pederson reported the synthesis of crown ethers and commented upon their
ability to selectively complex metal cations.14-15 Since these seminal reports many
crown ethers have been synthesised and their binding to metal cations has been
studied in detail. A crown ether has been defined as a compound with multiple
oxygen atoms incorporated in a monocyclic backbone and the name “crown”
derives from the actual cavity shape of the macrocycle, which in many cases
adopts the topology of a crown.17 Representative examples of crown ether are
shown below (Figure 1-4).
Due to the oxygen lone pairs in the structure, the cavity of the crown ether is
electron rich. This is where the cation binds.
The electric potential surface is a measure
of charge distribution. Red indicates regions
of negative charge, green shows the neutral
area, blue shows the region of positive
charge. We can see from the image that the
positive charge is distributed over a very
large area and that the centre of the crown
ether is negatively charged.
[Image from: http://www.chem.ucla.edu/harding/crownethers.html]
12
In order for a given ligand set embedded within a crown ether to bind effectively to
its “guest”, the cavity size of the crown ether is very important. For example,
Bordunov et al. revealed in 1996 that when the 5-chloro-8-hydroxyquinoline
(CHQ) group was attached to the ring via position 7 (9), it was selective for Mg2+
compared to other alkali and alkaline earth metals. On the other hand if the CHQ
was attached via 2 position (8), it became selective for K+ over other alkaline
metals and Ba2+ over other metal ions.18
The study of crown ethers and its definition has expanded dramatically over the
years following the synthesis of other macrocycle compounds containing nitrogen
(aza-crown ether) and sulphur (thiacrown ether). The interest in the synthesis of
aza-crown compounds is continuing to grow. Their complexation properties lie
between those with all oxygen atoms in which they complex alkali and alkaline
earth metal and those crown with all nitrogen atoms in which complexes heavy
metal cations. Therefore, these mixed properties make aza-crown ethers very
interesting for researchers. Examples of both crowns are shown (Figure 1-5).
13
According to Pederson, crown ethers can exhibit excellent binding strength and
selectivity towards alkali and alkaline earth metals.14 These properties make crown
ethers an excellent synthetic compound to mimic many of the naturally occurring
cyclic antibiotics. Alkaline and alkaline earth metals are an important part of
biological system and crown ethers are important ligands in the study of chemistry
of these metal ions. Crown ethers are used in areas such as biological mimics,
reaction catalysts, sensors, recovery/removal of specific species and separations.19
Reports have shown that derivatives of crown ethers have potential in anti-tumour
agent.
1.2.1.1
Synthesis of crown ether
The Williamson ether synthesis is commonly used in the synthesis of macrocyclic
polyethers. This classic reaction involves the SN2 displacement of an alkyl halide
with an alkoxide anion21 when a diol and dihalide are reacted together in presence
of a base. Recently it was reported that the halide leaving group could be replaced
by a much more reactive tosylate or mesylate leaving group.20 Generally in these
reactions, sodium hydride or potassium tert-butoxide is used as a base together
with a strongly co-ordinating dipolar, aprotic, solvent such as DMF or THF, which
facilitates the SN2 reaction mechanism.
14
The synthesis of macrocycle 16 typifies the general strategies used for the
synthesis of cyclic polyethers. In this case, monoprotection of hydroquinione 12
afforded 13 which could then be capped with a di-tosylate 14 affording ether 15.
Catalytic hydrogenolysis of 15 unmasked the corresponding bis-phenol which was
again reacted with a di-tosylate 14 in the presence of sodium hydride as base
resulting in the isolation of the crown ether 16 in 31% yield.23
1.3
Mixed-donor Macrocycles
The synthesis and properties of mixed-donor macrocycles has attracted a lot of
attention in recent years. These types of compounds could be suitable for a wide
range of applications, from molecular recognition to chromatographic separation of
metal cations.
Previously, the importance of crown ethers and their ability to bind alkali and
alkaline earth metal ions was reviewed and discussed. However, one factor which
needs to be mentioned is their limited ability to bind transition metal ions.
Transition metal ions such as iron, copper and zinc are vital for everyday life. On
the other hand, some transition metal ions such as cadmium and mercury are toxic.
It’s known that transition metal ions play a role in some neurological diseases such
as Alzheimer’s diseases. Therefore, the ability of these mixed donor macrocycles
to complex transition metal ions and selectively detect and possibly remove such
ions could be useful in various areas and widespread potential uses in water
treatment, environmental monitoring, animal and human health.22-24
The synthesis of mixed-donor macrocycles has broadened the chemistry of crown
ethers. One advantage of mixed-donor macrocycles over the single-donor
macrocycles lies in their ability to offer the coordination of both hard sigma-donor
N-ligands and soft sigma-donor and possibly -acceptor S-ligands.22 In 1969,
Busch24 reported that thioether-based ligands could coordinate metals and since
then different complexes was synthesised by Danks and Lindoy in 1998 and 2010
respectively.54,55
15
Much research has been conducted with a view to establishing the factors which
determine the strength of metal-ligand interactions and also the geometry of the
complexes which result from such interactions. In 1997, Bradshaw et al.26 reported
that 1,10-dithia-18-crown-6 formed higher affinity complexes with Hg2+ and Ag2+
compared to 18-crown-6. However, the results were vice versa for alkali metal
cations.
Vögtle et al. first reported the use of crown-type polyethers as transport mimics.
These workers were able to prepare a number of crown ethers in order to replicate
ion transport across membranes present in biological systems.27
In 1976, E. Weber and F. Vögtle28 reported the synthesis of new cyclic neutral
ligands of different ring sizes and of new heteroatom sequences.
The synthesis of macrocycles 19 and 20, which proceeded in moderate yields when
conducted under high dilution conditions, employed KOH in ethanol as base in
order to promote the cyclisation over polymerisation reactions. Curiously benzene
was also employed as a co-solvent in such reactions. Interestingly, attempted
synthesis of macrocycle 21 resulted in an unexpected ring contraction to afford the
macrocycle 19 (Scheme 1-2).
16
1.3.1
Templating Effects
When it comes to the synthesis of macrocylic molecules it’s important for chemists
to choose the appropriate methods to obtain the desired structure. Synthesis of
macrocyclic compounds involves reactions of multifunctional monomers. If the
correct conditions are not chosen, there is the possibility of competition between
macrocyclisation and polymerisation. In the example below (scheme 1-3),
triethylamine or KOH is used as a base. This would either afford the crown ether
26 or the polymeric compound 27. The presence of K+ ion in pathway A is the
difference in the two pathways. The K+ ion allows the reactant to arrange itself into
a cycle like intermediate 24 that is pre-organised to form the crown ether. The
potassium ion is therefore considered as the template for the reaction and this is
known as the template effect.22-29
17
Notably, when this reaction is performed in the absence of a potassium counter ion
derived from the base, cyclisation does not occur. Frequently therefore
polymerisation is the result of such reactions when organic bases such Et3N are
used in these cyclisation reactions. The base selection is therefore very important
for synthesis of crown ethers.
It was originally documented that potassium ions have a templating effect which
enables cyclisation to proceed in favour of polymerisation. Subsequently many
studies have shown that a range of cationic species (such as alkali and alkaline
earth metal, transition metals and lanthanides) can also act as templating agents.
Such an effect was reported by the Bailey group who observed that the presence of
the Cs+ ion was pivotal to the synthesis macrocycle 30.
18
1.3.2
The Caesium Effect
In the last two decades the use of caesium salts in many synthetic conversions has
received a lot of interest. Caesium is used in variety of organic synthesis. For
example, palladium catalysed coupling reactions like Suzuki coupling or the
Buchwald amination.30 It’s also been used in more straightforward nucleophilic
substitution reactions.
The use of caesium salts in macrocyclisation reactions has been shown to have a
positive effect on cyclisation. In the mid 1980s, Kellogg31 carried out a
macrocyclisation reaction forming a C-O bond using a variety of carbonate salts
(Figure 1-6). It was found that use of a caesium ion was superior to other alkali
metal counterparts with respect to yields. Since then, a lot of research has been
done into the full extent of this principle. Furthermore, use of caesium ions was
found to have an effect on reaction time and most such conversions proceed under
mild conditions. Caesium bases have shown to control chemo-selectivity and have
been shown to be compatible with a wide range of functional groups. The
improved reactivity has been defined as the ‘caesium effect’. The exact cause of
the caesium effect is still not known.
Different types of caesium reagents have been used in macrocyclisation reactions.32
Due to the low solubility of caesium fluoride, it’s less desirable for cyclisation in
comparison to caesium carbonate or the hydroxide analogue. Between the two,
caesium carbonate is preferred over caesium hydroxide, because it’s less
hydroscopic and therefore easier to handle.
19
1.4
Macrocycles as Catalysts
During 2001 the Bailey group began to investigate the possibility of creating a new
type of enantioselective catalyst or enzyme mimic.22-33 The group’s initial studies
began with the development of a general strategy for the synthesis of novel
peptide-derived macrocycles. The macrocyclic pyridine derivative 33 was
identified as an initial target, because the macrocyclic ring substituent might be
used to alter the chemistry of the pyridine nitrogen. It was important structurally to
position the source of asymmetry within the compound close to the pyridine
nitrogen, but leaving enough space for chemical reactions to take place at the
pyridine nitrogen. Alpha-amino acids were therefore used as a source of this
chirality. These macrocycles are all C2-symmetric. Ensuring similar chiral
environment of both side of the macrocycle, regardless of the direction of approach
taken by incoming species e.g. nucleophile (Figure 1-7).
Recently, Sethi reported the potential binding of macrocyclic compounds with
organic guests such as glycine amide, acetyl L-alanine, L-alanine amide and acetyl
glycine. One example is the triethylene glycol-base macrocycle 36. The results
indicated that binding of such organic guests to the host are entropically driven.
The most stable binding was acetyl L-alanine and the least stable with L-alanine34
(Scheme 1-6).
20
Chiral crown ether macrocycles have been identified as potential “nucleophilic
asymmetric catalysts”, in that they comply with requirements delineated by Fu et
al. where the presence of an electron rich donor group and steric hindrance are
required for high selectivity in reactions catalysed in this manner.
In order to validate the use of nucleophilic catalysis in epoxide ring-opening
reactions, Bailey synthesised the pyridine N-oxide macrocycle 41. Reaction of 37
with SiCl4 afforded 2-chloro-2-phenylethanol 39 in high yields, and in preference
to 40.
In order to confirm that the epoxide ring-opening was facilitated by the presence of
41, a number of control reactions were carried out as it was thought that the byproduct HCl could also ring open the epoxide. In these blank reactions it was
observed that, in the absence of 41, ring opening of 37 was wholly none-selective
and afforded an equimolar mixture of 39 and 40. The optical purity of the product
39 produced in this reaction has yet to be established (Scheme 1-7).
In 2011, Veitía’s group35 synthesised two series of chiral azapyridinomacrocycles,
containing a pyridine N-oxide as a key structural feature and alpha-amino acid
were used as a readily available source of this chirality (Figure 1-8).
21
In this study, azapyridinomacrocycles were used as organocatalysts in the
asymmetric allylation of p-nitrobenzaldehyde 46 with allyltrichlorosilane 47
(Scheme 1-8).
The 12-membered ring azapyridinomacrocycle N-oxides PyCyN-OX[12]N4 (42)
and (43) were tested first and the results were negative. Only 48% of conversion
rate and 12% of ee were reported. No major differences were observed between the
two functionalised 12-membered macrocycles and only slight improvements in
conversion rate were seen when DCM or THF were used as solvent respectively.
Next, the 15-membered macrocycle PyCyN-OX[15]N5 (44) and (45) was used as
possibly better catalysts. The results reported (Table 1-1) shows good improvement
in reaction rate and asymmetric conversion.
22
Table 1-1: Allylation of p-nitrobenzaldehyde with allyltrichlorosilane catalyzed by
15-membered azapyridinomacrocycles N-oxides
Entry
Catalyst
No Temp/ °C Time/h Yield (%)
ee (%)
confiq
1
36a
20
72
28
10
(S)-(-)
2
36b
20
72
48
2
(R)-(-)
3
36b
0
72
27
3
(R)-(-)
4
36c
20
48
60
5
(R)-(-)
5
36c
0
48
42
6
(R)-(-)
6
37a
20
24
83
13
(S)-(-)
7
37a
0
24
72
8
(S)-(-)
8
37a
-38
24
58
14
(S)-(-)
9
37a
-38
24
43
40
(S)-(-)
10[e]
37a
-38
24
65
5
(S)-(-)
23
1.4.1
Application of crown ethers (single/mixed donor)
As discovered previously, crown compounds are used in many field e.g. extraction.
However, their application in organic synthesis has shown great progress. Crown
ethers are capable to make inorganic alkali metals and salts soluble even in nonpolar solvents. Crown ethers are therefore used as catalysts by chemists.
Sharghi et al. looked into using different types of crown ethers as catalysts in the
ring opening of epoxides (Scheme 1-9). The reaction was carried out under mild
conditions using 0.01 mol% of catalyst (49a-c). The catalysts 49a-c were
synthesised by the Sharghi group. They have also carried out these experiments
with available crown ethers (50-52), in order to compare the differences.36
The outcome of the reaction was positive and gave over 90% regioselectivity. For
reactions in which the modified catalysts (49a-c) were used, the reaction times
ranged from 25-90 minutes, resulting in 90% yield for 49a and 55% yield for 49c
respectfully. Use of the other modified catalysts was not much success.
Furthermore, for the crown ether 50-52 reaction times ranged from 60 – 90 minutes
and yields varying from 55 – 70%. The catalyst 49a was found to be the most
effective in this reaction. Therefore, further epoxide ring opening reactions were
carried out and regioselective thiocyanate products were obtained with over 75%
yield for ten different epoxides.
24
1.4.1.1
Miscellaneous applications of crown ethers in synthesis
Crown ethers have found application in the promotion of Michael addition
reactions under the conditions of phase transfer catalysis. The advantages of using
crown ethers in this particular reaction are high yields and more importantly high
stereoselectivity37 (Scheme 1-10).
Potassium permanganate is a strong oxidising agent. Its ionic character makes it
insoluble or partially insoluble in organic solvents. Therefore, a solubilising agent
is required. In the presence of crown ethers the reaction can be performed in nonpolar organic solvents38 (Scheme 1-11).
Using crown ethers as phase transfer catalysts in condensation reactions, it was
observed that the reaction rates were increased by 102~105 times.39
25
Reduction of 4-methyl-cyclohexane can result in formation of both isomers. The
use of crown ethers in this reaction however resulted in much higher yields and
better selectivity towards the trans-isomer40 (Scheme 1-13).
26
RESULTS AND DISCUSSION
27
2
2.1
Results and Discussion
Pyridine-based Macrocycles
2.1.1
Introduction
Previous work carried out in the Quayle group has focused on the synthesis of
novel macrocyclic receptors which have potential application in asymmetric
synthesis and in the interrogation of molecular recognition phenomena. In
particular, the synthesis of chiral macromolecules such as 66 and 72 has recently
been accomplished with a view to invocating their application as nucleophilic
catalysts. The synthesis of macrocycles 66 and 72 is shown below (schemes 2-1
and 2-2).
28
In a related area, recent work within the Quayle group has also been directed
toward the synthesis of molecular sensors for the detection and determination of
metabolites or specific metal ions in biological systems. Here we wish to develop
a modular approach to the
synthesis
of
receptor
molecules which can sense
the presence of, for example,
heavy
metals
in
various
organs within the body.
In
this approach we wish to
attach a “recognition/transport
domain”
to
a
“reporter”
domain such that interaction
of a metal ion with the
receptor can be reported to an observer.
In practice our “first generation sensors” are to be derived from azo-dyes which
are to be attached to a macrocycle (recognition domain) which are also decorated
with carbohydrates as the “carrier” domain.
29
Scheme 2-3: Possible route to the synthesis of complex 76
Validation of this design concept is now in progress, where we have shown that
macrocyclic species can be attached to suitable spacers via “click” chemistry
(Scheme 2-4).
Scheme 2-4: CuSO4.5H2O, sodium ascorbate, EtOH /H2O (3:1), rt, 12 hrs, 19 %.51
More recently we have also shown that azo-dyes can also be attached, again using
“click chemistry” to macrocyclic “recognition” domains, as exemplified in Scheme
2-5
30
Scheme 2-5: CuSO4.5H2O, sodium ascorbate, THF /H2O (3:1), 50 °C, 12 hrs, 57 %.51
The next phase of this programme of research requires that the sensing domain
(e.g. an azo-dye) be attached, with direct electronic interaction, to the recognition
domain, such that complexation of the macrocycle to a metal ion results in a
change in the chromophore of the dye.
2.1.2
Aims and Objectives
In the current project we wished to establish:

whether a viable route to functionalised pyridine-containing macrocycles such
as 84 could be developed, and

that macrocycles such as 84 and 104 could be conjugated with functionalised
azo-dyes using Heck, Stille or related cross-coupling reactions.
31
Scheme 2-6: Planned route to functionalized azo-dyes.
We reasoned that the target pyridine-containing macrocycle 84 could itself be
prepared from the diol 89, which itself should be accessible from chelidonic acid
87 (Scheme 2-8). Although the preparation of 86 from chelidonic acid is reported
in the literature, previous work within the group indicated that this seemingly
simple set of transformations was, in reality problematic, hence providing the
impetus for the present study.
Scheme 2-7: Proposed route to macrocycle 84
2.2
Discussion of Results
During this programme of research we developed an effective method for synthesis
of the ditosylate 91, which proved to be a useful surrogate for the tri-bromide 86 in
subsequent alkylation reactions leading to the desired macrocycle 84 (Scheme 2-8).
32
Overall Scheme of synthesis of macrocycle 84
Scheme 2-8: a) Na, MeOH, diethyl oxalate, acetone. b) 37% aqueous ammonia, 48h, rt. c) SOCl 2,
MeOH, rt, 24h. d) TBAB, P 2O5, toluene, 4h, 110 °C. e) NaBH4, EtOH, 24h, 80 °C. f) TsCl, CH2Cl2,
KOH, 0 °C, 1h. g) 2,2-thiodiethanethiol, KOH, toluene/EtOH. h) 37% HBr/AcOH, rt. 2h.
2.2.1
Preparation of bromo-ditosylate 90
To prepare macrocycles, it’s important to have a very useful building block to start
with. One of those useful starting materials is 4-bromo-2,6-pyridinedimethyl
ditosylate 90. Since the bromo-ditosylate 90 is a very useful building block, a
general method for its preparation is important. To start its synthesis, we begin
with the preparation of chelidonic acid 87.
Chelidonic acid 87 was prepared by addition of dry acetone and diethyl oxalate to
sodium ethoxide solution (Scheme 2-9). After addition, the reaction was refluxed
and HCl/water was added. Crude chelidonic acid was produced in 42% yield.
Unfortunately when the crude product from this reaction was recrystallised (from
water) the overall yield was much reduced, affording only a 10-15% yield of
purified material. Given the relatively low yield of this reaction, initial
investigations focussed upon the optimisation of this classic, aldol- cyclisation
33
process. As the crude compound was fairly clean, it was decided to carry on to the
next stage with the crude compound.
A number of workers have reported the synthesis of chelidonic acid 87 using very
similar methods but the one factor which was different was the timing of acetone
addition. We have tried to add the acetone after the addition of diethyl oxalate to
the sodium ethoxide solution. This approach didn’t go very well, resulting in a very
low yield. The next factor which was looked at was the solvents. In order for the
reaction to work, it was important to use dry and fresh solvents. Both solvents were
dried using molecular sieves. The reaction was run using dry solvents prepared 48
hours prior to the experiment and good improvements were seen in terms of yield.
Another reaction was run using solvents dried 24h prior to the experiment and the
results showed further improvements in yield. One further reaction was carried out
using solvents dried 12-15 hours prior to the experiment. Again further
improvement in yield was seen and 42% yield was the highest which was achieved.
It is clearly evident in this reaction that the quality of the dry solvents had a major
impact on yield (Scheme 2-9).
Scheme 2-9: Synthesis of chelidonic acid 87
Once obtained in a pure state chelidonic acid 87 was efficiently converted into
chelidamic acid 91 merely by reaction with concentrated aqueous ammonia for 2
days, resulting in the isolation of the pure product in 70% yield (Scheme 2-10).
Scheme 2-10: Synthesis of chelidamic acid 91
34
The synthesis of dimethyl chelidamate 92 was first achieved by refluxing
chelidamic acid 91 with thionyl chloride overnight then adding MeOH. This
method gave very poor yields42. Therefore, an alternative method reported by
Pellegatti41 was investigated. Thionyl chloride was reacted with methanol at low
temperature and then chelidamic acid was added and the reaction was refluxed
overnight resulting in dimethyl chelidamate 92 in near quantitative yield (Scheme
2-11).
After much experimentation we discovered that diester 92 was best converted to
bromo-diester 88 using P2O5 in the presence of TBAB in 64% isolated yield
(Scheme 2-11). This reagent combination proved to be far superior to other, more
common used reagents such as phosphorus pentabromide53, which generally
afforded complex reaction mixtures and involved more complex work-up and
purification procedures. In the next step, the bromo-diester was reduced to bromodiol 89 using sodium borohydride in ethanol46 as solvent.
Scheme 2-11: Route to the synthesis of diol 89 from chelidamic acid 91
On occasion this reaction could also prove to be problematic, as removal of boronresidues could be difficult to achieve (Soxhlet extraction can be used to remove the
impurity). Recrystalisation of the crude product of this reduction reaction from
water afforded diol 89 in a high state of purity, in reproducible yields of ca. 74%.
35
2.2.1.1
Esterification of chelidamic acid
Scheme 2-12: Mechanism of esterification
Chelidamate ester 92 was synthesised in near quantitative yield and the formation
of the ester confirmed by 1H NMR.
Figure 2-1: 1H NMR of chelidamate ester 92 in MeOD
2.2.1.2
Preparation of bromide 88
Conversion of chelidamate methyl ester into the 4-bromopyridine derivative 88 is
usually carried out under harsh conditions using PBr3, PBr5 or POBr353. Use such
of reagents does, however have drawbacks such as handling of hazardous reagents,
36
production of hydrogen bromide and reaction-temperature control. Therefore, a
more useful method was used using P2O5 and tetrabuylammonium bromide
(TBAB).
For bromination of chelidamate ester, the P2O5 will form the leaving moiety and
tetrabutylammonium bromide as a source of bromide ion. Chelidamate ester 92
was reacted with excess of TBAB in hot toluene for 4 hours in presence of P 2O5.
After workup, bromo-ester was afforded in 76% yield. This operationally simple
reaction could be carried out on a multi-gram scale, thereby facilitating
Figure 2-2: 1H NMR of bromo-diester in CDCl3
37
2.2.1.3
Reduction of bromo-diester
Scheme 2-13: Mechanism of reduction
The bromo-diester 88 was reduced to bromo-diol 89 using sodium borohydride.
This approved reaction is favoured over other methods, because it can be run under
mild conditions. Sodium borohydride is easier to use and handle compared to the
powerful reducing agent lithium aluminium hydride.
The reduction of the diester is proceeding slowly at first. After that the mothoxy
leaving
group
reacts
with
sodium
borohydride
to
form
sodium
methoxyborohydride. The sodium methoxyborohydride is a much stronger
reducing agent, therefore forcing the completion of the reduction.
38
Given that the Quayle group had, in the recent past, used the dibromoether 65 in
the
synthesis
the
macrocycle
66,
the
synthesis
of
4-bromo-2,6-
bis(bromomethyl)pyridine 86 was next attempted. In the parent system, this
transformation can be accomplished by heating the diol 89 in 37% HBr-acetic acid.
Unfortunately, in our hands repeating this reaction on the bromo-diol 89 merely
afforded a mixture of products, consisting of the dibromide and starting material,
which could not be driven over to the desired tri-bromide 86. Therefore,
conversion of the diol 89 into the tosylate 90 was attempted, as it was considered
that ditosylate of this compound would also act as a suitable alkylating agent in the
macrocyclisation reactions.46,47 Tosylation of the diol 89 using tosyl chloride in the
presence of KOH as base, afforded the desired di-tosylate 90, a crystalline solid, in
reproducibly good yields (ca. 70%) on a multigram scale (Scheme 2-14).
Scheme 2-14: Synthesis of ditosylate 90
Figure 2-3: 1H NMR of ditosylate 90 in CDCl3
39
2.2.2
Preparation of macrocycle 84
The synthesis of the novel macrocycle 84 was accomplished using a modification
of the procedure reported earlier by Weber and Vögtle28. Reaction of bromoditosylate 90 with commercially available 2,2-thioethanethiol 93 using KOH as
base in an ethanol-toluene solvent system cleanly led to the formation of the
desired thia-crown 84 in 48% yield as an off-white coloured crystalline solid.
The structure of the crown 84 was
confirmed spectroscopically and
also by way of a single crystal Xray analysis (Figure 2-4). The Xray structure of 84 revealed that, in
common with many thio-crowns
which possess [–S-CH2-CH2-S-]n
units, that the S-C-C-S torsion
angles are all close to 180° (see
Appendix), in order to maximise
lone pair-lone pair repulsion.
Figure 2-4: Crystal structure of crown ether 84
Scheme 2-15: Synthesis of macrocycle 84
40
Figure 2-5: 1H NMR of macrocycle 84 in CDCl3
2.2.2.1
Attempted synthesis of macrocycles using different spacers
Cyclisation of three different macrocycles was attempted with various thiol spacers
using KOH and ethanol. However, 1H NMR spectrum revealed no reaction was
taken place (scheme 2-15, 2-16 and 2-17).
Scheme 2-16: Synthesis of macrocycle 96 and 97
41
Scheme 2-17: Attempted synthesis of macrocycle 99
2.2.3
Oxidation of Macrocycle
Bailey group’s previous experience on macrocycle derivatives leads them to
investigate the use of 4-dimethylaminopyridine (DMAP) derivatives (e.g. 100) in
acyl-transfer catalysis instead of the unfunctionalised pyridine ring. It was found,
due to the presence of the 4-dimethylamino group, the ring becomes susceptible to
intramolecular cleavage. This may be caused by the attack of the nitrogen lone pair
at the ester carbonyl.
In 2001, Fu and his co-workers experimented in oxidising the pyridine to form the
electron rich N-oxide. This could act as a ligation site.
Recently, the Quayle group carried out the oxidation of the macrocycle using
mCPBA in DCM at room temperature for 48 hours.
42
Scheme 2-18: Synthesis of macrocycle 102
2.2.4
Oxidation of bromo-ditosylate 90 and the synthesis of a crown-N-oxide
It was decided within the group to convert the di-tosylate 90 into the N-oxide 103
first, then taking it forward to form the macrocyclic N-oxide 104 as oppose to
oxidising the macrocycle itself.
Oxidation of di-tosylate 90
was cleanly
accomplished using m-CPBA in methylene chloride at room temperature for 48
hours, affording the N-oxide 103 in 64% yield after recrystallisation from
methylenechloride–petrol (Scheme2-19).
Scheme 2-19: Synthesis of macrocyclic N-oxide 104
43
Figure 2-6: 1H NMR of N-oxide 103
Conversion of di-tosylate 90 to the N-oxide 103 was accompanied by characteristic
changes in its 1H NMR spectrum. The signal for the H-2 moved downfield from
7.37 ppm to 7.60 ppm after oxidation, the 4-proton signal shifted downfield from
4.95 ppm to 5.18 ppm, the 3,7 and 4, 6-proton signals both doublets shifted
downfield by 0.12 ppm and the 9-proton signal have has also shifted downfield
from 2.38 ppm to 2.48 ppm. Mass spectrometry also confirmed the synthesis of the
N-oxide 72 (m/z [M+H]+ = 542).
Comparing the 1H NMR spectrum of macrocycle 84 to the 1H NMR spectrum of
macrocyclic N-oxide 104, few changes were observed. The signal for the 1-proton
shifted downfield from 7.49 ppm (84) to 7.57 ppm (104) after oxidation, the 2proton signal shifted downfield from 3.79 ppm to 4.00 ppm, and the 3-proton
signals also shifted downfield from 2.52 ppm to 2.75 ppm. Mass spectrometry also
confirmed the synthesis of the macrocyclic N-oxide 104 (m/z [M+Na]+ = 374).
44
2.2.4
Attempted Pd-Coupling reaction
The conjugation of the functionalised macrocycle 84 with phenylacetylene 105
using Heck chemistry was also briefly examined but proved to be unsuccessful.
The reaction was carried out by reacting macrocycle 84 with phenylacetylene 105,
palladium catalyst and copper iodide under nitrogen and then adding Pri2NH
followed by THF. It is not clear why this reaction failed – this may possibly be due
to the presence of the thioether moities which are able to deactivate, in some
manner, the palladium catalyst. This aspect of the project will be the subject of
future research.
Scheme 2-20: Synthesis of macrocycle 106
3.
Conclusion
In conclusion, a practical route to the synthesis of bromo-ditosylate 90 and N-oxide
103 was developed from chelidonic acid 87. Both cross-linkers were taken forward
to produce macrocyle 84 and macrocyclic N-oxide 104 successfully in respectable
yields. Attempts were made to synthesis macrocycles 96, 97 and 102 by applying
the same method, but all three reactions failed. This may suggest that the use of a
tosylate leaving group in these reactions is not optimal: in situ conversion of the
tosylate to the bis-halide (Finkelstein reaction) should provide a solution to this
impasse.
45
3.1 Future Work
Future work will necessarily concentrate upon the development of a coupling
procedure which will enable conjugation of the functionalised crown ethers such as
84 with suitable dyes or fluorescing agents. Once this has been achieved ligand
binding studies with various metals ions (e.g. Cu2+, Zn2+) will be investigated in
order to generate proof of principle that co-ordination of the receptor to the host
results in a change in the UV/fluorescence spectrum of the complex.
It is
envisaged that a library of complexes, e.g. based upon structures such as 107 can
be prepared using this modular approach in order to develop a sensor for specific
metal ions in biological systems.
46
EXPERIMENTAL
47
4
4.1
Experimental
General Experimental
All reactions were carried out in clean and dry glassware under nitrogen
atmosphere, unless stated otherwise. Acetone, EtOH, and MeOH were dried over
molecular sieves. THF was distilled from sodium wire and benzophenone. Dried
toluene was obtained from the PureSolv MD solvent Purification System. All
reaction temperatures are given in degrees Celsius (ºC), when a temperature is not
given, the reaction was therefore carried out in room temperature. All chemicals
obtained from supplier were used without further purifications, unless stated
otherwise. Petrol refers to the fraction of petroleum ether that has a boiling point
between 40 – 60 ºC.
The melting point of compounds was obtained by Sanyo Gallenkamp apparatus.
Infra red were recorded on a Genesis FTIR machine and quoted in cm-1.
Deutorated chloroform was used as a solvent to record Nuclear Magnetic
Resonance (NMR), unless stated otherwise. 1H NMR was recorded on Bruker 300
(300 MHz) and Bruker 400 (400 MHz) spectrometers. Signal splitting patterns are
described as singlet (s), doublet (d), triplet (t), quartet (q), quintet (qn), broad
singlet (br. s) or multiplet (m). Chemical shifts are shown in parts per million
(ppm). Carbon NMR spectra were recorded on a Varian INOVA unity 300
spectrometer at 75 MHz or Bruker spectrometer 125 MHz.
Micromass Trio 200 spectrometer was used to record low resolution mass spectra
and for high resolution spectra a Kratos Concept IS spectra was used.
Single crystal X-ray structure determinations were carried out by the school of
chemistry x-ray structure services using AXS SMART Apex Bruker.
Glass plates coated with Merck HF 254/366 silica gel were used for thin layer
chromatography (TLC). Flash column chromatography was carried out using silica
gel 60H (40-60 nm, 230-3-00 mesh) for Merck.
48
4.2
Cross-linkers
Synthesis of 4-Oxo-4H-pyran-2,6-dicarboxylic acid 43
A solution of sodium ethoxide was prepared by dissolving sodium (2.4 g, 0.1 mol)
in 36 mL of dry ethanol. To this mixture was added a mixture of dry acetone (4
mL, 0.05 mmol) and diethyl oxalate (14.5 g, 0.11 mol). During the addition of two
mixtures a yellow precipitate formed. The reaction was stirred for an hour at 60 °C
to complete the reaction, then 20 mL of 37% of HCl and 10 mL of water was
added and it was left to stir for one day at 50 °C. Excess ethanol was removed
under reduced pressure, and then 30 mL of water and 5 mL of HCl was added and
was left to stir at ambient temperature for a further period of 3 – 4 days. The crude
product which had been deposited was removed by filtration, washed with water
and then acetone to afford the title compound as a brown-coloured solid (11.54 g,
42%).
1
H NMR: (MeOD, 300 MHz) δ/ppm 7.01 (2H, s, ArH)
13
C NMR: (MeOD, 300 MHz) δ/ppm 119.96 (C2), 156.97 (C3), 162.44 (C4),
182.84 (C1)
IR υmax (film): 1229 (s), 1583 (m), 1633 (m), 1742 (s), 2560 (w), 3078 (w) cm-1
Melting point: 245 – 248 °C (Lit: 157 °C43)
MS (ES+): m/z [M+H]+ 185; [M+Na]+ 207
Accurate Mass: [C7H4O6-e] requires 184.0008 found 184.0021
49
Synthesis of 1,4-Dihydro-4-oxo-2,6-pyridinedicarboxylic acid 43
Aqueous ammonia (80 mL of a 35% aqueous solution) was added to chelidonic
acid (7.91 g, 42.9 mmol) dropwise at 0 °C. Upon completing the addition the
reaction mixture was stirred for two days at room temperature. Excess ammonia
was removed under reduced pressure and the solid was boiled with 80 mL of water
together with 1.6 g of charcoal for 5 minutes. The mixture was filtered and the cold
solution was acidified with 37 % aqueous HCl to about pH 1. The white crystals
were filtered off and washed with ice cold water 3 times to give 5.53 g (70%) of
the desired product.
1
H NMR: (MeOD, 300 MHz) δ/ppm 6.95 (2H, s, ArH)
13
C NMR: (MeOD, 300 MHz) δ/ppm 117.29 (C2), 145.37 (C3), 165.95 (C4),
184.44 (C1)
IR υmax (film): 1336 (s), 1392 (s), 1460 (m), 1609 (s), 1710 (m), 2498 (m), 3120
(w), 3446 (w), 3605 (m) cm-1
Meting point = 253 - 255 °C (lit: 248 °C44)
MS (ES+): m/z [M+H]+ 183; [M+Na]+ 205
Accurate Mass: [C7H6NO5-e] requires 184.0246 found 184.0241
50
Synthesis of 2,6-Pyridinedicarboxylic acid, 1,4-dihydro-4-oxo-, 2,6-dimethyl
ester 41
Thionyl chloride (22.3 mL, 306 mmol, 8 eq) was added dropwise to methanol (70
mL) cooled at -10 °C. Chelidamic acid (7 g, 38.2 mmol) was also added to the
mixture. The solution was left to stir for 24 hours at room temperature and then
heated at reflux for an additional 2 hours. The excess of thionyl chloride and the
solvent was removed under reduce pressure to give the compound 92 as a white
solid (7.85 g, 97%).
1
H NMR: (MeOD, 300 MHz) δ/ppm 3.99 (6H, s, CH3), 7.78 (2H, s, ArH)
13
C NMR: (MeOD, 300 MHz) δ/ppm 54.85 (C5), 117.74 (C2), 145.6 (C3), 161.65
(C4), 174.71 (C1)
IR υmax (film): 1187 (s), 1348 (s), 1478 (m), 1558 (s), 1724 (m), 3106 (m), 3307
(m) cm-1
Meting point = 162 - 165 °C (Lit: 169 – 170 °C45)
MS (ES+): m/z [M+H]+ 212; [M+Na]+ 234
Accurate Mass: [C9H10NO5-e] requires 212.0552 found 212.0554
51
Synthesis of 2,6-Pyridinedicarboxylic acid, 4-bromo-, 2,6-dimethyl ester 49
Phosphorus pentoxide (42.5 g, 147.2 mmol), tetrabutylammonium bromide (38.3 g,
118.9 mmol) and dry toluene (150 mL) was introduced into one flask and heated
for an hour at 80 °C. 4-hydroxy-2,6-pyridine-dicarboxylic acid dimethyl ester 92
(5.0 g, 23.7 mmol) was dissolved in toluene and added slowly to the reaction. The
mixture was left to stir for 4 hours at 110 °C. After cooling the mixture to room
temperature, the supernatant was taken aside while the remaining oily residue was
triturated with toluene for an hour. Both organic phases were poured into water
and stirred for 2 hours. Water was separated and the organic phase was dried over
Mg2SO4 and concentrated in vacuo to give 4.15 g (64%) white beige solid.
1
H NMR: (MeOD, 300 MHz) δ/ppm 4.06 (6H, s, CH3), 8.49 (2H, s, ArH)
13
C NMR: (MeOD, 300 MHz) δ/ppm 53.48 (C5), 131.3 (C2), 135.11 (C1), 149.13
(C3), 164.03 (C4)
IR υmax (film): 1146 (s), 1246 (s), 1263 (m), 1326 (s), 1442 (m), 1714 (m), 2951
(w)
3077 (w) cm-1
Meting point = 153 - 156 °C (155 – 156 °C50)
Microanalysis: Found: C, 39.07; H, 3.09; N, 5.12; Br, 29.07 %. C9H8BrNO4
requires C, 39.44; H, 2.94; N, 5.11; Br, 29.15 %.
52
Synthesis of 4-bromo-2,6-pyridinedimethanol 46
Bromo ester 88 (5.0 g, 18.2 mmol) was dropped into dry EtOH (130 mL) and the
mixture was cooled to 0 °C. To this suspension, NaBH4 (3.33 g, 88 mmol) was
added and the mixture stirred at 0 °C for a hour, at room temperature for another
hour and at reflux temperature for 1 day. Acetone (85 mL) was added and the
mixture refluxed for an extra hour. The solvent was removed in vacuo and the
waxy residue was triturated with saturated aqueous Na2CO3 solution (55 mL) and
stirred for 1 hour. The solvent was removed in vacuo and then the residue
recrystallised from water to give 2.95 g (74%) of pale white solid.
1
H NMR: (DMSO, 500 MHz) δ/ppm 4.53 (4H, s, CH2), 7.52 (2H, s, ArH)
13
C NMR: (MeOD, 75 MHz) δ/ppm 63.61 (C4), 121.04 (C2), 133.20 (C1), 163.19
(C3)
IR υmax (film): 1305 (s), 1361 (m), 1403 (s), 1566 (s), 1566 (s), 2763 (w), 3093
(w),
3344 (m) cm-1
Meting point = 152 - 156 °C (Lit: 158 – 160 °C46)
Microanalysis: Found: C, 38.39; H, 3.86; N, 6.13 %. C7H8BrNO2 requires C,
38.56; H, 3.7; N, 6.42 %.
53
Synthesis of 4-bromo-2,6-bis(tosyloxymethyl)pyridine 47
To a pre-cooled mixture of CH2Cl2 (18 mL) and KOH (8.3 g) in water (10 mL),
bromo diol 89 was added. Tosyl chloride (2.67 g, 14 mmol) was also added and the
resulting mixture was stirred vigorously for a few minutes. The resulting emulsion
was stirred at 0 °C for about an hour. The mixture was poured into water (35 mL)
and extracted with CH2Cl2 (35 mL). The organic phase was washed with brine,
dried over MgSO4 and concentrated in vacuo. The residue was recrystallised from
hexane and ethyl acetate to give bis-tosylate as white flakes in 45% yield.
1
H NMR: (CDCl3, 300 MHz) δ/ppm 2.38 (6H, s, CH3), 4.95 (4H, s, CH2), 7.27
(2H, d, J = 8 Hz, ArH), 7.37 (2H, s, ArH), 7.73 (2H, d, J = 8 Hz, ArH)
13
C NMR: (MeOD, 75 MHz) δ/ppm 21.67 (C9), 70.39 (C4), 124.50 (C2), 128.07
(C6), 130.01 (C7), 133.0 (C1), 145.39 (C5, C8), 154.91 (C3)
IR υmax (film): 1122 (s), 1172 (s), 1291 (m), 1303 (s), 1359 (m), 1367 (m), 1447
(m), 1571 (m), 1596 (w), 2950 (m) cm-1
Melting point: 107 – 110 °C (Lit: 110 – 111 °C48)
MS (ES+): m/z [M+H]+ 526; [M+Na]+ 548
Accurate Mass: C21H20BrNO6S2-e requires 525.9985 found 525.9988
Microanalysis: Found: C, 48.3; H, 4.05; N, 2.94; Br, 15.49; S, 11.35 %.
C21H20BrNO6S2 requires C, 47.91; H, 3.83; N, 2.66; Br, 15.18; S, 12.18 %.
54
Synthesis of 4-bromo-2,6-bis((tosyloxy)methyl)pyridine 1-oxide 22
To a solution of bis-tosylate 90 (1 g, 1.9 mmol) in dry dichloromethane, m-CPBA
(1.64 g, 9.5 mmol) was added and the reaction stirred at room temperature for 48h.
The reaction was quenched by addition of 0.1 M solution of NaOH (2 x 100 mL)
and the organic phase dried over MgSO4. Solvent was removed in vacuo and crude
compound recrystallised from dichloromethane and petroleum ether to give
compound 103 (0.66 g, 64%).
1
H NMR: (CDCl3, 300 MHz) δ/ppm 2.39 (6H, s, CH3), 5.09 (4H, s, CH2), 7.3
(2H, d, J = 7.9 Hz, ArH), 7.52 (2H, s, ArH), 7.77 (2H, d, J = 8.3 Hz, ArH)
13
C NMR: (MeOD, 300 MHz) δ/ppm 21.72 (C9), 64.45 (C4), 125.75 (C1), 128.17
(C2), 130.22 (C6), 131.93 (C7), 145.83 (C5, C8), 146.27 (C3)
IR υmax (film): 1122 (s), 1172 (s), 1294 (s), 1304 (s), 1371 (m), 1407 (m), 1437
(m), 1573 (m), 1596 (w), 3049 (m), 3107 (m) cm-1
Melting point: 118 – 120 °C
MS (ES+): m/z [M+H]+ 542
Accurate Mass: C21H20BrNO7S2-e requires 541.9947 found 541.9938
55
4.3
Macrocycles
Synthesis of 13-bromo-3,6,9-trithia-15-azabicyclo[9.3.1]pentadeca-1(15),11,13triene 28
To a stirred solution of 4-bromo-2,6-bis(tosyloxymethyl)pyridine 90 (1.11 g, 2.11
mmol) in toluene (25 mL), 2,2-thiodiethanethiol (0.28 mL, 2.11 mmol), and KOH
(0.24 g, 4.22 mmol) in ethanol/H2O 50:1 (25 mL) was added and stirred at room
temperature for 24 hours. Solvent was removed in vacuo, the residue dissolved in
DCM and washed with water (6 times). The organic phase was dried over MgSO4
and solvent removed in vacuo. The crude compound was further purified by
column chromatography (DCM:Pet) to afford 0.341 g, 48% of pure compound.
1
H NMR: (CDCl3, 400 MHz) δ/ppm 2.52 (8H, s, CH2), 3.79 (4H, s, CH2), 7.49
(2H, s, ArH)
13
C NMR: (CDCl3, 100 MHz) δ/ppm 30.07 (C6), 31.00 (C5), 35.39 (C4), 125.68
(C2), 158.67 (C3)
IR υmax (film): 1187 (s), 1348 (s), 1478 (m), 1558 (s), 1724 (m), 3106 (m), 3307
(m) cm-1
MS (ES+): m/z [M+H]+ 336
Accurate Mass: [C11H14BrNS3-e] requires 335.9547 found 335.9545
Microanalysis: Found: C, 39.16; H, 4.17; N, 3.82 %. C11H14BrNS3 requires C,
39.28; H, 4.2; N, 4.16 %.
56
Synthesis of 13-bromo-3,6,9-trithia-15-azabicyclo[9.3.1]pentadeca-1(15),11,13triene 15-oxide 28
To a stirred solution of compound 103 (0.5 g, 0.92 mmol) in toluene (12 mL), 2,2thiodiethanethiol (0.12 mL, 0.92 mmol), and KOH (0.1 g, 1.84 mmol) in
ethanol/H2O 50:1 (12 mL) was added and stirred at room temperature for 24 hours.
Solvent was removed in vacuo, the residue dissolved in dichloromethane and
washed with water (6 times). The organic phase was dried over MgSO4 and solvent
removed in vacuo. The crude compound was further purified by column
chromatography (DCM:Pet) to afford compound 104 (0.23 g, 32%).
1
H NMR: (CDCl3, 400 MHz) δ/ppm 2.75 (8H, s, CH2), 4.00 (4H, s, CH2), 7.57
(2H, s, ArH)
13
C NMR: (CDCl, 400 MHz) δ/ppm 27.39 (C6), 31.54 (C5), 31.90 (C4), 128.63
(C2), 151.66 (C3)
MS (ES+): m/z [M+Na]+ 374
Accurate Mass: [C21H14BrONS3-e] requires 351.9498 found 351.9494
57
4.4 Unsuccessful attempts at the synthesis of three further
macrocycles
General methods
To a stirred solution of 4-bromo-2,6-bis(tosyloxymethyl)pyridine 90 (1 eq.) in
toluene (12 mL/mmol), thiol spacer (1 eq.), and KOH (2 eq.) in ethanol/H2O 50:1
(12 mL/mmol) was added and stirred at room temperature for 24 hours. Solvent
was removed in vacuo, the residue dissolved in DCM and washed with water (6
times). The organic phase was dried over MgSO4 and solvent removed in vacuo.
The crude compound was further purified by column chromatography (DCM:Pet)
to afford the desired compound.
Attempted Synthesis of 13-bromo-6-oxa-3,9-trithia-15azabicyclo[9.3.1]pentadeca-1(15),11,13-triene
Using general method mentioned above, 4-bromo-2,6-bis(tosyloxymethyl)pyridine
(0.5 g, 0.95 mmol) in toluene (12 mL), 2,2-thiodiethanethiol (0.12 mL, 0.95
mmol), and KOH (0.11 g, 1.9 mmol) in ethanol/H2O 50:1 (12 mL). Examination
of the crude reaction mixture by 1H NMR indicated that none of the desired
macrocycle 96 had been formed.
58
Attempted synthesis of 16-bromo-6,9-dioxa-3,12-dithia-18azabicyclo[12.3.1]octadeca-1(18),14,16-triene
Using general method mentioned above, 4-bromo-2,6-bis(tosyloxymethyl)pyridine
(0.5 g, 0.95 mmol) in toluene (12 mL), 2,2′-(Ethylenedioxy)diethanethiol (0.15
mL, 0.95 mmol), and KOH (0.11 g, 1.9 mmol) in ethanol/H2O 50:1 (12 mL).
Examination of the crude reaction mixture by 1H NMR indicated that none of the
desired macrocycle 97 had been formed.
Attempted synthesis of 19-bromo(4S,14S)-4,14-Dimethyl-3,15-bis-(toluene-4sulfonyl)-6,9,12-trithia-3,15,21-triaza-bicyclo[15.3.1]henicosa-1(20),17(21),18triene
Using general method mentioned above, 4-bromo-2,6-bis(tosyloxymethyl)pyridine
(0.5 g, 0.95 mmol) in toluene (12 mL), spacer 101 (0.55 g, 0.95 mmol), and KOH
(0.11 g, 1.9 mmol) in ethanol/H2O 50:1 (12 mL). Examination of the crude
reaction mixture by 1H NMR indicated that none of the desired macrocycle 102
had been formed.
59
Attempted synthesis of 13-(phenylethynyl)-3,6,9-trithia-15azabicyclo[9.3.1]pentadeca-1(15),11,13-triene
Macrocycle 84 (0.5 g, 1.49 mmol), phenylacetylene (0.16 mL, 1.49 mmol),
Pd(PPh3)2Cl2 (0.021 g, 0.03 mmol) and CuI (0.012 g, 0.0623 mmol) were placed
under nitrogen atmosphere. Dry degassed THF (10 mL) and Pri2NH was added
and the reaction was left to stir for 24 hours in a dark room. The dark brown
solution was filtered and dried in vacuo and the crude compound was purified by
column chromatography, unfortunately none of the desired product 106 could be
isolated.
60
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DMAP, Tröger's Base and Sulfamide, PhD Thesis, University of Manchester,
2006.
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Appendix
Table 8. Crystal data and structure refinement for crown ether 82
63
Identification code
Empirical formula
Formula weight
Temperature
Wavelength
Crystal system
Space group
Unit cell dimensions
Volume
Z
Density (calculated)
Absorption coefficient
F(000)
Crystal size
Theta range for data collection
Index ranges
s3707ma
C11 H14 Br N S3
336.32
180(2) K
1.54178 Å
Orthorhombic
Pbcn
a = 13.0722(6) Å
b = 7.8927(4) Å
c = 25.4406(12) Å
2624.8(2) Å3
8
1.702 Mg/m3
8.498 mm-1
= 90°.
= 90°.
1360
0.21 x 0.20 x 0.16 mm3
3.47 to 72.29°.
-13<=h<=16, -9<=k<=9, -27<=l<=31
Reflections collected
Independent reflections
Completeness to theta = 66.60°
Absorption correction
Max. and min. transmission
Refinement method
Data / restraints / parameters
Goodness-of-fit on F2
Final R indices [I>2sigma(I)]
15382
2585 [R(int) = 0.0710]
99.8 %
Semi-empirical from equivalents
0.3434 and 0.206104
Full-matrix least-squares on F2
2585 / 0 / 145
1.083
R1 = 0.0383, wR2 = 0.0984
R indices (all data)
Largest diff. peak and hole
R1 = 0.0401, wR2 = 0.0999
0.711 and -0.936 e.Å-3
64
Table 9. Atomic coordinates ( x 104) and equivalent isotropic displacement
parameters (Å2x 103)
for s3707ma. U(eq) is defined as one third of the trace of the orthogonalized Uij
tensor.
__________________________________________________________________
______________
x
y
z
U(eq)
__________________________________________________________________
______________
Br(1)
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
6418(1)
6378(2)
6153(2)
6109(2)
5836(2)
4125(2)
3517(2)
4385(2)
4645(2)
1670(1)
3004(3)
4716(3)
5607(3)
7454(3)
6825(3)
5218(4)
3176(3)
1649(3)
2754(1)
2137(1)
2164(1)
1693(1)
1688(1)
1038(1)
1124(1)
342(1)
677(1)
37(1)
20(1)
20(1)
19(1)
25(1)
28(1)
32(1)
23(1)
23(1)
C(9)
6742(2)
2476(3)
678(1)
21(1)
C(10)
6525(2)
3233(3)
1211(1)
17(1)
C(11)
6556(2)
2226(3)
1659(1)
20(1)
N(1)
6299(2)
4894(3)
1222(1)
17(1)
S(1)
4460(1)
7836(1)
1660(1)
29(1)
S(2)
3179(1)
4160(1)
516(1)
32(1)
S(3)
5880(1)
739(1)
513(1)
26(1)
__________________________________________________________________
______________
65
Table 10. Bond lengths [Å] and angles [°] for s3707ma.
_____________________________________________________
Br(1)-C(1)
1.891(3)
C(1)-C(11)
1.382(4)
C(1)-C(2)
1.384(4)
C(2)-C(3)
1.392(4)
C(2)-H(2)
0.9500
C(3)-N(1)
1.346(3)
C(3)-C(4)
1.501(3)
C(4)-S(1)
C(4)-H(4A)
C(4)-H(4B)
C(5)-C(6)
C(5)-S(1)
C(5)-H(5A)
C(5)-H(5B)
C(6)-S(2)
C(6)-H(6A)
1.825(3)
0.9900
0.9900
1.512(4)
1.826(3)
0.9900
0.9900
1.814(3)
0.9900
C(6)-H(6B)
C(7)-C(8)
C(7)-S(2)
C(7)-H(7A)
C(7)-H(7B)
C(8)-S(3)
C(8)-H(8A)
C(8)-H(8B)
C(9)-C(10)
0.9900
1.515(4)
1.812(3)
0.9900
0.9900
1.816(3)
0.9900
0.9900
1.509(3)
C(9)-S(3)
C(9)-H(9A)
C(9)-H(9B)
C(10)-N(1)
C(10)-C(11)
C(11)-H(11)
1.824(3)
0.9900
0.9900
1.344(3)
1.389(4)
0.9500
C(11)-C(1)-C(2)120.9(2)
C(11)-C(1)-Br(1)118.6(2)
C(2)-C(1)-Br(1)120.5(2)
C(1)-C(2)-C(3) 117.3(2)
66
C(1)-C(2)-H(2) 121.3
C(3)-C(2)-H(2) 121.3
N(1)-C(3)-C(2) 123.2(2)
N(1)-C(3)-C(4) 116.3(2)
C(2)-C(3)-C(4) 120.5(2)
C(3)-C(4)-S(1) 113.31(19)
C(3)-C(4)-H(4A)108.9
S(1)-C(4)-H(4A)108.9
C(3)-C(4)-H(4B)108.9
S(1)-C(4)-H(4B)108.9
H(4A)-C(4)-H(4B)107.7
C(6)-C(5)-S(1) 111.5(2)
C(6)-C(5)-H(5A)109.3
S(1)-C(5)-H(5A)109.3
C(6)-C(5)-H(5B)109.3
S(1)-C(5)-H(5B)109.3
H(5A)-C(5)-H(5B)108.0
C(5)-C(6)-S(2) 113.0(2)
C(5)-C(6)-H(6A)109.0
S(2)-C(6)-H(6A)109.0
C(5)-C(6)-H(6B)109.0
S(2)-C(6)-H(6B)109.0
H(6A)-C(6)-H(6B)107.8
C(8)-C(7)-S(2) 113.53(19)
C(8)-C(7)-H(7A)108.9
S(2)-C(7)-H(7A)108.9
C(8)-C(7)-H(7B)108.9
S(2)-C(7)-H(7B)108.9
H(7A)-C(7)-H(7B)107.7
C(7)-C(8)-S(3) 112.64(18)
C(7)-C(8)-H(8A)109.1
S(3)-C(8)-H(8A)109.1
C(7)-C(8)-H(8B)109.1
S(3)-C(8)-H(8B)109.1
H(8A)-C(8)-H(8B)107.8
C(10)-C(9)-S(3)112.85(17)
C(10)-C(9)-H(9A)109.0
S(3)-C(9)-H(9A)109.0
67
C(10)-C(9)-H(9B)109.0
S(3)-C(9)-H(9B)109.0
H(9A)-C(9)-H(9B)107.8
N(1)-C(10)-C(11)123.2(2)
N(1)-C(10)-C(9)116.5(2)
C(11)-C(10)-C(9)120.3(2)
C(1)-C(11)-C(10)117.5(2)
C(1)-C(11)-H(11)121.2
C(10)-C(11)-H(11)121.2
C(10)-N(1)-C(3)117.8(2)
C(4)-S(1)-C(5) 101.41(13)
C(7)-S(2)-C(6) 101.16(13)
C(8)-S(3)-C(9) 101.46(12)
_____________________________________________________________
Symmetry transformations used to generate equivalent atoms:
Table 11. Anisotropic displacement parameters (Å2x 103) for s3707ma. The
anisotropic
displacement factor exponent takes the form: - 2[ h2 a*2U11 + ... + 2 h k a* b*
U12 ]
__________________________________________________________________
____________
U11
U22
U33
U23
U13
U12
__________________________________________________________________
____________
Br(1)
56(1)
35(1)
19(1)
9(1)
4(1)
16(1)
C(1)
22(1)
21(1)
18(1)
3(1)
-1(1)
2(1)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
C(9)
C(10)
25(1)
21(1)
37(1)
34(1)
38(2)
29(1)
31(1)
26(1)
18(1)
18(1)
15(1)
13(1)
22(1)
28(2)
22(1)
20(1)
20(1)
17(1)
16(1)
21(1)
24(1)
28(1)
31(2)
19(1)
19(1)
17(1)
17(1)
-4(1)
-3(1)
-3(1)
7(1)
-3(1)
0(1)
-1(1)
-3(1)
-2(1)
1(1)
0(1)
1(1)
-2(1)
13(1)
2(1)
1(1)
3(1)
0(1)
0(1)
-2(1)
-3(1)
4(1)
0(1)
-2(1)
-6(1)
1(1)
-1(1)
C(11)
N(1)
23(1)
21(1)
15(1)
15(1)
21(1)
16(1)
0(1)
0(1)
-1(1)
1(1)
1(1)
-2(1)
68
S(1)
39(1)
20(1)
28(1)
-2(1)
6(1)
10(1)
S(2)
25(1)
34(1)
37(1)
-2(1)
-1(1)
-1(1)
S(3)
38(1)
15(1)
24(1)
-7(1)
-1(1)
1(1)
__________________________________________________________________
____________ Table 12. Hydrogen coordinates ( x 104) and isotropic
displacement parameters (Å2x 10 3)
for s3707ma.
__________________________________________________________________
______________
x
y
z
U(eq)
__________________________________________________________________
______________
H(2)
H(4A)
H(4B)
H(5A)
H(5B)
6033
6163
6115
3717
4758
5260
7998
7994
7623
6555
2491
1380
2009
823
842
24
30
30
33
33
H(6A)
H(6B)
H(7A)
H(7B)
H(8A)
H(8B)
H(9A)
H(9B)
H(11)
2883
3924
4358
4938
4109
4647
7456
6679
6695
5497
4433
2822
4025
777
1990
2055
3372
1047
1319
1344
-31
377
631
1052
672
408
1638
39
39
28
28
28
28
25
25
24
__________________________________________________________________
______________
69
Table 13. Torsion angles [°] for s3707ma.
________________________________________________________________
C(11)-C(1)-C(2)-C(3)
0.3(4)
Br(1)-C(1)-C(2)-C(3)
-178.28(18)
C(1)-C(2)-C(3)-N(1)
-1.7(4)
C(1)-C(2)-C(3)-C(4)
178.0(2)
N(1)-C(3)-C(4)-S(1)
92.9(2)
C(2)-C(3)-C(4)-S(1)
-86.8(3)
S(1)-C(5)-C(6)-S(2)
-179.40(15)
S(2)-C(7)-C(8)-S(3)
S(3)-C(9)-C(10)-N(1)
S(3)-C(9)-C(10)-C(11)
C(2)-C(1)-C(11)-C(10)
Br(1)-C(1)-C(11)-C(10)
N(1)-C(10)-C(11)-C(1)
C(9)-C(10)-C(11)-C(1)
C(11)-C(10)-N(1)-C(3)
C(9)-C(10)-N(1)-C(3)
-177.67(13)
-121.4(2)
58.2(3)
1.5(4)
-179.88(18)
-2.2(4)
178.2(2)
0.9(3)
-179.5(2)
C(2)-C(3)-N(1)-C(10)
1.1(4)
C(4)-C(3)-N(1)-C(10)
-178.6(2)
C(3)-C(4)-S(1)-C(5)
-60.8(2)
C(6)-C(5)-S(1)-C(4)
109.2(2)
C(8)-C(7)-S(2)-C(6)
74.1(2)
C(5)-C(6)-S(2)-C(7)
76.7(2)
C(7)-C(8)-S(3)-C(9)
63.3(2)
C(10)-C(9)-S(3)-C(8)
47.7(2)
________________________________________________________________
Symmetry transformations used to generate equivalent atoms:
Table 14. Hydrogen bonds for s3707ma [Å and °].
__________________________________________________________________
__________
D-H...A
d(D-H)
d(H...A)
d(D...A)
<(DHA)
__________________________________________________________________
__________
70
X-ray crystal structure of Macrocycle 82
71