Ethoxyvinylarenes as Versatile Intermediates for
Heterocycle Synthesis
Marianne Swindlehurst
PhD Thesis
2016
Supervisor: Dr D. Whelligan
Co-Supervisor: Dr I. Cunningham
i
Contents
Contents
ii
Abbreviations
iv
Abstract
iv
Declaration
vi
Copyright
vi
1 Introduction
1
1.1 General Introduction
1
1.2 Introduction to Heterocyclic Aromatics (Heteroaromatics)
2
1.3 Pyrroloarenes (Indoles and Azaindoles)
3
1.3.1 Introduction
3
1.3.2 Occurrences and uses of Pyrroloarenes (Indoles and Azaindoles)
5
1.3.3 Synthesis of Pyrroloarenes
11
1.3.3.1 Established syntheses and their limitations
11
1.3.3.2 Synthesis via Ethoxyvinyl(amino)arenes
18
1.3.4 Protection and Reactions of Pyrroloarenes
23
1.4 Furoarenes (Benzofurans and Furopyridines)
27
1.4.1 Introduction
27
1.4.2 Occurrences and uses of Furoarenes (Benzofurans and Furopyridines)
28
1.4.3 Synthesis of Furoarenes
32
1.4.3.1 Established syntheses and their limitations
32
1.4.3.2 Proposed synthesis via ethoxyvinyl(hydroxyl)arenes
36
1.4.4 Reactions of Furoarenes
38
1.5 Reactions of ethoxyvinyl compounds with electrophiles
1.5.1 Bromination Reactions
42
Error! Bookmark not defined.
1.5.2 Iodination Reactions
48
1.6 Aims and Objectives
50
2 Results and Discussion
52
2.1 Synthesis of Ethoxyvinylborolane
54
ii
2.2 3-Halopyrroloarenes
58
2.2.1 Introduction and Aims
58
2.2.2 Suzuki Coupling of Ethoxyvinylborolane with Haloaminopyridines
59
2.2.3 Acid-Mediated Cyclisation and bromination of Ethoxyvinyl(amino)pyridines to
Pyrrolopyridines
65
2.2.4 One-step Halo-cyclisation of Ethoxyvinyl(amino)arenes
67
2.2.4.1 3-Ethoxyvinyl-4-aminopyridine isomer
67
2.2.4.2 One pot, one-step bromo-cyclisation of other azaindole regioisomers
71
2.2.5 Two-step, one-pot Cyclisation-Halogenation of Ethoxyvinyl(amino)arenes
75
2.3 Furoarenes
77
2.3.1 Introduction and Aims
77
2.3.2 Synthesis of Halohydroxypyridines
78
2.3.3 Attempted Suzuki Coupling of Ethoxyvinylborolane with Halohydroxypyridines 81
2.4 Anti-malarial pre-cursors
85
2.4.1 Synthesis via Heck Reaction
85
2.4.1.1 Introduction and aims
85
2.4.1.2 Vinyl glutarimide
88
2.4.1.3 Attempted Heck reaction
93
2.4.2 Synthesis via sp2-sp3 Suzuki Reaction
100
2.4.2.1 Introduction and aims
100
2.4.2.2 Glutarimylethyl boronic ester
100
2.4.2.3 sp2-sp3 Suzuki coupling with Bromopyrroloarenes
107
3 Conclusions and Future Work
109
4 Experimental
113
5 References
132
iii
Abbreviations
The following abbreviations are used in this report:
acac
Ad
APCI
b.p.
cod
Conc.
COSY
d
DBDMH
DCM
DMA
DMF
DMSO
dppb
dppf
GC-MS
h
HBPin
HMBC
HRMS
HSQC
IR
LCMS
m
Me
min
mmol
mol
m.p.
MS
NBS
NCS
NMR
q
R
rt
RuPhos
s
SM
Acetylacetone
Adamantyl
Atmospheric Pressure Chemical Ionisation
Boiling point
cyclooctadiene
Concentrated
Correlation spectroscopy
Doublet
1,3-Dibromo-5,5-dimethylhydantoin
Dichloromethane
Dimethylacetamide
Dimethylformamide
Dimethyl sulfoxide
1,4-Bis(diphenylphosphino)butane
1,1'-Bis(diphenylphosphino)ferrocene
Gas chromatography – mass spectroscopy
Hours
Pinacolborane
Heteronuclear Multiple Bond Correlation
High resolution mass spectroscopy
Heteronuclear single quantum correlation
Infra red
Liquid chromatography mass spectroscopy
Multiplet
Methyl
Minutes
Millimole
Mole
Melting point
Mass spectroscopy
N-Bromosuccinimide
N-Chlorosuccinimide
Nuclear magnetic resonance
Quartet
Alkyl
Room temperature
2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl
Singlet
Starting material
iv
SPhos
t
TFA
THF
TLC
XPhos
2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl
Triplet
Trifluoroacetic acid
Tetrahydrofuran
Thin layer chromatography
2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl
v
Abstract
In the field of drug discovery, pyrrolopyridine moieties are often incorporated into bioactive
molecules. This is due to their ability to form both pi-stacking and hydrogen bonding
interactions when binding to target proteins. This project aimed to provide a robust and
rapid method of synthesis that will provide access to substituted pyrrolopyridines. The work
is
based
on
a
previously
published
method
involving
the
synthesis
of
ethoxyvinyl(amino)arenes, by Suzuki reaction of halo-aminoarenes, followed by cyclisation.
It was hoped this method would be advanced by applying alternative cyclisation reactions to
the ethoxyvinyl(amino)arenes to give 3-substituted products in one step. In comparison
with previous methods, this route would be inexpensive, robust and applicable to a wide
range of substrates. It was also envisaged that alternative starting materials could be used
to make it a more generalised method for the synthesis of bicyclic arenes.
Work began with testing the reproducibility of the previously published method of
synthesising the ethoxyvinyl(amino)arenes. This was done successfully, although a change in
ligand (SPhos to RuPhos) proved beneficial, with seven different analogues being
synthesised in yields ranging from 36% to 98%. This same reaction was attempted with halohydroxypyridines, with a novel route to furopyridines in mind, but with no success. The
synthesis of non-commercially available halo-hydroxypyridines themselves also proved to be
challenging with no material being isolated.
Various methods were tested for the bromo-cyclisation of ethoxyvinyl(amino)arenes to 3bromopyrrolopyridines. A two-step method using acid cyclisation followed by bromination
was entirely successful. Two-step, one-pot and one-step methods both appeared to
promote polymerisation/oligermisation. Success was achieved with a one-step method
employing an acid additive but only on selected ethoxyvinyl(amino)arene isomers and with
varying yields.
The work was extended to the attempted synthesis of anti-malarial precursors using the
bromo-pyrrolopyridine isomers as building blocks and converting them to alkyl-linked
glutarimides. This led to the successful and novel synthesis of the reactants vinyl glutarimide
iv
and glutarimylethylborolane. However, successful conditions for their palladium catalysed
cross coupling with the bromides were not found.
v
Declaration
The work contained in this thesis was carried out in the Department of Chemistry, University
of Surrey between September 2011 and September 2015. All the work is that of the author
unless otherwise indicated with references. It has not previously been submitted for a
degree at this or any other university.
Copyright
The copyright of this thesis rests with the author. No quotation from it should be published
without their prior written consent and information derived from it should be
acknowledged.
vi
1 Introduction
1.1 General Introduction
The research described in this thesis involves the synthesis and substitution of bicyclic
aromatic heterocycles, consisting of fused 6- and 5-membered rings, containing at least one
heteroatom in each of the rings. Their appearance in nature is limited but they are prolific in
the field of drug discovery.1 Although methods for synthesising these structures have been
known for many years, each is limited to a certain isomer or number of isomers, and usually
involves specific substitutions on the azaindole rings.2-7 It is for this reason that research into
novel, more efficient methods for their synthesis is beneficial. The particular moieties of
interest here are pyrrolopyridines (also named azaindoles), e.g. 1 (Fig. 1.1), and related
pyrroloarenes (diazaindoles) and furopyridines, e.g. 2. (Fig. 1.1), and related furoarenes.
Fig. 1.1
This research aimed to provide a robust synthetic method to access all regioisomers of both
of these classes of compound with and without substitution at the 3-position. The work is
based on a previously published method of synthesising azaindoles 5 via stable
ethoxyvinylarene intermediates 4 accessed from halo-aminoarenes 3 using a Suzuki reaction
(Scheme 1.1).8
1
Scheme 1.1
The proposed method of substitution at the 3-position involves treating ethoxyvinylarene 4
with electrophiles other than acid in order to promote the proposed mechanism shown
below (Scheme 1.2).
Scheme 1.2
This chapter provides an introduction to each of the bicyclic heterocycles: their occurrences
and uses followed by current methods of their synthesis. This will be followed by a short
review of the reactions relevant to this research, including the Suzuki reaction (due to its
use in the formation of the ethoxyvinylarene intermediate 4) and ring-closing cyclisation
reactions mediated by electrophiles.
1.2 Introduction to Heterocyclic Aromatics (Heteroaromatics)
Heterocyclic aromatics (shortened to heteroaromatics) are prolific in drug discovery as their
flat and hydrophobic nature facilitates strong binding to proteins and their rigidity and
hydrogen bonding sites permit specific interactions with the target protein.9
2
Hydrogen bonds are largely polar attractions that occur between hydrogen bound to an
electronegative atom, such as nitrogen, and an atom with a lone pair, such as oxygen. In
drug discovery such interactions must be fine-tuned in terms of position, direction and
strength to allow the drug to bind strongly and specifically to the target
biomacromolecule.10 An example of such interactions can be seen in Figure 1.2 which shows
the X-ray co-crystal structure of an azaindole potential anti-thrombotic agent in complex
with factor VIIa.11 In the azaindole, the pyrrole NH moiety makes a hydrogen bond with
Ser195 while the pyridine N-atom makes a water-bridged hydrogen bond with Gln217.
Synthetic methods which enable all regioisomers of a heteroaromatic to be made are
therefore of great value during lead optimisation when the optimal position of a hydrogen
bonding group must be established.
Fig. 1.2 Generated using PyMOL from PDB:2FLR11
1.3 Pyrroloarenes (Indoles and Azaindoles)
1.3.1 Introduction
Pyrroloarenes are bicyclic heteroaromatics that include both indoles and azaindoles. An
indole is a six-membered ring fused to a five-membered ring that contains a nitrogen atom 6
(Fig. 1.3).
3
Fig. 1.3
An azaindole 7 is a bicyclic heterocycle that contains a six-membered ring fused to a fivemembered ring each containing a nitrogen atom (Fig. 1.4).
Fig. 1.4
The nitrogen atom in the 6-membered ring (the pyridine) can be in position 4, 5, 6, or 7 (Fig.
1.5).1 The two nitrogen atoms provide two hydrogen bonding sites, the pyrrole-NH being a
hydrogen bond donor and the pyridine-N a hydrogen bond acceptor.
Fig. 1.5
The position of the nitrogen in the pyridine ring creates two things to consider. Firstly, how
changing the position of the nitrogen affects its role as a hydrogen bond acceptor when
binding to biomacromolecules. This is a fairly simple concept as the best position of the
pyridine’s nitrogen is the one that is best matched with its hydrogen bond donor in the
binding site of the molecule it is interacting with. The second thing to consider is how the
position of the pyridine’s nitrogen affects the whole molecule’s reactivity in both the
synthesis of the azaindole itself, and reactions of the azaindole.
Looking at the difference in structures between the indole 6 and the azaindole 7, it can be
perceived how the extra hydrogen bonding site provided by the extra nitrogen atom can
4
help with the interaction between itself and the active site of the target biomacromolecule.
Having two sites at which hydrogen bonding occurs means that the interaction is stronger. It
also means that the interaction is more rigid, holding the molecule better in place allowing
the position and direction of the interaction to be more successfully controlled. These
factors promote better interaction and therefore improved activity.
1.3.2 Occurrences and uses of Pyrroloarenes (Indoles and Azaindoles)
Indoles can be found very commonly in nature. The indole structure itself has been isolated
from places such as the sea water of the Xiamen Sea, the leaves of the salvia divinorum,
North Sea bacterium, rape flower and many more.12-15 In terms of substituted indoles that
can be found in nature, there are more than 6000. These include molecules such as
tryptamine 12 and L-tryptophan 13 (Fig. 1.6). Tryptamine 12 can be found in places such as
in the seeds of Centaurea montana, L-tryptophan 13 is one of the 20 naturally occurring
amino acids and is therefore found ubiquitously in nature.16,17
Fig. 1.6
In contrast, azaindoles occur only rarely in nature. In fact, the 7-azaindole isomer is the only
unsubstituted isomer to have been isolated from natural products and only from one place
which is coal tar.18 As far as substituted azaindoles are concerned, the number of available
molecules found naturally vary depending on the isomer in question, although none come
remotely close to that of indole. The least occurring isomer is 5-azaindole which can be
found as isoperlolyrine 14 or ingenine B 15 (Fig. 1.7) isolated from the Indian Gloriosa
5
superba L., a flowering plant, and the Acanthostrongylophora ingens, a marine sponge,
respectively.19,20
Fig. 1.7
Approximately six examples of naturally occurring molecules containing the 4-azaindole
isomer have been published. Examples include quindoline 16 and jusbetonin 17 (Fig. 1.8).
Quindoline has been isolated from the west African medicinal plant, Cryptolepis
sanguinolenta (Asclepidaceae), which has anti-malarial properties and jusbetonin was
isolated from the leaves of Justica betonica L. (Acanthaceae), which was collected from the
Chittoor District in India.21,22
Fig. 1.8
The 7-azaindole isomer has been isolated in around 14 substituted forms as well as in its
unsubstituted state. Some examples include Variolin B 18 and Grossularine II 19 (Fig. 1.9)
which are both marine compounds with anti-tumoral properties.23-25
6
Fig. 1.9
Variolin B 18 was isolated from the Antarctic sponge Kirkpatricka varialosa, and
Grossularine II 19 was isolated from the tunicate (a marine filter feeder), Dendrodoa
grossularia. Both, it has been speculated, exert cytotoxic activity on tumors via DNA
intercalation.26,27,25,28 This is where a planar, usually polycyclic aromatic molecule, such as
Variolin B 18, slides between two base pairs in a DNA helix. This can shift the base pairs,
causing the DNA to unwind to a degree, inhibiting replication, transcription and DNA
repair.29 The latter leads to DNA mutations.
By far the most commonly occurring of the azaindole isomers is 6-azaindole which has
around 600 naturally occurring molecules containing its structure. These include compounds
such as harmine 20 and betacarboline 21 (Fig. 1.10).
Fig. 1.10
Harmine 20 has been isolated from many places including the seeds of the flowering plant
Peganumharmala Linn, the marine brown alga Melanothamnus afaqhusainii and the stems
and large branches of Banisteriopsis caapi cultivar Da Vine which was collected from
Hawaii.30-33 Betacarboline 21 has also been isolated from a variety of places, examples of
7
which include Indonesian sponge, Strychnos potatorum L. (root bark) and the ground leaves
of Ophiorrhiza acuminata L. (Rubiaceae).34-36
1.3.3 Applications of Pyrrolopyridines
Azaindoles are bioisosteres of indoles, which are known to be a key structural element for
many biologically active molecules,1 but the additional nitrogen atom may also provide
extra hydrogen bonding sites for target binding. They therefore find widespread application
in drug discovery as inhibitors, agonists and antagonists. Several examples follow.
The azaindole-maleimide 22 (Fig. 1.11) is a checkpoint 1 kinase (Chk1) inhibitor.37 Chk1 is an
enzyme that phosphorylates cdc25, an important phosphatase in cell cycle control. Chk1
inhibitors are used in research against cancer as, in theory, they should be able to selectively
force cancer cells to bypass the G2 checkpoint of the cell cycle and enter a premature and
lethal mitosis.37
Fig. 1.11 Azaindole Chk1 inhibitor
Another example of an azaindole-containing inhibitor is the glycogen synthase kinase 3-β
(GSK3-β) inhibitor 23 (Fig. 1.12).38 Research into GSK3-β inhibitors aims to treat diabetes
and cancer.39,40
8
Fig. 1.12 Azaindole GSK3-β inhibitor
Azaindole 24 (Fig. 1.13) is a D4 antagonist which blocks the dopamine-4 receptor which has
been linked to both neurological and psychiatric conditions, such as schizophrenia,
Parkinson’s disease, bipolar disorder and eating disorders.41 It is already a successful target
for other compounds used as drugs to treat schizophrenia and Parkinson’s disease. 41
Fig. 1.13 Azaindole D4 antagonist
Azaindole 25 (Fig. 1.14) is a highly selective, ATP-competitive rho-kinase (ROCK) inhibitor.42
It has been shown to have the ability to induce vasorelaxation in both in vitro and in vivo
experiments.42 It was concluded that the structure is a valuable pharmacological tool to help
make clear the physiological and pathophysiological role of ROCK and therefore offers a
novel therapeutic approach for treating cardiovascular diseases.42
9
Fig. 1.14 Azaindole 1 - ROCK inhibitor
The 3,5-diaryl-7-azaindole 26 (Fig. 1.15) was, at the time of publishing, one of the most
potent in vitro inhibitors of DYRK1A kinase (IC50 = 3 nM).43 Docking studies showed that
multiple hydrogen bonds bound the molecule to the peptide backbone of the target’s
structure, thus demonstrating the importance of the extra nitrogen atom in the azaindole
scaffold making extra hydrogen bonding sites available compared to its indole or
indonaphthene analogues. Complementary studies also showed that the molecule is noncytotoxic allowing it to be studied as a potential treatment for neurodegenerative
pathologies such as Down’s syndrome and early onset Alzheimer’s disease.43
Fig. 1.15 3,5-diaryl-7-azaindole for potential neurodegenerative pathology treatment.
The 4-azaindole 27 (Fig. 1.16) is a non-covalent inhibitor of DprE1, an enzyme in
Mycobacterium tuberculosis44 involved in the conversion of decaprenylphosphoryl-β-Dribose (DPR) to decaprenylphosphoryl-β-D-arabinofuranose (DPA) which is involved in the
biosynthesis of the cell wall. After proving successful in mouse models for TB, it has the
potential to be used to treat TB in humans, a research priority due to the number of strains
of TB that are now resistant to current drugs.44
10
Fig. 1.16 Potential azaindole TB treatment
It is worthy of note that all but one of the synthetic bioactive azaindoles described above
are 7-azaindoles. This is most likely due to the commercial availability and lower cost of
unsubstituted 7-azaindole which may have arisen through its use in metal complexes which
have luminescent properties and have been used in blue organic light emitting devices. 45 7Azaindole as a free molecule in solution has no emission in the visible spectrum and only a
very weak one in its solid state (λ ca. 400 nm).46 However, when in its ionic form, it exhibits
a bright blue emission in both its solid state and in solution. Unfortunately, the anion is
unstable towards air and moisture. One way to overcome this is to bind it to a central metal
ion, such as aluminium(III), which will create a stable complex and allow its use in blue
organic light emitting devices.46
1.3.4 Synthesis of Pyrroloarenes
1.3.4.1 Established syntheses and their limitations
When considering the synthesis of azaindoles, the most obvious place to begin is at the
traditional methods of synthesising indoles. These include the Fischer indole synthesis
(Scheme 1.3) and the Reissert synthesis (Scheme 1.5).47,48
11
Scheme 1.3 Fischer Indole Synthesis
The Fischer indole synthesis shown in scheme 1.3, which used alcoholic hydrogen chloride
as catalyst, was the original reaction discovered. It took place in 1883, although the product
was not identified until 1884.47 Since this time, the reaction has become a very well used
and versatile method for the synthesis of indoles, proving successful on many different
starting materials under many different conditions.47 One of its limitations however, is its
use for the synthesis of azaindoles. Here, the pyridine nucleus is deactivated as a
nucleophile by the inductive effect and conjugative electron-withdrawal of the
electronegative nitrogen atom, so the formation of the new C-C bond is found to be
inhibited.47 However, it seems that under more harsh conditions such as increased
temperature or the addition of zinc chloride, synthesis of some azaindoles is possible. 47 The
Fischer indole synthesis has been reported to be effective for 4- and 6-azaindoles (80% and
60% yields, respectively) which necessarily contained an electron-donating methoxy group
(Scheme 1.4) to activate the pyridine core.2
Scheme 1.4. Fischer indole synthesis
The Reissert synthesis (Scheme 1.5) is an alternative method for the synthesis of indoles. It
involves the deprotonation of the alkyl in conjugation with the nitro group followed by the
attack of a diester. Reduction of the nitro group then leads to the cyclisation of the pyrrole
ring. The Reissert synthesis gives a different ideal substitution pattern on the benzene ring
to that of the Fischer indole synthesis whereby the substitution usually occurs on the 6
position of the indole rather than the 5 position which is found in the Fischer synthesis.
12
Scheme 1.5 Reissert Synthesis
The Reissert synthesis is known to work for 4-, 5-, and 6-azaindoles,4 however compound 38
is formed in only 42% yield, and the second step to azaindole 39 occurs with 84% yield.4
Scheme 1.6 Reissert synthesis of Azaindole
It should be noted that neither of these reactions work for the synthesis of 7-azaindoles.
This is likely due to the position of the nitrogen in the pyridine ring and its proximity to the
(intermediate) amino group. The electronegative nature of the nitrogen atom means that it
pulls electron density away from these groups through both conjugative and induction
effects causing these groups to be less available within the reaction.
Both of these conventional methods of synthesis, originally designed for indoles, produce
poor yields, may involve time-consuming steps to complete and cannot provide access to all
azaindole regioisomers.45 It is also important to note that these reactions always result in a
substituted azaindole product. Therefore, a synthetic method with few, if not one, step that
can be applied to a variety of azaindoles, with the possibility of producing an unsubstituted
product is desirable.
Other literature methods of synthesising azaindoles are reviewed below.
Calvett et al. synthesised 2,3-diphenylazaindoles by reacting 4-acetamido-3-iodopyridine 40
with diphenylacetylene 41 (Scheme 1.7).5 This involved a Larock heteroannulation
13
reaction.49 However, this method is not applicable to the synthesis of unsubstituted
azaindoles which would require acetylene gas.
Scheme 1.7 Reaction of 4-Acetamido-3-iodopyridine with Diphenylacetylene
Another example puts two methyl groups on the pyrrole ring and a methoxy group on the
pyridine ring of the azaindole (Scheme 1.8) through use of butanone in a Fischer indole
synthesis. Interestingly, the protected hydrazine precursor 44 was obtained by halogenmetal exchange of 5-bromo-2-methoxypyridine followed by reaction with di-tert-butyl
azodicarboxylate.6
Scheme 1.8 Reaction of 5-bromo-2-methoxypyridine with BocN=NBoc
Published methods for the synthesis of all four regioisomers of azaindole have been
thoroughly reviewed by Mérour and Joseph.50 More specific organometallic methods for
their synthesis have been reviewed by Song.1
Isocyanide rearrangement is a method reported for the synthesis of 5-azaindoles (Scheme
1.9).50,51 This is a multicomponent reaction that uses silicon-tethered diynes, tert-butyl
isocyanide and 2 equivalents of nitriles.49,50 The mechanism involves insertion of the
isocyanide into the zirconium-carbon bond which leads to a iminoacylzirconium complex 46
which is then subjected to intramolecular heterocyclisation. 49,50
14
Scheme 1.9 Isocyanide Rearrangement for synthesis of substituted 5-azaindoles
The ring opening of 2H-azirines can be used to synthesise 6-azaindoles (Scheme 1.10).50,52 It
involves the amination of aromatic C-H bonds via FeCl2-catalysed ring opening of the 2Hazirine.
50,52
This method can be used to synthesise both indoles and 6-azaindoles, but the
amount of catalyst required for each is very different. The indole synthesis requires only 5%
catalyst whereas the 6-azaindole requires 50% catalyst and the product is obtained in only
43% yield.50,52 This demonstrates how much more difficult azaindoles are to synthesise
compared to plain indoles where an electrophilic attack on the electron-poor pyridine is
required as part of the mechanism.
Scheme 1.10 Synthesis of 6-azaindoles using a ring opening of 2H-arizines method
For the formation of 7-azaindoles, a reaction beginning with 2-aminopicoline has been used
(Scheme 1.11) whereby 2-arylamino-3-(1-hydroxyalkyl)pyridine 51 was heated at 270 °C to
cause the dehydration of the tertiary alcohol to form a vinyl intermediate 52.50 This then
underwent a 5-endo-trig ring closure to give the intermediate 53 followed by oxidation of
the pyrrole ring to form the product 54. 50 The product was formed in 51% yield. 50
15
Scheme 1.11 Formation of 7-azaindole using 2-aminopicoline
For the synthesis of 4-azaindoles, [1,3]-dipolar addition has been used.50,53 In this synthesis
the starting imide reacts with dimethyl acetylenedicarboxylate (DMAD) to form the 4azaindole in a [1,3]-dipolar reaction followed by a ring transformation.49,52 Yields ranged
from 15% to 27%.49,52
Scheme 1.12 Formation of 4-azaindole using [1,3]-dipolar addition
These examples of synthesising azaindoles again have the same drawbacks as previously
seen. All are methods that are not applicable to all azaindole regioisomers and all produce
products substituted on the pyridine and/or the pyrrole ring. The reason is that changing
the position of the nitrogen atom in the pyridine ring changes the electronics of the system
so, in many cases an additional substituent on the pyridine ring is required to increase its
reactivity. In addition, many methods produce 2- or 3-substituted azaindoles due to them
mechanistically requiring acetylene gas or similar to produce unsubstituted analogues and
even if this could be easily used, is likely to react at both ends. These factors make a catchall method hard to come by.
Published methods for the synthesis of unsubstituted azaindoles do exist. For example,
Gorugantula et al. have developed a method that provides both the 4- and 7-azaindole
isomers in 65% and 41% yield, respectively (Scheme 1.13).54 The reaction involves a
palladium catalysed, carbon monoxide mediated N-heterocyclisation. The limitations of this
16
method include the use of carbon monoxide at pressure, lengthy time scales- the 7azaindole isomer requires over a week to synthesise- and it is not applicable to all four
regioisomers, although there is no mention of the other isomers by the authors.54
Scheme 1.13 Synthesis of unsubstituted 4- and 7-azaindoles
Zhang et al. have published a method for the synthesis of unsubstituted 4- and 6-azaindole
isomers.55 This involved reacting nitropyridines with excess vinyl Grignard reagent to obtain
the desired azaindoles, using the Bartoli cyclisation reaction.55 This method however,
involves synthesising 7-chloro substituted azaindole first, and then removing the chlorine
separately (Scheme 1.14).55
Scheme 1.14 Synthesis of unsubstituted 4- and 6-azaindoles
Synthesis for the unsubstituted 5-azaindole has also been published (Scheme 1.15).56 This
involves heating an alkynyl(amino)pyridine at 200°C in a microwave for 15 minutes to
induce cyclisation in 82% yield.56 The alkynyl precursor 64 was accessed via a Sonogashira
type alkynylation from a commercially available starting material thus avoiding the use of
acetylene gas which would also have produced disubstituted acetylenes.56
Scheme 1.15 Synthesis of unsubstituted 5-azaindole
17
This therefore shows, that although there are methods available for the synthesis of
unsubstituted azaindoles, there is not one that can be used to synthesise all the different
isomers. It should also be noted that all the methods of synthesis for unsubstituted
azaindoles involve intramolecular cyclisation reactions.
1.3.4.2 Synthesis via Ethoxyvinyl(amino)arenes
In the work descried in this thesis, the method used for the synthesis of the azaindoles
involves
the
previously
published
synthesis
and
use
of
stable
ethoxyvinyl(amino)areneswhich are made to undergo intramolecular electrophilic
cyclisation (Scheme 1.16).8
Scheme 1.16
The ethoxyvinyl(amino)arenes are accessed by the Suzuki reaction between an aryl halide
and ethoxyvinylborolane. For this reason, a discussion of the Suzuki reaction follows.
The Suzuki reaction, first published in 1979, is a cross coupling reaction between a boronic
acid or ester, and an organic halide or triflate using a palladium catalyst (Scheme 1.17).57
Scheme 1.17
18
The Suzuki catalytic cycle can be seen in Scheme 1.18. The first step involves oxidative
addition of a palladium(0) complex to the aromatic halide generating a palladium(II)
intermediate. This then undergoes transmetallation with the alkenyl boronate. Reductive
elimination produces the final product and regenerates the palladium(0) catalyst. The
transmetallation step in the Suzuki coupling is unique in that it requires a base such as
NaOtBu (shown below) to speed up the transmetallation by producing the borate. This
‘activated boronic acid’ possesses enhanced polarisation of the organic ligand and promotes
the transmetallation.48
Scheme 1.18
The result of a Suzuki reaction is the formation of a new C-C bond between sp2 carbon
atoms. The biaryl products which are accessible by this reaction are found in several
molecular frameworks in drugs and polymers so the reaction is highly used. The reasons for
it being more widely used than the equivalent Stille and Negishi couplings are the mild
reaction conditions, the wide variety of commercially available boronic acids/esters and the
low toxicity and impact of boronic acids/esters, relative to other organometallic reagents
such as organotins, and the easier handling and disposal of the reaction by-products.58
Finally, the reaction conditions are amenable to large scale industrial synthesis of
pharmaceuticals and fine chemicals.58
19
1.3.4.2.1 Amino-substituted substrates in Suzuki reactions
In order to use the Suzuki reaction in the published ethoxyvinylarene-azaindole synthesis,
conditions were required which couple starting materials bearing an amine group. There are
examples in the literature where this has already been achieved (Schemes 1.19, 1.20).59,60
Scheme 1.19
Scheme 1.20
This reaction uses K3PO4 as base, toluene as solvent, palladium acetate as catalyst precursor,
and SPhos as the ligand. The use of this particular ligand and catalyst is particularly relevant
here as Buchwald et al. found that the use of a catalyst formed in situ from these two
compounds worked very well for Suzuki-Miyaura type cross-coupling reactions with aryl
chlorides.59 This was the basis for the work by Whelligan et al. and the reason for their
selection in this project with these conditions.8
1.3.4.2.2 Suzuki reaction on heterocycles
It was also necessary for the azaindole syntheses to find conditions which permit Suzuki
coupling of halo-heterocycles. The literature shows that the Suzuki reaction can be carried
out on different heterocycles (Schemes 1.21, 1.22).61
20
Scheme 1.21
Scheme 1.22
Although the examples shown here use chlorides, heteroaromatic bromides and iodides can
also be coupled in Suzuki reactions. The focus on chloroarenes results from their lower cost
and ready commercial availability.8 Another thing to note is that the aforementioned
heterocycle reactions use XPhos as opposed to SPhos, as Billingsley et al. found that the
SPhos/Pd(OAc)2 combination proved inefficient for reactions involving unactivated
heteroaryl chlorides, whereas the use of XPhos did not lead to loss of activity.61
1.3.4.2.3 Suzuki reaction on amino-substituted heterocycles
Finally, prior to the azaindole synthesis by Whelligan et al, there were also published
examples of the Suzuki reaction being carried out on heterocycles bearing amino
substituents (Schemes 1.23).61,62
Scheme 1.23
21
Importantly, Buchwald et al. published a paper showing successful Suzuki coupling of a
number of amino substituted substrates, all in good yields (79% - 99%, Scheme 1.24, Table
1.1).63
Scheme 1.24
Table 1.1 - Suzuki couplings of amino substituted substrates.63
Aryl Chloride
Product
Yield (%)
99
82
95
79
92
97
92
22
Prior to Buchwald’s papers, there were few reports of successful Suzuki couplings of aminoheteroaryls.63 Usually the amino group had been protected prior to the coupling as it has
been suggested that the it binds to the metal centre of the catalyst and halts the catalytic
cycle.63 However, with use of the monodentate, hindered ligand SPhos, the resulting Pdcatalyst prevented this and permitted successful Suzuki couplings of amino bearing
heterocycles.
Hence,
this was the system employed for the synthesis of
ethoxyvinyl(amino)arene precursors to azaindoles.
1.3.5 Protection and Reactions of Pyrroloarenes
The reactivity of azaindoles depends on the type of reaction. Electrophilic aromatic
substitution will occur at the 3-position whereas other reactions are most likely to occur at
the 1-position as this contains the most acidic proton, followed by the proton in the 2position. To achieve reaction in the 2-position, protection of the NH group is required.
Electrophilic aromatic substitution may also require protection of the NH group depending
on the individual reaction. The pyridine ring in the azaindole is notoriously hard to
functionalise but it is possible, for example, if the pyrrole ring is already fully functionalised.
1.3.5.1 Reaction at the 1-position
Functionalisation at the pyrrole nitrogen atom, the 1-position, occurs for all of the azaindole
isomers. For example N-amination has been reported on 7-azaindole in 97% yield (Scheme
1.25).45,64
Scheme 1.25
N-Arylation has been demonstrated on 6-azaindole (Scheme 1.26).4,65 This occurred
between an iodo derivative 86 and the 6-azaindole 85 in the presence of catalytic Pd2(dba)3
with a biphenyl-2-yl(dicyclohexyl)phosphine ligand during a research programme targeting
a new, selective mGlu5 receptor antagonist. 4,65
23
Scheme 1.26
An example of N-alkylation by a benzyl chloride was given during the synthesis of novel
inhibitors 90 of VEGFR-1/2 kinases. It is on 5-azaindole and is shown in Scheme 1.27.4,66
Scheme 1.27
1.3.5.2 Reaction at the 2-position
As discussed above, functionalisation at the 2-position usually requires protection of the
pyrrole NH first. The characteristics of a good protecting group include being easy to apply
and easy to remove so as not to lose any material, and also to be inert to the desired
reaction that it is protecting from. One of the most common protecting groups for
azaindoles is the boc group 91 (tert-butyloxycarbonyl) (Fig. 1.17)
Fig. 1.17 Boc protecting group
24
The boc group can be attached to the amine group using di-tert-butyl dicarbonate under
aqueous conditions and then removed again using hydrochloric acid in methanol. An
example of 2-functionalisation of a Boc-protected azaindole can be seen in scheme 1.28.67
Scheme 1.28
Another protecting group often used for azainoles is the phenylsulfonyl group. This
electron-withdrawing group also helps activate the ring towards deprotonation at the 2position.
For example, 7-azaindole was first protected as a phenylsulfone and then
deprotonated at the 2-position with LDA before methylation with methyl iodide (Scheme
1.29).68 The protected azaindole was produced in 87% yield and the methylated product in
96% yield.68
Scheme 1.29
2-Aroylazaindoles were synthesised and explored as potential antimitotic agents.4,69
Similarly to above, 1-phenylsulfonyl-5-methoxy-4-azaindole 98 was lithiated in the C-2
position, using LDA, and condensed with methoxybenzoyl chloride to give 99 in 44% yield
(Scheme 1.30). 4,69
25
Scheme 1.30
An example can also be seen for the 2-stannylation of 5-azaindole, again first protected as
the phenylsulfone (Scheme 1.31).4,70
Scheme 1.31
1.3.5.3 Reaction at the 3-position
Azaindoles do react with electrophiles at the 3-position, in an analogous manner to indoles,
but with much lower activity due to the reduction in nucleophilicity by the additional
nitrogen atom.50 Of the reactions that can occur at the 3-position of azaindoles, there is one
that is particularly relevant to this research, and that is the bromination reaction. The first
reported bromination of azaindoles occurred in 1956 where Robison brominated 7azaindole in 81% yield using bromine in CCl4 at 0 °C.71 Following this Yakhontov et al
successfully brominated 4- and 5-azaindole (89 and 99% crude yields, respectively) with
bromine in dioxane at 15 °C for 1 h.72 A method to brominate all azaindole regioisomers in
the 3-position was later developed by Gallou, who also included the bromination of some 2substituted azaindoles.73,74 This novel method used copper(II) bromide in MeCN at room
temperature as can be seen in Scheme 1.32.
Scheme 1.32
26
Other halogens can also be used in place of bromine. The first iodination of 7-azaindole used
iodine in CCl4 and CHCl3.75 The first chlorination of 7-azaindole used NCS in CCl4 and CHCl3.76
However, in the research conducted for this dissertation, it was hoped to be able to
brominate in the same step as the cyclisation in order to minimise the number of steps
required in the synthesis.
1.4 Furoarenes (Benzofurans and Furopyridines)
1.4.1 Introduction
Furoarenes are aromatic bicyclic heterocycles that include both benzofurans and
furopyridines. A benzofuran is a benzene ring fused to an aromatic five-membered ring that
contains an oxygen atom 104 (Fig. 1.18).
Fig. 1.18
A furopyridine is a bicyclic heterocycle that contains an aromatic six-membered ring
containing a nitrogen atom fused to a five-membered ring containing an oxygen atom 105
(Fig. 1.19).
Fig. 1.19
The nitrogen atom in the 6-membered ring (the pyridine) can be in position 4, 5, 6, or 7 (Fig.
1.20).
27
Fig. 1.20
Furopyridines are analogous to pyrrolopyridines but possess a hydrogen bond acceptor, in
the form of an oxygen atom, where the pyrrolopyridine has an N-H hydrogen bond donor.
This creates a molecule with a different, but equally useful activity to the azaindoles,
allowing interactions with a different range of molecules whose active sites may contain
hydrogen bond donors to interact with the furopyridine’s two hydrogen bond acceptors. As
with the azaindoles, the position of the nitrogen atom in the pyridine ring must be carefully
considered in terms of its reactivity in both its synthesis and reactions.
1.4.2 Occurrences and uses of Furoarenes (Benzofurans and
Furopyridines)
Benzofuran has never been isolated from a natural product. However, the structure does
occur in nature in substituted forms. For example, 9-methoxy-7H-furo[3,2-g][1]benzopyran7-one 110 (Fig. 1.21) has been isolated from many natural products such as the leaves of the
medicinal shrub Angelica keiskei from Korea; the leaves, fruits and stems of the herb Ruta
graveolens from Italy and the roots of the herb Peucedanum praeruptorum, also from
Korea.77-79
Fig. 1.21
Another example is coumestrol 111 (Fig. 1.22), a benzofuran containing structure that has
been isolated from several plants including the roots of the Campylotropis hirtella found in
China, the roots of the Pueraria iobata found in Korea, and the tuberous roots of the
Pueraria mirifica found in northern Thailand.80-82
28
Fig. 1.22
Furopyridines are very rarely found in nature.83 One derivative that has been found is
Citridone A 112 (Fig. 1.23), a natural product isolated from the fermentation broth of the
fungus Penicillium sp. FKI-1938, which actually consists of a pyridone (a tautomeric form of a
hydroxypyridine) fused to a dihydrofuran.84 It has been shown to exhibit reinforcement
effects toward miconazole (an imidazole antifungal agent) activity against Candida albicans
(a fungus that causes infections in patients with compromised immune systems).84,85
Fig. 1.23 Citridone A
Interestingly, apart from Citridone A, there are no naturally occurring structures that include
the 4-, 5-, or 6-isomers of the furopyridines. The 7-furopyridine moiety however, has been
identified in around 145 compounds isolated from natural sources. For example,
skimmianine 113 (Fig. 1.24) has been isolated from many sources including the roots of the
Zanthoxylum atchoum from the Ivory coast, the leaves, fruits and stems of the tree Ruta
graveolens from Italy (which also contained the benzofuran containing compound 9methoxy-7H-furo[3,2-g][1]benzopyran-7-one 110) and the leaves of the tree Evodia lepta
from Thailand.78,86,87
29
Fig. 1.24
Another example is dictamnine 114 (Fig. 1.25), isolated from the root bark of the Dictamnus
angustifolius, the stems and roots of the Clausena iansium from China and the stem bark of
the Hortia superba from Brazil.88-90
Fig. 1.25
One more example of the 7-furopyridine isomer occurring in nature is kokusaginine 115 (Fig.
1.26). This structure can be isolated from places including the leaves of the Ruta angustifolia
from Indonesia, the twigs of the Glycosmis cochinchinensis from northern Thailand, and the
leaves of the Melicopetriphylla collected from Japan.91-93
Fig. 1.26
Something to be noted within all three of these structures containing the 7-isomer is that all
are part of a bigger three ring structure whereby an additional benzene ring is attached to
the pyridine ring. In fact, in all 145 naturally occurring structures that contain this isomer, all
contain this third ring, although some with varying amounts of saturation. Therefore, it
seems the only time a furopyridine occurs in nature is when it is the 7-furopyridine isomer
and when this third ring is part of the molecule’s substitution.
30
Although furopyridines rarely occur in nature, they have often been used in medicinal
chemistry. For example, furopyridine-substituted pyrimidines have found use as HCV
(hepatitis C virus) replication inhibitors.94 Interestingly, prior research had provided
benzofuran substituted pyrimidine 116 (Fig.1.27) but it was found that by replacing the
benzene ring with a pyridine ring to give 117, the activity improved from an EC50 of 300 nM
to 70 nM.94
Fig. 1.27 Benzofuran and pyridofuran HCV replication inhibitors
Other example drugs containing a furopyridine moiety include the potent HIV protease
inhibitor, L-754,394 118, and the HIV reverse transcriptase inhibitor, PNU-142721 119 (Fig.
1.28).83,95,96
L-754,394
PNU-142721
Fig. 1.28
31
1.4.3 Synthesis of Furoarenes
1.4.3.1 Established syntheses and their limitations
Syntheses of furopyridines are based on those of benzofurans.97 One method for
synthesising benzofurans is the Perkin rearrangement where a coumarin 120 is reacted with
hydroxide (Scheme 1.33).98,99
Scheme 1.33
This method, originally discovered in 1871, involves a two-step mechanism whereby the first
stage is a relatively rapid base-catalysed ring hydrolysis of the 3-halocoumarin to give (E)-2halo-3-(2-hydroxyphenyl)acrylic acid, followed by a relatively slow cyclisation process. 96,97
Another common synthesis of benzofurans involves a Sonogashira reaction between 2halophenols and alkynes followed by cyclisation of the resulting 2-alkynylphenols.100,101 This
method has also been applied to the synthesis of furopyridines as shown in the example in
Scheme 1.34. Here, the final furopyridine 125 is unsubstituted at the 2- or 3-positions
because trimethylsilylacetylene was chosen for the Sonogashira reaction. The TMS group is
partially lost in the CuI-mediated cyclisation step in EtOH/Et3N and the remaining 2-TMSfuropyridine 124 is converted to 125 by the addition of potassium carbonate.
32
Scheme 1.34
A later method developed by Larock used iodine to mediate the cyclisation of
alkynylanisoles and this simultaneously installed an iodine atom at the 3-position (Scheme
1.35).102,103
Scheme 1.35
This method has also been shown to work for furopyridines such as that shown in scheme
1.36.103
Scheme 1.36
Again however, this method was only applied to one of the pyridine isomers and produces a
substituted product. There are other methods in the literature for the synthesis of
pyridofurans; some of these are discussed below.
33
An unusual method for synthesising furopyridines involves building the pyridine onto a
furan through a photocyclisation process (Scheme 1.37).104 This reaction can also be used to
synthesise thio-pyridines (Scheme 1.37), and also pyrrolopyridines.104 The proposed
mechanism is shown in Scheme 1.38 and involves a six π-electron photoannulation process
with formation of a secondary amine which loses molecular hydrogen under
irradiation.104,105 The reaction conditions are mild but the yield varies from 8% to 98%.
However, as far as the authors were aware, there was no other general method for
synthesising all three types of pyridines. It should be noted that all products reported via
this method contained substituted pyridines.
Scheme 1.37
Scheme 1.38
34
An interesting alternative method to access furopyridines involves heteroatomic C-H
insertion into alkylidenecarbenes (Scheme 1.39).106 This reaction takes place under very
mild conditions and gives reasonable yields (from 44% to 86%), such as 65% for 2phenylfuropyridine. It also works for meta starting materials, producing a mixture of both
isomers as separable products.106 Once again, all products reported are substituted versions
of the furopyridines, and the method has not been extended to include pyrrolopyridines. It
is also limited to producing only one of the pyridine isomers.
Scheme 1.39
There are methods in the literature for synthesising unsubstituted versions of the
pyridofurans. For example, 4-pyridofuran 143 has been synthesised in 85% yield via a onepot Sonogashira coupling/heteroannulation sequence as can be seen in scheme 1.40.107
However, the hydroxy group requires acetylation prior to the Sonogashira, adding an extra
step to the sequence.
Scheme 1.40
35
Similarly, 6-pyridofuran 146 can also be synthesised unsubstituted using a Sonogashira
coupling reaction (Scheme 1.41).108
Scheme 1.41
Acetylation is avoided when 2-fluoro-3-alkynylpyridine 147 is synthesised. This is then
converted to 7-pyridofuran using hydroxide, presumably via an SNAr reaction-cyclization
cascade sequence (Scheme 1.42).109
Scheme 1.42
In summary, although there are methods for the synthesis of unsubstituted pyridofurans,
there is not one that has been shown able to access all the different isomers.
1.4.3.2 Proposed synthesis via ethoxyvinyl(hydroxyl)arenes
In this work, the proposed method for the synthesis of the pyridofurans involves the
synthesis and use of stable ethoxyvinyl(hydroxy)arene intermediates followed by
intramolecular electrophilic cyclisation (Scheme 1.43).
Scheme 1.43
36
As with the azaindoles, the proposed synthesis of the ethoxyvinyl(hydroxy)arenes is via the
Suzuki reaction of hydroxy-halo-pyridines with an ethoxyvinylborolane.8 The Suzuki reaction
is explained in chapter 1.3.4.2.
1.4.3.2.1 Hydroxy-substituted substrates in Suzuki reactions
In order to synthesise the ethoxyvinyl(hydroxy)arene intermediates to use in the proposed
pyridofuran synthesis, conditions needed to be found that allowed the use of hydroxy
containing starting materials in Suzuki couplings. Examples can be found in the
literature.59,110 It was found that the same conditions that were used for amino substituted
substrates could also be used for hydroxy substituted substrates as shown in scheme 1.44.
Scheme 1.44
These conditions, using a particular ligand-catalyst system formed in situ, are the ones
Buchwald et al. found that worked very well for Suzuki-Miyaura type cross coupling
reactions with aryl chlorides, and so formed the basis for the work by Whelligan et al.8,59
There are also examples in the literature of hydroxy-substituted substrates that are not
aromatic ring structures (Scheme 1.45).110
Scheme 1.45
These examples show that it is possible to carry out Suzuki coupling reactions on starting
materials bearing a hydroxy group.
37
1.4.3.2.2 Suzuki reaction on hydroxy-substituted heterocycles
As well as finding conditions that support the presence of a hydroxy group on the starting
material, it is also desirable to find conditions that allow for the presence of a hydroxy group
specifically on a heterocycle. One such example can be seen in scheme 1.46.62
Scheme 1.46
While XPhos was found to be a successful ligand in the Suzuki reaction of chloro-aminopyridines, the coupling of the heterocycle with a hydroxy substituent uses a different ligand.
It is still a phosphorus containing ligand but this time the researchers, Kudo et al., set out to
find a versatile ligand specifically for nitrogen containing heterocycles that was cheaper than
some of the more traditional ligands and, due to previous success, decided to use PCy3.62
The hydroxy group is tolerated without a problem, no other isomers were used.
1.4.4 Reactions of Furoarenes
The literature contains very few examples of reactions taking place on unsubstituted
furopyridines. This is in contrary to benzofuran which has many reported functionalisations,
for example its di-bromination or its Pd-catalysed C-2 arylation reaction with an aryl halide
(schemes 1.47 and 1.48 respectively).111,112
Scheme 1.47
38
Scheme 1.48
In the case of furopyridines it appears to be far more common that substituents are
incorporated as part of the original synthesis of the furopyridine. This is most likely due to
the fact that these molecules are very rarely found in nature and so have to be synthesised
therefore reducing the number of steps in the synthesis is advantageous. The second reason
is that one of the most common methods of synthesis uses a Sonogashira coupling reaction
whereby the o-hydroxyalkynylpyridines are unstable molecules which cyclise readily to give
substituted furopyridines (Scheme 1.49).103,107
Scheme 1.49
However, there are some examples of the functionalisation of furopyridines. For example, 4furopyridine has been substituted in the 2-position by deprotonation with butyl lithium
followed by reaction with varying electrophiles (Table 1.2).107
39
Table 1.2 – Functionalisation of 4-furopyridine in the 2-position107
a
b
Electrophile
Yield (%)
168
Br
76
169a
CH(OH)Ph
95
170a
SMe
89
171a
SiMe3
70
172b
SnBu3
84
173a
CHO
85
Condensation was performed at -78 °C
Condensation was performed for 15 min
The yields of these reactions are good to high proving that although not common,
substitution of these molecules can be successful.
Examples can also be seen for the 5-furopyridine isomer although these are more limited to
reactions such as halogenation and nitration (Schemes 1.50 and 1.51 respectively).113,114
Scheme 1.50
Scheme 1.51
40
For the 6-furopyridine isomer, it is a similar situation to the 4-furopyridine isomer whereby
the molecule has been substituted in the 2-position, in good to high yields, by varying
electrophiles after deprotonation using butyl lithium (Table 1.3).108
Table 1.3 – Functionalisation of 6-furopyridine in the 2-position.108
Electrophile
Yields (%)
180
SiMe3
77
181
D
76b
182
Cl
71c
183
CH(OH)Ph
81
184
SMe
78
185
Br
75c
186
SnBu3
80d
b
DCl/D2O (DCl 35 wt % in D2O, 20 equiv) was used as electrophile
Trapping step was performed at -95 °C
d
Trapping step was performed for 15 min at -95 °C
c
With the 7-furopyridine isomer, published reactions are simple halogenations and nitrations
like those of the 5-isomer (Schemes 1.52 and 1.53).114
Scheme 1.52
Scheme 1.53
41
It can be noted that although these are the same reactions and reaction conditions that
were used for the 5-isomer, the yields are noticeably higher for the 7-isomer.
Overall it seems that reactions taking place on furopyridines are limited. However, the work
in this project aims to put a bromine ‘handle’ in the 3-position of the furopyridines, rather
than reacting unsubstituted structures such as these, to allow further conversions to be
carried out.
1.5 Reactions of Ethoxyvinyl Compounds with Brominating Agents
1.5.1 Bromination Reactions
Bromine or bromine-containing molecules are commonly used in organic reactions. The
electrophilic addition of bromine to alkenes is very well known and provides an opportunity
for a variety of subsequent reactions to take place on the molecule because bromine makes
a very good leaving group due to its ability to stabilise the negative charge.
Scheme 1.54
Quite often only single bromination is desired as opposed to the double bromination seen in
the example above. This is particularly true if the purpose of bromination is to provide a
‘handle’ to enable further reactions. To achieve this, brominating agents such as Nbromosuccinimide (NBS) can be used which only have one bromine atom available. An
example of its use is in the Wohl-Ziegler reaction which involves the bromination of
cyclohexene with NBS producing a single brominated product as seen below.
42
Scheme 1.55
However, this does not prevent a mixture of products including di- or even tri-brominated
products forming alongside singularly brominated product and unreacted starting material
from being formed. It depends on the reactants used and the conditions employed.48
Reactions that can be used to build up a molecule once a bromine ‘handle’ is present are
nucleophilic substitution reactions as well as coupling reactions. The latter involves the
formation of a new carbon-carbon bond. As previously mentioned bromine containing
molecules can also act as electrophiles that both attack a molecule and promote
intramolecular cyclisation in the same step (Scheme 1.54).
It can be seen that bromination reactions are both varied and of great use. However, it is
important to look at bromination reactions on molecules similar to those that are intended
to be used within this thesis to identify what unwanted side reactions may take place when
carrying out this research.
Part of the research described in this thesis involves modifying the published acid-catalysed
cyclisation of ethoxyvinyl(amino)arenes, to give azaindoles, to use alternative electrophiles
to H+ and provide 3-substituted azaindoles.
The proposed electrophilic substitution
mechanism, using E+ as an example electrophile, is shown in Scheme 1.56.
Scheme 1.56
43
There are examples of related reactions (electrophilic attack of ethoxyvinyl compounds,
electrophilic cyclisations) in the literature and these are discussed below.
The first example (Scheme 1.57) uses bromine (Br2) as the electrophile to brominate an
ethoxyalkene and shows that the substrate is reactive to such electrophiles at low
temperature despite also bearing an electron-withdrawing group. This is of relevance to an
ethoxyvinylpyridine where the N-atom is in conjugation with the alkene.
Scheme 1.57
Of more interest are reactions where the electrophile both attacks and promotes cyclisation
in the same step. The reactions shown in Schemes 1.58 and 1.59 are of particular interest as
they involve intramolecular nucleophilic attack on a bromonium ion intermediate.
Scheme 1.58
44
Scheme 1.59
The proposed mechanism for the reaction of Scheme 1.59 can be seen in Scheme 1.60
below. It involves formation of a bromonium ion from the C=C of the allene unit to give an
intermediate which is then attacked by the aryl group. Loss of MeOH gives the desired
product.
Scheme 1.60
Although these reactions show the potential of cyclising onto an intermediate bromonium
ion, no examples were found which used an amino or hydroxy group as the intramolecular
nucleophile. Nevertheless, it was thought that conditions would be found to promote the
favourable conversion of ethoxyvinylarenes into 3-substituted aromatic azaindoles and
furopyridines.
45
The bromination of aniline is rapid and results in poly-brominated products. The amino
group is highly activating, and ortho, para directing. This can be overcome by protecting it,
for example by forming an amide, thus making it less activating and promoting monobromination. It is likely a mixture of ortho and para products will still form but para should
be the dominating product and should be separable from the ortho product. Another way to
overcome this is by swapping the brominating agent from bromine to NBS. It has been
found that by reacting aniline with NBS in the presence of a catalyst, NH 4OAc, para
substituted bromoaniline is produced without the need for a protecting group.115
Scheme 1.61
This reaction also works for 2-aminopyridine, producing a mono-brominated product in 98%
yield with the bromine atom still placed para to the amino group (Scheme 1.62).115
Scheme 1.62
A similar multi-bromination occurs with aminopyrroles although this is mainly at the alpha
positions due to the intermediate’s ability to support the positive charge. However,
monobromination has been reported in the 2-position of the pyrrole ring when NBS is used
as the brominating agent. Conditions include DMF or DCM as solvent with a Lewis acid
catalyst (Scheme 1.63).116,117
46
Scheme 1.63
Monobromination of indoles in the 3-position can be achieved using Br2 and trimethyltin
chloride at -78°C to room temperature (Scheme 1.64).118
Scheme 1.64
The first bromination of pyrrolopyridines was reported in 1956 when Robison brominated 7azaindole in 81% yield.71 Bromine was used in CCl4 at 0 °C. Following this Yakhontov et al
successfully brominated 4- and 5-azaindole (89 and 99% crude yields, respectively) with
bromine in dioxane at 15 °C for 1 h.72 A method to brominate all azaindole regioisomers in
the 3-position was later developed by Gallou, who also included the bromination of some 2substituted azaindoles.73,74 This novel method used copper(II) bromide in MeCN at room
temperature as can be seen in Scheme 1.65.
Scheme 1.65
Other halogens can also be used in place of bromine. The first iodination of 7-azaindole used
iodine in CCl4 and CHCl3.75 The first chlorination of 7-azaindole used NCS in CCl4 and CHCl3.76
47
It can be seen that bromination can be a difficult reaction to control and that the reaction
conditions are very important. This will be especially true in this work as the target is not
only mono-bromination but to cyclise at the same time.
1.5.2 Iodination Reactions
Iodine works in much the same way as bromine. The first iodination of 7-azaindole was
published in 1969.75 It involved the use of iodine in CCl4 which was added to 7-azaindole in
CHCl3 (Scheme 1.66).75
Scheme 1.66
Later methods for the iodination of 7-azaindole used iodine and KOH in DMF at room
temperature, as well as iodine and potassium iodide in aqueous ethanol.70,119-121 As NBS is a
more convenient reagent for bromination, so NIS (N-iodosuccinimide) is a more convenient
reagent for iodination. NIS has been used for various substituted azaindoles in varying
solvents including THF (Scheme 1.67), acetone, DMF and DCM.122-125
Scheme 1.67
The bromination of benzene requires a Lewis acid catalyst to polarise the bromine bond,
making it electrophilic enough to complete the reaction. Iodine on the other hand requires
an acidic oxidising agent such as nitric acid as a reagent in order to iodinate benzene. This is
due to the extra shielding of electrons that iodine has. An example of this can be seen in
scheme 1.68.126
48
Scheme 1.68
However, more modern methods for this reaction, such as that employing a silver salt
catalyst seen in scheme 1.69, do not require the acidic oxidising agent for the reaction to
proceed.127
Scheme 1.69
Iodination has also been shown to work on heterocycles such as pyridine.128 This involved a
two-step reaction producing a final yield of 50%.128
Scheme 1.70
It has already been shown that the reaction works for 7-azaindole (Scheme 1.66) but it also
works for other isomers such as 5-azaindole (Scheme 1.71).70
Scheme 1.71
49
Interestingly, there is no recorded reaction of iodination taking place on an unsubstituted
furopyridine in the 3-position for any of the isomers. It is unknown as to whether it has been
attempted or not. However, it has been achieved on substituted furopyridines (Scheme
1.72).129
Scheme 1.72
1.6 Aims and Objectives
The aims of the research project are outlined below (and summarised in Scheme 1.73) along
with the steps taken to achieve them.
1 Preliminary Work – Establish reproducibility of azaindole synthesis published by
Whelligan et al. and generate ethoxyvinyl(amino)arenes:

Synthesise ethoxyvinylborolane starting material

Synthesise ethoxyvinyl(amino)arenes following published procedure
2 Investigate the reaction of ethoxyvinyl(amino)arenes with alternative electrophiles to
acid to potentially give 3-substituted azaindoles, especially bromides.
3 Develop a synthesis of ethoxyvinyl(hydroxy)arenes as precursors to furopyridines.

Synthesise halo-hydroxy-arene starting materials by halogenating hydroxyarenes
in the ortho position

Establish conditions to couple these with ethoxyvinylborolane in a Suzuki
reaction

Cyclise the ethoxyvinyl(hydroxy)arenes to give furopyridines
50
4 Demonstrate the utility of the method through access to medicinally relevant molecules.
Scheme 1.73 – Summary of the aims of the project
51
2 Results and Discussion
As previously discussed in chapter 1.1, azaindoles are prolific in the field of drug discovery
but their appearance in nature is limited.1 Although methods for synthesising these
structures have been known for many years, each is limited to a certain isomer or number
of isomers, and usually involves specific substitutions on the azaindole rings. 2-7 The
aforementioned two-step method, reported by Whelligan et al, for synthesising both
substituted and unsubstituted azaindoles gives reasonable yields for all isomers with no
need for protecting groups (Scheme 2.1).8
Scheme 2.1
The cyclisation step shown in scheme 2.1 uses acetic acid as an electrophile and is proposed
to work through the mechanism below (Scheme 2.2). It is hypothesised that, if the
electrophilic proton of the acid is replaced by an electrophilic bromine atom, in the form of,
for example, N-bromosuccinimide, the cyclisation should result in the simultaneous
installation of a bromine atom in the 3-position of the azaindole.
52
Scheme 2.2
Examples of intramolecular cyclisation reactions resulting in a brominated product have
been described in the literature, as discussed on page 44 (Scheme 2.3).130
Scheme 2.3
Therefore, it is hypothesised that, with the use of the electrophilic brominating agent, it will
be possible to synthesise all isomers of azaindole with a bromine atom in the 3-position
using the same method. This will then be extended to the use of substituted azaindole
examples. Further to this, the same method will be used to synthesise all isomers of
furopyridine with a bromine atom in the 3-position (Fig. 2.1). The utility of the method will
then be demonstrated through access to medicinally relevant molecules through
subsequent reactions such as Heck or Suzuki couplings.
53
Fig. 2.1
The differing position of the nitrogen atoms in these molecules greatly changes the
electronics of the amino and ethoxyvinyl groups attached to them and will mean that the
method may work better for some isomers than others. However, as the published method
on which this work is based was successful for all isomers, it is anticipated that the same will
be true for this bromination-cyclisation.
Before work could begin on the novel method, first the reagent ethoxyvinylborolane 230
needed to be synthesised for use in the
Suzuki couplings to create
the
ethoxyvinyl(amino)arenes 224.
2.1 Synthesis of Ethoxyvinylborolane
The ethoxyvinylborolane 230 was synthesised according to the published procedure
(Scheme 2.4), by reacting ethoxyethyne 229 with HBPin (4,4,5,5-tetramethyl-1,3,2dioxaborolane, 228) in a hydroboration reaction using a zirconium catalyst.8,131
Scheme 2.4
54
The reaction produced reasonable yields of 76% on both 1 g and 4 g scales, compared to the
literature value of 92%.8 It was then scaled up to a 10 g reaction which was run twice and
combined for the work-up and purification to produce an overall yield of 17.8 g (89%). NMR
showed the product to be pure. Literature searches suggest that this is the largest scale,
published synthesis of this product to date8 although it is commercially available.132
During the project, it was found that the ethoxyvinylborolane could be more simply purified
by precipitation of the catalyst by addition of hexane or petrol followed by filtration through
Celite®. Although the product appeared pure by NMR (Fig. 2.2) and could be Suzuki coupled
on small scale, for larger batches the subsequent reactions failed leaving only starting aryl
halides by GC-MS.
Fig. 2.2
This was assumed to be the result of an inorganic contaminant which was undetectable by
NMR. After some optimisation, the purification method that was found to produce
ethoxyvinylborolane which was functional in Suzuki reactions, for all batch sizes, involved
precipitating out the catalyst using hexane or petrol and then filtering the material through
a pad of alumina with a layer of Celite® on top. Following this protocol, yields of the
borolane of up to 98% were achieved.
At one point during the project, the starting material ethoxyethyne became commercially
unavailable. This meant that an alternative method for synthesising the borolane compound
was required. A literature search revealed a method that used a rhodium catalyst with ethyl
55
vinyl ether to produce the desired product (Scheme 2.5).133 The paper contained no yields
for the reactions or any methods for purification.
Scheme 2.5
Nevertheless, the reaction was trialled and the crude reaction mixture analysed by GC-MS
(fig. 2.3).
Fig. 2.3
The chromatogram showed several peaks but that at 11.2 mins appeared to be product with
the correct mass spectrum and retention time when compared to previously isolated
material (fig. 2.4). The peak at 10.1 mins is pinacol, a by-product of the starting material
HBPin (4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 231)
Fig. 2.4
56
Due to the mixture of peaks in the crude product, the usual method of purification for the
ethoxyvinylborolane would not have been suitable so flash chromatography was attempted
instead. However, the product did not fully elute from the column and only a small amount
was isolated which was still mixed with impurities undetectable by TLC but present by
GCMS. It was suspected that the borolane compound may be unstable to silica and so an
alumina column was tested instead but produced the same results. Following this a stability
test was set up using silica, Celite®, neutral alumina, basic alumina and air:
Ethoxyvinylborolane was weighed into five separate conical flasks, an internal standard was
added to each (dodecane) and then the different solids being tested (air as a reference)
were added and left to stir. GC-MS samples were taken after 30 mins and again after 24 h.
The results can be seen in Table 2.1.
Table 2.1 – Stability testing of Ethoxyvinylborolane
Peak Ratio (Dodecane/Product)
Silica
Celite
Neutral Alumina
Basic Alumina
Air
After 30 mins
After 24 hrs
0.14
0.14
0.14
0.14
0.14
0.14
0.14
0.14
0.14
0.14
The results show that after 24 hours there is no decomposition of the borolane compound
under any of the conditions. This makes it difficult to rationalise why there is a difficulty in
purifying the compound. It may be that its high affinity for silica means that the polar
solvents that are required to move it through the column do not allow the separation of the
contaminants from the product. However, during this work ethoxyethyne became
commercially available again so it was decided to return to the previous method of
synthesis.
57
2.2 3-Halopyrroloarenes
2.2.1 Introduction and Aims
As previously mentioned, a method has been developed by Whelligan et al. that involves
the synthesis of azaindoles through stable ethoxyvinylarene intermediates. 8 The method
involves a Suzuki coupling reaction followed by acid mediated cyclisation using acetic acid
(scheme 2.6).8
Scheme 2.6
The method was shown to work for all isomers of azaindole as well as some substituted
versions.8 It was therefore hypothesised that by replacing the acid with an alternative
electrophile such as bromine, the simultaneous insertion of a bromine would occur in the 3position during the cyclisation (Scheme 2.7).
Scheme 2.7
58
Although it was noted that the varying isomers will have varying reactivites, it was
anticipated that as the previously published method was successful on all isomers, that this
method should also produce positive results for all isomers.
To summarise, all of the 3-halopyrroloarenes that are to be synthesised using this novel
method can be seen in figure 2.5.
Fig. 2.5
In order to achieve this first the Suzuki coupling will need to be completed on all starting
materials, followed by the electrophilic bromination cyclisation step.
2.2.2 Suzuki Coupling of Ethoxyvinylborolane with Haloaminopyridines
The coupling of halo-aminopyridines with ethoxyvinylborolane was carried out using the
method previously published by Whelligan et al.8 As in this paper, it was decided that
repetition of the syntheses of the various regioisomers should begin with the isomer
theoretically least amenable to the reaction to ensure conditions were optimal for all
isomers. The most challenging of the pyridine isomers for the Suzuki coupling should be 3chloro-4-aminopyridine because the chlorine atom is meta to the pyridine’s nitrogen atom,
and therefore less activated, and the amino group is para to the pyridine’s nitrogen which
causes the whole molecule to be rather basic (pKa = 7.2) and strongly coordinating.8,134
The first attempt at repeating the coupling of the 3-chloro-4-aminopyridine gave a yield of
only 28%, compared to the literature value of 69%.8 The reaction used Pd(OAc)2 as the
catalyst, SPhos as the ligand, KOH as the base and acetonitrile as the solvent (Scheme 2.8).
59
Scheme 2.8
Increasing the reaction time and the amount of catalyst / ligand had no positive effect on
the yield. When the base was swapped for KOtBu, the reaction did not proceed (only
starting material was detected by GC-MS). The use of RuPhos instead of SPhos, however,
had a positive impact. The results are summarised in Table 2.2.
60
Table 2.2 – Optimisation of conditions for Suzuki coupling of 3-chloro-4-aminopyridine.
Entry Base
Ligand
Temp Time Yield
(°C)
(h)
(%)
1
KOH
SPhos
82
18
28
2
KOH
SPhos
82
36
3
3
KOH
SPhos
82
18
17
4
KOH
SPhos
82
18
44
5
KOtBu SPhos
82
18
0
6
KOH
82
18
54
RuPhos
Notes
Reaction in round bottom
flask. Ethylacetate and
isopropanol used in flash
column chromatography
Reaction in round bottom
flask. Ethylacetate and
isopropanol used in flash
column chromatography
Reaction in Schlenk tube.
Ethylacetate
and
isopropanol used in flash
column chromatography
Reaction in Schlenk tube.
Ammonia in methanol and
DCM used in flash column
chromatography
Reaction in Schlenk tube.
Ammonia in methanol and
DCM used in flash column
chromatography
Reaction in Schlenk tube.
Ammonia in methanol and
DCM used in flash column
chromatography
The reason for RuPhos being more effective than SPhos is not clear. Essentially, the only
difference is that RuPhos has two ortho isopropyl groups on the biphenyl whereas SPhos has
two methyl groups. RuPhos will therefore have increased steric hindrance, which should
mean it is harder for the ligand to bind to the metal. However, it is believed that the
monoligated L1Pd intermediate is a key species in the Suzuki coupling catalytic cycle and
that bulky and electron-donating ligands stabilise this over bisligated species (Fig. 2.6).135,136
Larger groups attached at the ortho position of the lower aryl ring increase the
concentration of L1Pd(0).136 Also, the increased size of the ligand overall slows the rate of
oxidation by fortuitous oxygen and allows a more stable palladium-arene interaction.136
61
Fig. 2.6
Following this optimisation, it was decided to scale up the reaction and a yield of 54% was
again obtained to provide 1.9 g of 3-ethoxyvinyl-4-aminopyridine. Next, 2-chloro-3aminopyridine was used to synthesise a different regioisomer of the intermediate. Two
parallel reactions were run, one using SPhos and the other RuPhos (Scheme 2.9). 8 As
expected, RuPhos gave the better result, 82% compared to 64%, although the literature
yield with SPhos was 98%.8
Scheme 2.9
62
Table 2.3 – Synthesis of ethoxyvinyl(amino)arenes.
Ethoxyvinyl(amino)arene
Yield (%)
82
54
98
81
81
36
84
It was decided to use RuPhos in place of SPhos for all other isomers and analogues. Yields
for each are given in Table 2.3. The NMR spectra for all ethoxyvinyl(amino)arenes showed
characteristic doublets at 6.76 ppm and 5.60 ppm, with coupling constants of 12.7 Hz, for
the double bond and a broad singlet for the NH2 which varied in chemical shift from 4.14
ppm to 4.53 ppm. Peaks in the aromatic region were all appropriate to the individual arene
substitution pattern. All mass spectra, obtained using GC-MS, show a characteristic loss of
29 from the mass ion peak, representing the loss of the ethyl group from the ethoxyvinyl
group.
63
The yields of the reaction were varied. The highest yield achieved was for the 3-amino-4ethoxyvinylpyridine. This is because the position of the nitrogen atom allows for the
activation of the carbon chlorine bond, helping the palladium insertion for the Suzuki
coupling reaction. This is due to the nitrogen being able to support the extra negative
charge that comes from the carbon of the carbon chlorine bond in a resonance form as can
be seen in figure 2.7.
Fig. 2.7
As well as this, the pKa is 6.04 which is less basic than other isomers and so perhaps less
coordinating to palladium which may be inhibitory. The lowest yield for the unsubstituted
pyridines was, as predicted, that of the 3-ethoxyvinyl-4-aminopyridine. As previously
discussed, this is due to its high basicity and its less activated chlorine atom. It was also
inferred by Itoh et al. that the strongly basic 4-aminopyridine could increase the propensity
for coordination to palladium, which in turn could result in a bis-(pyridine) complex, thus
terminating the catalytic cycle.134 The other two unsubstituted pyridine isomers gave yields
in between these two extremes, having neither the strong basicity of the 3-ethoxyvinyl-4aminopyridine nor the activating property of the chlorine atom of the 3-amino-4ethoxyvinylpyridine. The yield for the coupling of 5-bromo-2-chloropyrimidin-4-amine was
only 36%. Part of the reason for this is that the Suzuki coupling reaction can work on both
the chlorine and the bromine atom. It was expected that the reaction would favour the
bromine atom as the chlorine-carbon bond is stronger than the bromine-carbon bond (bond
dissociation energies for Ph-X: Cl: 96 kcal mol-1, Br: 81 kcal mol-1)137 which makes it harder
for Pd0 to oxidatively insert into the aryl chloride.137 However, although the bromine was the
favoured position for the coupling, the reaction still occurred in the chlorine position and as
such lowered the final yield. The GC-MS peak area ratio for the bromine favoured product
to the chlorine favoured product was 7.62 : 1.00.
64
With all desired ethoxyvinyl(amino)arenes in hand, investigation into the one-step
bromination-cyclisation could begin (Section 2.2.4) although due to a sudden collaborative
requirement for the bromo-pyrrolopyridines, they were first synthesised in two steps
(Section 2.2.3).
2.2.3 Acid-Mediated Cyclisation of Ethoxyvinyl(amino)pyridines to
Pyrrolopyridines followed by Bromination
Before research into the one-pot, one-step bromo-cyclisation of ethoxyvinyl(amino)arenes
was begun, a collaboration was established which required the rapid synthesis of the 3bromoazaindoles plus further analogues. Preliminary investigations had shown that the
one-pot, one-step reaction was not facile so a more standard, two-pot, two-step synthesis
was used.
The synthesis involved bromination of the appropriate pyrroloarene which was either
purchased
or
synthesised
by
acetic-acid
mediated
cyclisation
ethoxyvinyl(amino)arene (Table 2.4) according to the published method.8
65
of
the
Table 2.4 – Synthesis and yields (in parentheses) of 3-bromopyrroloarenes.
Entry
Ethoxyvinylarene
Starting Material
1
n.d.1
Pyrroloarene
(Entry 1a – 7a)
(purchased)
3-Bromo-pyrroloarene
(Entry 1b – 7b)
(82%)
2
(54%)
(93%)
(69%)
(85%)
3
4
(72%)
(74%)
n.d.1
(purchased)
(73%)
(75%)
(67%)
5
(81%)
6
(36%)
(87%)
(76%)
7
(84%)
1n.d.
(77%)
(78%)
= not done.
As shown in Table 2.4, all of the seven starting materials were successfully converted to the
3-brominated versions. Yields for both the acid cyclisation and the bromination were high,
ranging from 67% to 93%. These reaction conditions did not seem to be too affected by the
position of the nitrogen atom in the pyridine ring, although the lower yields for the
cyclisation reactions occur on the 2-aminopyridine isomers where the pyridine nitrogen
atom is in conjugation with the amino group, increasing the basicity of the molecule (pKa 2aminopyridine = 6.86 vs pyridine = 5.23) but decreasing the nucleophilicity of the amino
group. Sigma withdrawal of electron density by the pyridine nitrogen atom will also
66
contribute to a reduction in the nucleophilicity of the amino group, so the cyclisation step
will most likely be slower.
This sigma withdrawal must be significant because 4-
aminopyridine isomer does not suffer from a low yield (93%) for the cyclisation reaction but
does suffer from conjugation of the amino group to the pyridine N-atom. If the literature
yields are considered, however, these arguments are not validated because all four of the
pyridine isomers (entries 1-4) were cyclised with yields of over 93%, therefore enforcing
that this method is very robust and is not affected by the position of the pyridine nitrogen
atom.8
3-Bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidine (entry 6b) is a novel compound, currently
unreported in the literature.
2.2.4 One-step Halo-cyclisation of Ethoxyvinyl(amino)arenes
As discussed in Section 1.1, it is hypothesised that if the acid in the cyclisation step was to
be replaced by an electrophilic halogenating agent then the resulting azaindole should
include a bromine atom in the 3- position.8 To investigate this, various brominating agents
were tested with the ethoxyvinyl(amino)arenes, beginning with the substrate deemed likely
to cause most problems, 4-amino-3-(ethoxyvinyl)-pyridine. The amino group of this isomer
is conjugated to the pyridine nitrogen atom, but distant from it, making it particularly basic
(the pKa of 4-aminopyridine is 9.17; c.f. 2-aminopyridine 6.86, 3-aminopyridine 5.98)138 and
nucleophilic and thus able to compete with the ethoxyvinyl group for bromination.
2.2.4.1 3-Ethoxyvinyl-4-aminopyridine isomer
For the purpose of rapidly determining successful reaction conditions, a carousel parallel
reactor was used with different combinations of solvent and halogenating agent, and
subsequently time and temperature. The different experiments are outlined in Table 2.5.
MeCN/H2O was chosen because it is the solvent system used by Yin and You130 for a
different bromo-cyclisation shown in Scheme 2.3 and the biphasic system, DCM/H2O was
chosen to replace the polar MeCN with a non-polar solvent.
67
Table 2.5 – Reaction conditions tested for one-step bromination-cyclisation.
Halogenating Solvent2,3
Temp Time
agent1
(°C)
(h)
1
NBS
DCM
rt
0.5
2
NBS
MeCN/H2O
rt
0.5
3
DBDMH
DCM/H2O
rt
0.5
4
DBDMH
DCM
-20
1
5
DBDMH
DCM/H2O
-20
1
6
DBDMH
MeCN/H2O
-20
1
7
DBDMH
DCM
rt
18
8
DBDMH
DCM/H2O
rt
18
9
DBDMH
MeCN/H2O
rt
18
10
I2
DCM
rt
18
11
I2
DCM/H2O
rt
18
12
I2
MeCN/H2O
rt
18
13
Br2
DCM
rt
18
14
Br2
DCM/H2O
rt
18
15
Br2
MeCN/H2O
rt
18
16
DBDMH
DCM/H2O
40
18
17
Br2
DCM
40
18
18
I2
DCM
40
18
1
NBS = N-bromosuccinimide, DBDMH = 1,3-Dibromo-5,5-dimethylhydantoin
2 MeCN/H O ratio of 20:1
2
3 DCM/H O ratio of 1:1
2
Entry
After an aqueous work up using sodium thiosulphate139 to quench remaining brominating
agent, all crude product mixtures were analysed using GC-MS. In the reactions using NBS, I2
or Br2 at rt and 40 °C (entries 1-2, 10-18), starting material (and succinimide for NBS
reactions) was the only peak identified, although other small unidentified peaks were
present. This suggested that no reaction had taken place and succinimide was generated
from NBS on work-up. However without an internal standard, or purification of the starting
material to give a yield of recovery, this cannot be proven because non-volatile, polar
products may not elute from a GC column. To try to eliminate the possibility that any
products made were undetectable by GC-MS, the samples were also run on the LC-MS. The
same result was found. The results of the experiments using DBDMH (entries 3-9) are
68
difficult to rationalise. GC-MS showed complete consumption of the starting material but no
significant product or by-product peaks. There was however, a broad peak (Fig. 2.8) whose
mass spectrum showed a mass of 196/198 (Fig. 2.9) suggesting it may be the desired
product. The peak at 13 mins is a by-product of the DBDMH.
Fig. 2.8
Fig. 2.9
Flash column chromatography was used to try to isolate this product but every attempt led
to loss of the material. It was decided that, in order to confirm whether it was the desired
product, the 3-bromoazaindole would be synthesised in an alternative two-step method and
the GC-MS retention times and mass spectra compared. The published acid catalysed
cyclisation was used to produce azaindole 249 and NBS in DMF was used to brominate it in
the 3-position according to a literature procedure used to produce nucleosides (Scheme
2.10).140
69
Scheme 2.10
The GC-MS chromatogram of 3-bromo-5-azaindole (250) showed a strong, sharp peak for
this product at 18.5 min (Fig. 2.10) which differed from that of the one-step product (21
min, broad). The mass spectrum (Fig. 2.11) however showed an identical fragmentation
pattern.
Fig. 2.10
Fig. 2.11
Due to the difference in retention times of the one-step product compared to the two-step
bromo-azaindole, but similarity of the mass spectra and the one-step product’s inability to
pass through a silica column, it was hypothesised that the material was in fact an oligomer
or polymer consisting of the same basic subunit which was seen as a fragment in the mass
70
spectrum. The suggested mechanism for this oligo-/polymerisation is shown below (Scheme
2.11).
Scheme 2.11
It is difficult to rationalise why the reaction would follow an intermolecular path instead of
an intramolecular path when the latter should be faster and with less entropic penalty.
2.2.4.2 One pot, one-step bromo-cyclisation of other ethoxyviny(amino)arenes
Due to the difficulties encountered with the one-pot, one-step bromo-cyclisation of 3ethoxyvinyl-4-aminopyridine, it seemed sensible to test the method on 2-ethoxyvinylaniline
where there could be no interference by a pyridine nitrogen atom. The starting material was
dissolved in acetonitrile and cooled to 0 °C. One equivalent of brominating agent (NBS) was
added and the reaction was stirred for 30 minutes (Scheme 2.12).
Scheme 2.12
A sample of the crude reaction mixture was taken for analysis by GC-MS. The chromatogram
suggested full conversion to the desired product, however, flash chromatography yielded no
71
product. A literature search explained this: the compound is unstable is not even available
to buy commercially. However, the result was still promising, as we knew that if it could be
made to work for the pyridines, these were stable enough for purification.
The first alternative azaindole isomer that was tried was 2-ethoxyvinyl-3-aminopyridine. The
same conditions were used as in Scheme 2.12. The crude sample analysed by GC-MS didn’t
show product, instead it showed a strong peak with m/z of 162. This suggested that 2ethoxy-4-azaindole 253 (Fig. 2.12) had been formed which was backed up by the
fragmentation pattern of the mass spectrum which showed a clear loss of 28 from the mass
ion peak, suggesting the loss of ethyl from the ethoxy group (with the oxygen reprotonated).
Fig. 2.12
The formation of 2-ethoxyazaindole 253 can be explained by reference to the proposed
mechanism of the bromo-cyclisation (Scheme 2.2). It can be assumed that the first two
steps go as planned but on the third step, HBr is eliminated instead of EtOH (Scheme 2.13).
Scheme 2.13
It was hypothesised that the reason this was happening was the improved leaving group
ability of bromide compared to ethoxide. The elimination could be taking either an E1 or E2
mechanistic route and elimination of HBr over HOEt could be further favoured by
72
stabilisation of partial carbocation character in the transition state of the E2 reaction, or the
carbocation intermediate of the E1 mechanism, by conjugation with the aromatic ring and
the lone pair of the amino group through the aromatic ring.
In order to improve the leaving group ability of ethoxy over bromide, one equivalent of
trifluoroacetic acid was added to the reaction mixture before the brominating agent was
added in order to protonate the ethoxy group. This proved successful, and the reaction
(Scheme 2.14) gave 3-bromo-4-azaindole in a yield of 67%.
Scheme 2.14
Following the success of this reaction, the other three pyridine isomers were tested. The
results can be seen in Table 2.6 below.
Table 2.6 – One-pot one-step bromo-cyclisation of all pyridine isomers
Starting material
Yield (%)
67
89
21
0
The results were varying, and unfortunately this method was still unsuccessful for the 3ethoxyvinyl-4-aminopyridine isomer and low yielding for the 3-ethoxyvinyl-2-aminopyridine
73
isomer, both of which have the amino group in conjugation with the pyridine nitrogen atom.
The basic and nucleophilic character of these molecules may lead to competing reactions
such as bromination on the pyridine nitrogen atom which consumes brominating agent and
prevents it from reacting with the ethoxyvinyl group.
The reaction with the 4-ethoxyvinyl-3-aminopyridine isomer worked very well giving a yield
of 89%. This is likely due to the pyridine nitrogen atom not being in conjugation with the
amino group and so the molecule has a reduced nucleophilicity compared to the 2-amino
and 4-aminopyridine isomers. The yield of this isomer is also higher than for the 2ethoxyvinyl-3-aminopyridine (67%) and this is thought to be due to the distance of the
ethoxyvinyl group from the pyridine nitrogen atom.
Both have the vinyl group in
conjugation with the nitrogen atom so both should have ethoxyvinyl groups more electron
poor than the other two enantiomers and this should inhibit bromination slightly. However,
the 2-ethoxyvinyl isomer also suffers from sigma withdrawal of electron density from the
ethoxyvinyl group because the pyridine nitrogen atom is only two bonds away. This further
reduces the rate of bromination which leads to a lower yield in the face of competing
reactions.
Future work would be to screen substituted pyridine isomers and other analogues to extend
the scope of this work and to investigate the actual mechanism by which TFA promotes the
desired bromo-cyclisation. As well as promoting elimination of the ethoxy group, the acid
may also be responsible for one or both of the following (Scheme 2.15):
1. Activating NBS by protonating a carbonyl group
2. Protonating the amino group and so reducing the nucleophilicity of the molecule
and thus inhibiting competing bromination of the pyridine
74
Scheme 2.15
2.2.5 Two-step, one-pot Cyclisation-Halogenation of
Ethoxyvinyl(amino)arenes
During the work on the one-pot, one-step method, owing to the difficulty of producing a
method for the bromination-cyclisation of 2-ethoxyvinyl-3-aminopyridine, it was decided to
try a one-pot, two-step method instead. This would hopefully prevent any polymerisation
while avoiding the need for work-up and purification after the first step. For the published
cyclisation to azaindole, acetic acid was used as catalyst and solvent and the reaction
required heating at reflux for 4 hours.
In the literature, acetic acid has been used
comparatively rarely as a solvent for brominations (although examples do exist)141,142
perhaps owing to its high boiling point (118 ⁰C) and inconvenient removal, so for the
cyclisation step, DCM was used as solvent and 0.18 equivalents of p-toluenesulfonic acid, a
strong, organic soluble acid, was added which should catalyse the cyclisation reaction at a
lower temperature and permit the use of an organic solvent which is conducive to the
subsequent bromination reaction in the same ‘pot’. Scheme 2.16 shows the proposed
synthetic route.
75
Scheme 2.16
A quick trial using 0.55 equivalents of p-toluenesulfonic acid and 1.1 equivalents of DBDMH
for 60 seconds showed an apparent product peak by GC-MS, however this was the same
later eluting, broad peak attributed to some kind of oligomer / polymer as found previously
in the one-step bromination-cyclisation of 3-ethoxyvinyl-4-aminopyridine. Therefore, the
acid step alone was analysed to see if it did lead to cyclisation to the azaindole in the
reaction time. Again, an apparent product peak was detected by GCMS with the correct
mass for azaindole 257 but it showed a differing retention time to the confirmed spectrum
of azaindole 257 synthesised previously using the published conditions.
2.2.6 Summary of Conversion of Ethoxyvinyl(amino)arenes into 3Bromopyrroloarenes
No
further
research
into
the
two-step,
one-pot
bromination-cyclisation
of
ethoxyvinyl(amino)arenes, to access 3-bromopyrrolopyridines, was carried out owing to the
complexity of the investigation compared to simply using the two-step, two-pot synthesis
which was successful for all analogues (Section 2.2.3). The one-step procedure had been
made to work for isomers with the amino group out of conjugation with the pyridine Natom through the addition of TFA (Section 2.2.4.2). In summary, for the synthesis of 3bromopyrrolopyridines from halo-amino-arenes, the routes shown in Scheme 2.17 are
suggested as most efficient.
76
Scheme 2.17
2.3 Furoarenes
2.3.1 Introduction and Aims
As well as providing azaindoles, it was desired to extend the scope of the synthetic method
to include a synthesis of pyridofurans. The proposal was that by starting from halohydroxypyridines instead of halo-aminopyridines and employing the same Suzuki coupling
with
ethoxyvinylborolane
followed
by
bromination-cyclisation,
access
to
3-
bromopyridofurans could be provided (Scheme 2.18).
X = N,O
Scheme 2.18
However, only some halo-hydroxypyridines were commercially available and certain of
them were particularly expensive. Their synthesis was therefore embarked upon.
77
To summarise, all of the 3-halofuroarenes that are to be synthesised using this novel
method can be seen in figure 2.13.
Fig. 2.13
2.3.2 Synthesis of Halohydroxypyridines
Methods for halogenating heteroaromatics have been previously reported. 143,144 In one
example, the catalyst used was sulfonic-acid-functionalised silica and NBS was the
brominating agent (Scheme 2.19).144
Scheme 2.19
In another example, 2 equivalents of NBS is used to di-brominate hydroxypyridines, then
bromine lithium exchange is used to remove a bromine and leave a mono-brominated
product (Scheme 2.20)145
Scheme 2.20
Canibano et al. also used NBS to brominate hydroxypyridines.146 Different solvents and
different equivalents of NBS were used. The results can be seen in table 2.7.
78
Table 2.7 – Canibano et al.’s bromination of hydroxypyridines
Hydroxypyridine
Solvent
Equiv
T
T
NBS
(°C)
(h)
2-Br
3-Br
5-Br
2-OH
CH3CN
1
Rt
48
11
89
2-OH
CCl4
1
Rt
48
3
29
2-OH
CCl4
2
Rt
48
6-Br
3,5-
2,6-
2,4,6-
Br2
Br2
Br3
34
s.m.
34
10
0
4-OH
CH3CN
1
Rt
72
4-OH
CCl4
2
Rt
24
12
44
44
10
0
4-OH
CCl4
1
Rt
72
35
32
33
3-OH
CH3CN
1
0
48
15
19
15
51
3-OH
CCl4
1
Rt
48
28
32
4
36
3-OH
CCl4
2
Rt
24
33
33
33
3-OH
CCl4
3.3
rt
72
100
Predominant halogenation of hydroxyarenes in the ortho position is desired as these are the
starting materials required for pyridofuran synthesis. Three different hydroxypyridine
isomers were tested using 1 equivalent of NBS under various conditions based on the
literature reactions above (Table 2.8). The products were analysed using GC-MS and proton
NMR.
79
Table 2.8 – Ortho bromination of hydroxypyridines
Entry
Starting
Material
1
2hydroxypyridine
3hydroxypyridine
3hydroxypyridine
4hydroxypyridine
3hydroxypyridine
3hydroxypyridine
3hydroxypyridine
2hydroxypyridine
4hydroxypyridine
4hydroxypyridine
4hydroxypyridine
4hydroxypyridine
4hydroxypyridine
2
3
4
5
6
7
8
9
10
11
12
13
Solvent
Catalyst
Catalyst
amount
(mol%)
Temp
(°C)
Time
(h)
GCMS Peak Area Ratio1
SM
mono-
di-
tri
MeCN
none
RT
48
0
30
70
0
MeCN
none
RT
48
0
30
70
0
DCE
AuCl3
1
RT
16
0
18
82
02
DCE
AuCl3
1
RT
16
0
18
82
02
DCE
FeCl2
20,000 RT
16
0
26
49
26
DCE
H2SO4
20,000 RT
16
0
87
12
1
DCE
H2SO4
20
RT
16
0
45
25
30
DCE
H2SO4
20
RT
16
0
45
25
30
DCE
H2SO4
20
RT
16
100
0
0
0
DCE
H2SO4
20
0
16
100
0
0
0
MeOH H2SO4
20
RT
16
100
0
0
0
MeOH H2SO4
20
0
16
100
0
0
0
H2SO4
20
RT
72
100
0
0
0
MeCN
1
Ratio of starting material (SM) to monobrominated product to dibrominated to tribrominated in
crude reaction mixture
2
Broad unexpected peaks
Although entry 6 shows a large proportion of mono-brominated hydroxypyridine, it could
not be separated from the di- and tri-substituted products and hence the position of the
bromine atom was not identified due to the complexity of the NMR spectrum. This also
indicates that the molar proportions of the reaction products were quite different to the
GCMS peak ratios due to differing ionisation abilities.
In the absence of a high yielding, selective electrophilic aromatic bromination, an alternative
synthetic method was tried. This involved a palladium-catalysed bromination, orthodirected by a carbamoyl group.147 In the literature, such a bromination of phenyl
dimethylcarbamate 268 is reported to occur for benzene in 89% yield (Scheme 2.21).147
80
Scheme 2.21
Before attempting the reaction on pyridine carbamates, a repeat of the literature reaction
was attempted. Formation of the carbamate was achieved with a yield of 50% and the
product’s structure was confirmed by GC-MS and NMR, in particular the presence of two 3H
singlets at 3.00 and 3.09 ppm representing each of the carbamate methyl groups which are
in different environments due to restricted rotation about the N-C=O bond.147
With the carbamate in hand, the bromination step was attempted, however only starting
material was seen by GC-MS despite having used a nitrogen atmosphere and Schlenk
techniques.
Before continuing with the development of syntheses of unavailable isomers of halohydroxypyridines, it was decided to test the Suzuki coupling with ethoxyvinylborolane on
commercially available 3-chloro-2-hydroxypyridine.
2.3.3 Attempted Suzuki Coupling of Ethoxyvinylborolane with
Halohydroxypyridines
Hydroxypyridines have quite different chemistry to aminopyridines such as increased
acidity: the pKa values (for removal of a proton from the neutral form, pKa2) for 2-, 3- and 4hydroxypyridine are 11.65, 8.75 and 11.12, in water respectively,148 compared to 27.7, 28.5
and 26.5 for the corresponding isomers of aminopyridines, although these values are in
DMSO.149 Hence, in the presence of strong base, the halo-hydroxypyridines would be
predominantly in the anionic form leaving the aromatic ring particularly electron rich. It was
therefore thought unlikely that their Suzuki coupling would have the same optimal
conditions as for halo-aminopyridines so a parallel reaction carousel was set up in the first
instance to screen conditions using a Pd(OAc)2-RuPhos catalyst (Table 2.9). To mitigate for
the effect of the strong base, weakly basic potassium fluoride was tested as this has been
81
shown to activate the boronate by coordination to the boron atom, in the same manner as
hydroxide as described in Section 1.3.3.2, but preserve base-labile functional groups.150,151
Table 2.9 – Reaction conditions tested for Suzuki coupling
Entry
Solvent
Base
Starting material consumed
(%)1
1
DMA
KF
97
2
DMA
K3PO4 88
3
DMA
KOH
90
4
MeCN
KF
15
5
MeCN
K3PO4 88
6
MeCN
KOH
80
7
Toluene KF
75
8
Toluene K3PO4 99
9
Toluene KOH
99
1
Starting material consumed was calculated using GC-MS peak areas for starting material and
dodecane internal standard and the calibration curve shown in fig. 2.14.
An internal standard (dodecane) was added to the crude reaction mixtures and they were
analysed using GC-MS. In all spectra, the main peaks present were starting material,
dodecane
and
pinacol,
a
by-product
resulting
from
hydrolysis
of
the
ethoxyvinyl(pinacol)borolane reactant. There were no peaks apparent due to the desired
product. In order to deduce whether products undetectable by GC-MS may have been
formed, a calibration curve was set up for starting material to allow quantitative calculation
of the amount remaining after reaction (fig. 2.14).
82
Calibration Curve for Starting Material for
Experiments in Table 2.9
1
y = 0.0005x
R² = 0.9816
0.9
0.8
0.7
Asm
Aref
0.6
0.5
0.4
0.3
0.2
0.1
0
0
500
1000
1500
2000
nsm
nref
Fig. 2.14. Asm = area of GC-MS peak for starting material; Aref = area of GC-MS peak for
internal standard (reference) dodecane; nsm = moles of starting material; nref = moles of
internal standard dodecane
The remaining starting material is shown in Table 2.9, above, and shows that the large
majority of it is consumed following all of the reactions under all of the tested conditions
except for that using KF in MeCN (entry 4).
One of the crude reaction mixtures (entry 2) was subjected to flash column chromatography
to check for recovery of starting material and any trace products which may provide an
explanation for failure of the reactions. Only starting material and an unexpected product,
which turned out to be dephosphorylated RuPhos 272 (Fig. 2.15), could be isolated.
83
Fig. 2.15 Dephosphorylated RuPhos
The structure of dephosphorylated RuPhos was confirmed by GC-MS and NMR. GC-MS
showed peaks at m/z = 119 and 91 which represent the fragments shown in Fig. 2.15. The
NMR spectrum shows a doublet at 1.1 ppm with an integration of 12 representing the
methyl groups of the isopropyl groups. A septet at 4.3 ppm with an integration of 2
corresponds to the CH of the isopropyl groups. There is then a doublet at 6.6 ppm with an
integration of 2 and a triplet, which couples to it according to COSY, at 7.1 ppm with an
integration of 1 which represent protons 3 and 4, respectively. For the unsubstituted phenyl
group, a multiplet at 7.2 ppm with an integration of 4 represents the ortho and meta
protons while the para proton is shown by a doublet at 7.2 ppm with an integration of 1.
In retrospect, although the 2-hydroxy-3-chloropyridine isomer was one of only two
commercially available, it may not have been the best choice for screening the reaction
conditions because the hydroxy group is conjugated to the pyridine N-atom so the
deprotonated form may be particularly coordinating to the Pd catalyst and poison it.
Furthermore, the chlorine atom is meta to the pyridine nitrogen atom and so out of
conjugation and less activated towards oxidative insertion by palladium.
Following these disappointing results and given the limits of time, it was decided that work
should concentrate on the use of 3-bromoazaindoles in novel methodology with in a
medicinal chemistry (potential antimalarials) context. Future work on the Suzuki coupling of
halo-hydroxypyridines could include screening a range of ligands, particularly more sterically
hindered ones in order to prevent coordination of pyridyloxanions, whilst keeping the
solvent and base constant.
84
2.4 Anti-malarial pre-cursors
2.4.1 Introduction and aims
Dihydrousambarensine 273 (Fig. 2.16) is a published anti-malarial compound isolated from
Strychnos species plants on which the Allin group has based novel indoloisoquinoline antimalarials 274 (Fig. 2.17).152,153 In the study of their structure-activity relationships, both
enantiomers of analogues varying at R, R1 and R2 were synthesised. Their antimalarial
activities, measured as IC50 values, were determined in a bioassay against cultures of red
blood cells infected with malaria (chloroquine resistant and non-resistant Plasmodium
falciparum). Selected results for analogues with R = Bn, R2 = H and varying R1 groups are
shown in Table 2.10, below for each enantiomeric series 274-L and 274-D.
Fig. 2.16
Fig. 2.17
Table 2.10 Published antimalarial activity of indoloisoquinolines 274 with R=Bn, R2=H152,153
Entry Series R1
IC50 (μM)
Entry Series R1
IC50 (μM)
1
274-L
H
n.d.
5
274-D H
5
2
274-L
Me
32
6
274-D Me
1.3
3
274-L
allyl
35
7
allyl
1.3
4
274-L
Bn
12
8
274-D Bn
9
274-D Cy-CH2 19
85
3.5
The D-enantiomeric series (entries 5-9) was shown to be more potent than the L-series
(entries 1-4) and variation of R1 was shown to have little impact on IC50 until the bulkier CyCH2 group led to a large increase (entry 9).
A collaboration with Allin was established to synthesise azaindole analogues of 274 with a
view to improving potency, perhaps through an additional interaction between the
compounds’ unknown biomacromolecular target and the extra hydrogen bond accepting
pyridine N-atom, or through changes to the electronics of pi-stacking interactions with the
arene. The incorporation of an extra nitrogen atom could also improve physical properties
such as solubility. Since changes to R1 had shown little impact on potency in the original
series, and for ease of synthesis, the proposed new azaindole inhibitors 275 (fig. 2.18) were
designed lacking the CH2OR1 group.
Fig. 2.18
Allin has synthesised the enantiopure indole analogue of 275 from the alcohol 276 derived
from (R)-tryptophan, according to Scheme 2.22, in which a key step is the acid-mediated
cyclisation of 277 to 278.
86
Scheme 2.22
For the proposed azaindoles 275, a shorter synthetic route was designed (Scheme 2.23)
which would take advantage of the 3-bromoazaindole syntheses developed earlier,
incorporate they key acid-mediated cyclisation used by Allin and require some novel
synthetic methodology.
87
Scheme 2.23
The route involves a Heck cross-coupling reaction between the 3-bromoazaindole and vinyl
glutarimide 284, followed by reduction of the product enimide 285. The resulting ethylbridged compound 283 should be amenable to the remaining acid mediated cyclisation and
pyrrole N-alkylation according to the published route (Scheme 2.23).154 The aim of the
research for this dissertation was to produce glutarimylethylazaindoles 286 as a variety of
regioisomers to be sent to the group of Allin for conversion into potential antimalarials 289.
The first step on the novel route was the synthesis of vinyl glutarimide.
2.4.2 Vinyl glutarimide
Only one method for the synthesis of vinyl glutarimide has been published in the literature
in 1941 the form of a patent.155 This involved heating glutarimide, acetylene gas and
mercuric phosphate at high pressure and is deemed too hazardous and complicated to
repeat
for
this project.
However,
vinylphthalimide
has been
made
tetrachloropalladate-mediated coupling with vinyl acetate (Scheme 2.24).156
88
using
a
Scheme 2.24
This reaction was applied to glutarimide (entry 1 of Table 2.10). A GC-MS of the crude
product mixture showed peaks for glutarimide and the product vinyl glutarimide with a ratio
of areas of 60:40. It was decided to put the sample in the microwave at 120 °C for one hour
to see if the conversion improved but there was no change. A new reaction was set up in
the microwave and run at 120°C (entry 2) for 1 hour and GC-MS showed the same ratio of
peak areas for gluarimide:vinyl glutarimide of 60:40. Flash column chromatography of this
mixture gave an actual yield of vinyl glutarimide of 22%.
In an attempt to improve the yield, a four-fold increase in the amount of catalyst was tried
(entry 3), but still a GC-MS peak ratio of only 60:40 was achieved. A variety of conditions
were tested which are summarised in Table 2.11.
89
Table 2.11 – Vinyl glutarimide reaction conditions
Entry
Solvent1
Temp Time (h)
(°C)
GC-MS peak
area ratio
(SM:Product)
1
Vinyl acetate
120
8+1
(microwave)
60:40
2
Vinyl acetate
120
1 (microwave)
60:40
3
Vinyl acetate
120
1 (microwave)
60:40
4
Vinyl acetate
73
24
90:10
5
Vinyl acetate
73 + 24 + 1
120
(microwave)
6
Vinyl acetate
73
48
50
Filtered after 24 h and
reheated with fresh
vinyl acetate and
catalyst
7
Vinyl acetate
73
48
25
Cooled in ice bath and
filtered, then reheated
8
Vinyl acetate
73
48
40
Power cut 1st night
9
Vinyl acetate
73
48
100:0
10
Vinyl acetate
73
96
80:20
11
DCM
40
24
100:0
26.8 equiv. vinyl acetate
12
H2O
100
24
100:0
26.8 equiv. vinyl acetate
13
MeOH
65
24
100:0
26.8 equiv. vinyl acetate
14
DMA
165
24
100:0
26.8 equiv. vinyl acetate
15
Vinyl acetate
73
24
90:10
Base – K2CO3
16
Vinyl acetate
73
24
90:10
Dry vinyl acetate2
17
Vinyl acetate
73
24
100:0
Dry vinyl acetate and
base – K2CO3
Yield Notes
(%)
22
4 mol% catalyst
60:40 + 60:40
1
Where solvent = vinyl acetate, 26.8 equiv. were used.
Vinyl acetate dried using distillation(MgSO4).
2
90
Attempted recreation of
power cut conditions
Entry 6 was based upon a literature search which also used the same solvent and catalyst
for the reaction but after 12 hours added 200 mg of activated charcoal, shook the solution
for 10 minutes, filtered off the solids, removed the solvent using distillation in a high
vacuum, then adding the same amount of catalyst and reagent, repeated the procedure.157
This did increase the yield to 50% but it also doubled the reaction time. In order to make
sure all solids were precipitated from the solution, the experiment was repeated but the
solution was cooled in an ice bath before filtration, however, this had a negative effect on
the yield possibly due to the glutarimide also precipitating out (entry 7).
During one experiment (entry 8), there was a power cut during the night and so it was
decided to leave the experiment to run a further 24 hours, this led to a reasonable yield of
40% and so it was decided to try and recreate these conditions (entry 9) by bringing the
reaction to reflux, then turning off the power overnight and then returning the reaction to
reflux for 24 hours. However, GCMS analysis of crude material showed only starting
material.
It was decided to try the reaction in solvent (entries 11-14) because glutarimide does not
fully dissolve in the vinyl acetate in the usual method. Protic (MeOH, H 2O) and aprotic
solvents (DCM, DMA) were tested but no reaction occurred in any as indicated by the
detection of only glutarimide starting material by GC-MS. This may be because the DCM
cannot reach high enough temperatures at reflux and the DMA, MeOH and H2O are too coordinating to let the palladium catalyst work.
Next, a base (K2CO3, pKa 10.25)158 was added to the reaction (entries 15 and 17) as it was
thought that deprotonation of the imide (pKa 8.3)159, would encourage its addition to vinylpalladium intermediate complexes. Unfortunately it had the opposite effect, reducing the
GC-MS glutarimide:vinyl glutarimide peak area ratio to 90:10. This may be because
carbonate and/or glutarimide anions bind to the Pd-catalyst strongly and prevent it from
completing its catalytic cycle.
The highest yield achieved with vinyl acetate (b.p. 72.7 °C) was 50% by including a filtration
and second heating period of 24 h. It was hypothesised that higher molecular weight vinyl
esters with higher boiling points would allow the reaction to be run at higher temperatures
under reflux and give higher yields by allowing more molecules to obtain the activation
91
energy as well as increasing the amount of glutarimide dissolving into the solvent. Indeed it
was found that both vinyl propionate (b.p. 94-95°C) and vinyl pivalate (b.p. 110°C) did fully
dissolve the glutarimide when heated at reflux. Both of these solvents increased the GC-MS
peak area ratio to 40:60. A parallel reaction carousel was next set up to optimise these
conditions (Table 2.12).
Table 2.12 – Optimisation of vinyl glutarimide synthesis using high b.p. vinylating agents
11+1
Entry
Solvent
B.p.
(°C)
Reaction conditions
Yield
(%)
1
Vinyl pivalate
110
1 mol % catalyst, 24 h
23
2
Vinyl pivalate
110
2 mol % catalyst, 48 h
38
3
Vinyl pivalate
110
1+11 mol % catalyst, 48 h
56
4
Vinyl propionate
94-95
1 mol % catalyst, 24 h
25
5
Vinyl propionate
94-95
2 mol % catalyst, 48 h
20
6
Vinyl propionate
94-95
1+1 mol % catalyst, 48 h
27
indicates a second addition of catalyst after 24 h.
The carousel reactions investigated whether the addition of fresh catalyst after 24 hours
and allowing the reaction to run for another 24 hours had a positive impact on the yield. It
also compared this to adding double the amount of the catalyst in the first place and letting
the reaction run for 48 hours. The results show that over all, vinyl pivalate is the better
solvent to use, most likely due to the higher temperature achieved. They also showed that
adding the catalyst in two batches improved the yield when using vinyl pivalate. This result
can be rationalised by it being a slow reaction, even at the higher temperature,which
requires the longer reaction time but the catalyst begins to degrade in 24 hours so the
addition of a fresh batch results in a higher conversion of the starting material to product.
Although this method produced the highest yield so far, the downside is that 48 hours is a
long time. It would be quicker if the reaction could be performed under high pressure and
92
temperature using the microwave but this is only possible on a small scale (~0.5 mmol), and
the vinyl glutarimide was required in large amounts (approx. 50 mmol).
As a final attempt at improving the yield, an alternative vinylation method was sought.
Alcohols and carboxylic acids have been reported to undergo vinylation using a gold
complex (AuClPPh3) and silver(I) acetate as catalysts and ethyl vinyl ether (Scheme 2.25).160
Scheme 2.25
Due to the similarity between the heteroatoms oxygen and nitrogen, it was decided to try
this method with glutarimide. Unfortunately, only starting material was detected by GC-MS
so the reaction was repeated but with the original vinyl acetate in place of the ethyl vinyl
ether. However, there was still no reaction. As the authors of the paper are unclear about
the mechanism by which the gold-catalysed reaction proceeds, it is difficult to rationalise
why this has not worked and therefore, how it could be modified to make it work. 160
Nevertheless, with vinyl glutarimide in hand from the Pd-catalysed reaction with vinyl
pivalate, research into the next step, its Heck reaction with 3-bromo-azaindoles could be
carried out.
2.4.3 Attempted Heck reaction
The Heck reaction is a palladium catalysed cross-coupling reaction that involves the creation
of a new carbon-carbon bond by reacting an unsaturated halide with an alkene in the
presence of a base (Scheme 2.26).161 The general mechanism involves oxidative insertion of
Pd0 into the alkenyl/aryl-halogen bond, migratory insertion of the alkene and then β-hydride
elimination to re-form an alkene with alkenyl/aryl group attached.
93
Scheme 2.26
In order to synthesise the antimalarial precursors, a Heck coupling reaction between the 3bromoazaindoles and vinyl glutarimide was envisaged. This is a novel reaction that is not
reported in the literature. However, a coupling between an aryl bromide and
vinylphthalimide has been reported to occur in 75-89% yield (Scheme 2.27) using tri-otolylphosphine as a ligand with the palladium catalyst.162
Scheme 2.27
It was therefore decided to begin with these reaction conditions for the coupling (Scheme
2.28).
94
Scheme 2.28
Unfortunately, after two attempts, this reaction proved unsuccessful, with both starting
materials remaining, by GC-MS, after the 24 h period.
Most Heck reactions are run with electron rich arenes and electron poor alkenes, however
in this case, vinyl glutarimide is an electron rich alkene. It was decided therefore, to return
to the literature and search for Heck conditions which permit coupling of electron rich
alkenes. A patent was found which describes the Heck reaction between an indole and a
relatively electron rich allyl amine (converted in situ to an ally amide) (Scheme 2.29). The
conditions are very similar to those in Scheme 2.27 with the base being the only
difference.163
Scheme 2.29
Due to the similarity of indoles to azaindoles, these were the next reaction conditions that
were tested. Unfortunately, the reaction was unsuccessful. Once again the crude GC-MS
showed unreacted starting materials and no obvious product peak. The reaction was next
tested under microwave conditions at a higher temperature, 130 °C for 1 h. Again however,
only starting materials were detected by GC-MS.
95
A return to the literature revealed a paper on an intramolecular Heck reaction between an
azaindole (Scheme 2.30) and an unsaturated ester, using the Hermann-Beller catalyst (Fig.
2.19), in 30% yield.164
Scheme 2.30
Fig. 2.19
There were also conditions published in the paper where a 20% yield was achieved using
Pd(OAc)2, P(o-Tolyl) and K2CO3.164 Owing to the cost of the Hermann-Beller catalyst and
Pd(OAc)2, P(o-Tolyl) and K2CO3 being already available in the laboratory, it was decided to try
this method with vinyl glutarimide. To begin with, the reaction was run at 60 °C to reduce
the risk of possible degradation of the starting materials or polymerisation of vinyl
glutarimide. After 8 h, GC-MS showed the starting materials were still present, so the
reaction was left to run overnight after which time, GC-MS still showed the presence of
starting materials and there was no obvious product peak either. The temperature was then
raised to 100 °C and left overnight. Once again, GC-MS showed starting materials and no
obvious product peak. The reaction was repeated at 120 °C overnight and this time GC-MS
showed that the vinyl group had been removed from the vinyl glutarimide, leaving just
glutarimide. These results suggest that higher temperatures destroy the reactant but at
lower temperatures the reaction does not proceed. Therefore, either the palladium is not
96
inserting into the carbon-halogen bond in the first place, or it is inserting but the
subsequent migratory insertion of the alkene is not taking place and so the syn addition
does not take place.
Datta et al have published another example of a Heck reaction using an electron rich vinyl
ether as the alkene and an aryl chloride (Scheme 2.31).165
Scheme 2.31
The palladium catalyst found to be most effective for this reaction was the Hermann-Beller
catalyst (Fig. 2.19).165 As this was the same catalyst that Angiolini et al also found to be the
best one for the Heck reaction, it was decided that it should be tried. 164 Therefore, an
experiment was set up that used the Hermann-Beller catalyst, Cy2NMe and [(t-Bu3)PH]BF4
(Scheme 2.32). The latter is an air stable pre-ligand for (t-Bu3)P which releases it on reaction
with the base Cy2NMe.166
Scheme 2.32
GC-MS of the crude reaction mixture showed that the vinyl glutarimide was intact but that
the 3-bromo-7-azaindole had been reduced to 7-azaindole. The reaction was repeated in
the presence of an internal standard (dodecane) for GC-MS. The mixture was analysed at
the beginning of the reaction (Fig. 2.20) and after 1 h at 160 °C in the microwave (Fig. 2.21).
97
Fig. 2.20
Fig. 2.21
These GC-MS chromatograms show clearly that the vinyl glutarimide peak (12.6 mins) is
present in both spectra, and that its relative area compared to that of dodecane (10.9 mins)
is unchanged. It can also be seen that the peak for the 3-bromo-7-azaindole (17.1 mins) is
clearly visible in the first chromatogram but absent from the second. Likewise, the peak for
7-azaindole (13.3 mins) is visible after the reaction but absent before.
A Heck reaction can go through two different pathways, the cationic pathway and the
neutral pathway (Scheme 2.33).165
Scheme 2.33
98
The neutral pathway involves passage through a neutral palladium(II) complex due to
coordination of the halide or alternative resulting from the first oxidative insertion step. In
the cationic pathway, the halide or alternative dissociates from the palladium leaving
acationic palladium(II) complex.167 The neutral palladium(II) complex will bind with electron
deficient alkenes as they are good π-acceptors but poor σ-donors.167 The cationic
palladium(II) complex however, will bind with electron-rich alkenes as they are poor πacceptors but good σ-donors.167 The cationic palladium(II) complex can be achieved by use
of chelating bidentate phosphine ligands, triflates as substrates (to provide noncoordinating triflate counterions after oxidative insertion), silver or thallium salts as
sequestering agents of halides and strong dieletric solvents such as DMSO.161,165,167
β-arylation
α-arylation
Scheme 2.34
Computational comparisons of the two pathways have suggested that the cationic pathway
is likely to produce a mixture of both the alpha and beta products, as shown for the reaction
of Datta et al in Scheme 2.34, as the reaction pathways for the two products are very close
in energy.168 Given the number of variables which are involved in favouring either (or both)
of the reaction pathways, it should be possible to find conditions that favour both the
cationic palladium(II) species and the formation of the beta product.168 Unfortunately, as
time was limited, it was decided to try to access the antimalarial precursors by a different
route which could also negate the subsequent hydrogenation step required if the Heck
coupling is used.
99
2.4.2 Synthesis via sp2-sp3 Suzuki Reaction
2.4.2.1 Introduction and aims
It was decided that a suitable alternative to the Heck reaction would be a Suzuki cross
coupling reaction (Scheme 2.35) using an sp3-carbon-boronic ester 317 which should be
accessible directly from vinyl glutarimide. Although this adds an extra step in accessing the
borolane, this only has to be carried out once to provide coupling agent for all azaindole
regioisomers and analogues. Furthermore, the coupling product 318 would not contain a
double bond, as it would following the above-described Heck reaction, so the hydrogenation
step leading to the antimalarial precursor would be removed.
Scheme 2.35
2.4.2.2 Glutarimylethyl boronic ester
The literature reaction most analogous to forming the desired 1-[2-(tetramethyl-1,3,2dioxaborolan-2-yl)ethyl]piperidine-2,6-dione 317 involved coupling of pinacolborane
(HBPin) to 1-vinyl-2-pyrrolidinone (Scheme 2.36).169
Scheme 2.36
100
Hence, these conditions were tested for the hydroboration of vinyl glutarimide.
The first issue encountered was the availability of the catalyst Rh(acac)(dppb). The
published paper stated that, “All chemicals were purchased from Aldrich Chemicals and
used as received with the exception of catecholborane.”169 However, no commercial source
of this catalyst could be found so its in situ generation by combining Rh(acac)(cod) and 1,4bis(diphenylphosphino)butane in the reaction mixture was attempted.
On first attempt, however, there was no reaction by GC-MS with only starting materials
being detected. The method had involved making a solution of HBPin in THF and adding it
dropwise to a solution of starting material and catalyst in THF before leaving to stir for 18 h
at room temperature. It was thought that the reaction could be improved if the catalyst
components were allowed to react in THF prior to addition of the starting materials. Simply
allowing the Rh(acac)(cod) and ligand to stir in solvent for two minutes before adding
further reaction components and proceeding as above produced a mixture of products
according to GC-MS (Fig. 2.22).
Fig. 2.22
The peak at 12.4 mins was unreacted vinyl glutarimide starting material. The peak at 11.6
mins, with a mass of 141, 2 higher than that of the starting material, strongly suggested
ethyl glutarimide resulting from reduction of vinyl glutarmide. The two biggest peaks at 18.4
mins and 19.8 mins both showed mass spectra with the correct mass (m/z = 267) for the
desired product but with different fragmentation patterns (Fig’s. 2.23 and 2.24,
respectively).
101
Fig. 2.23
Fig. 2.24
Finally, the chromatogram peaks at 23.8 mins and 24.1 mins both showed the mass of a
product resulting from double addition of the HBPin group (m/z = 392), again with different
fragmentation patterns (Fig’s. 2.25 and 2.26, respectively).
Fig. 2.25
102
Fig. 2.26
In accordance with the published reaction, these products are most likely the result of the
HBPin adding α (324) or β (323) to the double bond creating both linear and branched
versions of the product (Scheme 2.33).169 For the double addition of HBPin (325), it is
unclear what the exact regioisomers are; whether α-disubstituted, β-disubstituted or α,βdisubstituted.
Scheme 2.33
In order to optimise reaction selectivity towards the desired linear product 323, a series of
catalyst ligands and solvents were tested in a parallel reaction carousel. An internal standard
(dodecane) was added so that, following the generation of calibration curves from future
isolated material, GC yields could be calculated.
103
Table 2.13 – Optimisation of reaction conditions for hydroboration of vinyl glutarimide.
Entry
Solvent
Ligand
SM* Reduced
SM*
Bis(2-diphenylphosphinophenyl)ether
1
THF
1.28
dppp
2
THF
0.64
Tris(2,4,6-trimethoxyphenyl)phosphine
3
THF
1.69
Ph
P
3
4
THF
0.91
Tricyclohexylphosphine
5
THF
0.79
Ad2BuP
6
THF
0.69
Bis(2-diphenylphosphinophenyl)ether
7
DCM
0.43
Ph3P
8
DCM
1.33
Tricyclohexylphosphine
9
DCM
0.09
Ad
BuP
2
10 DCM
0.51
11 MeCN Bis(2-diphenylphosphinophenyl)ether 0.00
Ph3P
12 MeCN
0.12
Tricyclohexylphosphine
13 MeCN
0.12
Ad2BuP
14 MeCN
0.38
dppb
15
THF
1.22
1,4-bis(dicyclohexylphosphino)butane
1.88
16
THF
1,5-bis(diphenylphosphino)pentane
0.49
17
THF
1,2-bis(diphenylphosphino)ethane
18
THF
0.15
Tricyclopentylphosphine
19
THF
2.32
Cy3P
20 Et2O
0.08
* Ratio of GC-MS peak area to internal standard
0.27
0.09
0.66
0.15
0.28
0.26
1.68
1.13
2.64
0.82
1.76
1.40
0.87
0.49
1.10
1.77
1.61
1.38
0.60
1.56
A*
B*
C*
D*
0.03
0.01
0.00
0.03
1.14
0.02
0.15
0.00
0.24
0.04
0.00
0.00
1.48
0.65
1.60
0.04
0.06
0.04
0.04
0.08
0.33
0.02
0.00
0.23
0.38
0.03
1.15
0.00
0.45
0.19
0.00
0.17
1.63
0.42
1.10
0.10
0.08
0.07
0.23
0.25
0.00
0.00
0.00
0.00
0.11
0.00
0.00
0.00
0.02
0.00
0.00
0.00
0.27
0.09
0.17
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.13
0.00
0.00
0.00
0.06
0.00
0.00
0.00
0.58
0.11
0.12
0.00
0.00
0.00
0.00
0.00
Reactions from the carousel which formed predominantly one of the regioisomers were
selected for scale-up and purification by flash chromatography (entries 5 and 7) in order to
characterise each regioisomer. The products were not UV active, but could be visualised on
TLC using a potassium permanganate stain which produced a weak yellow spot. The first
isomer isolated was characterised by 1H NMR which showed a 1H quartet at 3.75 ppm, this
corresponded to the N-CHMe(BPin) proton of the α-substitutedproduct 324. GC-MS of the
purified product confirmed it to be ‘Isomer A’ with retention time 18.4 min. Interestingly,
the same ligand (tricyclohexylphosphine) but different solvent (DCM) (entry 9) appeared to
104
be more selective for the other isomer. The second isomer (entry 7) was scaled up and the
product purified using flash chromatography. In this case, the 1H NMR spectrum confirmed
the major product was the β-substituted regioisomer 323 by the presence of two 2H triplets
at 3.88 ppm and 1.07 ppm for each of the CH2 groups of the alkyl chain. GC-MS of the
purified product confirmed it to be ‘Isomer B’ with retention time 19.8 min.
Using the isolated material, GC-MS calibration curves were set up for each isomer (Fig.
2.27and Fig. 2.28) and GC yields calculated for the reactions screened (Table 2.14).
Calibration curve - Isomer A (324)
2.5
y = 0.9166x
R² = 0.9836
AIsomerA
Areference
2
1.5
1
0.5
0
0
0.5
1
1.5
2
2.5
3
nIsomerA
nreference
Fig. 2.27
Calibration curve - Isomer B (323)
1.2
y = 0.4562x
R² = 0.9922
AIsomerB
Areference
1
0.8
0.6
0.4
0.2
0
0
0.5
1
1.5
nIsomerB
nreference
Fig. 2.28
105
2
2.5
3
Table 2.17 - Carousel reaction to optimise conditions for HBPin coupling, with GC-MS yields
for isomers A (324) and B (323).
Solvent Ligand
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
THF
THF
THF
THF
THF
THF
DCM
DCM
DCM
DCM
MeCN
MeCN
MeCN
MeCN
THF
THF
THF
THF
THF
Et2O
Isomer A
(% yield)
Bis(2-diphenylphosphinophenyl)ether 1
Dppp
0
Tris(2,4,6-trimethoxyphenyl)phosphine 0
Ph3P
1
Tricyclohexylphosphine
23
Ad2BuP
0
Bis(2-diphenylphosphinophenyl)ether 3
Ph3P
0
Tricyclohexylphosphine
5
Ad2BuP
1
Bis(2-diphenylphosphinophenyl)ether 0
Ph3P
0
Tricyclohexylphosphine
30
Ad2BuP
13
Dppb
33
1,4-bis(dicyclohexylphosphino)butane 1
1,5-bis(diphenylphosphino)pentane
1
1,2-bis(diphenylphosphino)ethane
1
Tricyclopentylphosphine
01
Cy3P
2
Isomer B
(% yield)
3
0
0
2
4
0
12
0
5
2
0
2
17
4
11
1
1
1
2
3
The table of results suggest that isomer B should only achieve an isolated yield of 11.6%
under the conditions of entry 7. However, on scale up a yield of 42% was achieved. It may
be that the reaction favours the scale up, or that the seals on the carousel tube were poor
allowing oxygen ingress, but the success is more likely to be attributed to the change to
anhydrous DCM; the carousel reactions were run in standard DCM, but when scaling up, in
an attempt to lower the amount of reduced vinyl glutarimide, dry DCM was used instead.
106
Successful synthesis of 1-[2-(tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]piperidine-2,6-dione
meant that work could continue onto the sp2-sp3 Suzuki coupling with 3bromopyrroloarenes.
2.4.2.3 sp2-sp3 Suzuki Coupling with 3-Bromopyrroloarenes
Traditionally a Suzuki coupling reaction takes place at sp 2 carbon atoms rather than sp3. For
the first step in the catalytic cycle (oxidative insertion of the palladium into the carbon
halogen bond), this rate is faster for an sp2 carbon-halogen bond because the increased
electron density in the double bond stabilises the insertion. For the later step
(transmetallation), with sp3 carbon-borolane molecules, there is a risk of β-hydride
elimination occurring, an unwanted side reaction that can only occur when hydrogen atoms
on the β-carbon are available. This latter problem is a risk in the coupling of the glutarimide,
but, sp2-sp3 and even sp3-sp3 Suzuki couplings have been reported in the literature and can
be successful with the right choice of ligand, palladium source, base and solvent.170
The literature example that was chosen upon which to base the reaction conditions was an
sp2-sp3 Suzuki coupling between an alkylboronic ester and an aromatic bromide (Scheme
2.37).
Scheme 2.37
A reaction was set up using these conditions. A sample of the crude reaction mixture was
analysed using GC-MS and this showed the bromoazaindole still intact but no peak for the
borolane or any by-products. This suggested decomposition of the borolane implying the
reaction conditions were too harsh for it.
107
Unfortunately, due to time constraints, work had to stop at this point. Future work would
include investigating the use of organotrifluoroborate salts instead of the alkylboronic ester
as there are many more successful examples of sp2-sp3 Suzuki coupling reactions using these
reactants published in the literature.171-179 One example using α-amino trifluoroborates can
be seen below in Scheme 2.38.173
Scheme 2.38
Of closest analogy to the desired glutarimylethylborate are the pyrrolidinone and
caprolactam analogues 333 and 334, reported by Molander, which initially failed to react in
a Suzuki coupling with 4-bromobenzonitrile 332 using PdCl2(dppf).CH2Cl2 as catalyst.
Switching to a RuPhos ligand in combination with Pd(OAc)2, however, led to successful
coupling (Scheme 2.39).180 Hence, in future work, this catalyst and conditions would be
tested first.
Scheme 2.39
108
3 Conclusions and Future Work
The chemistry described in this thesis has proved very challenging and at times unsuccessful
within the time constraints but some interesting and novel breakthroughs have been
achieved.
The literature synthesis of ethoxyvinyl(amino)arenes using a Suzuki coupling was
successfully validated but it was found that a switch of ligand from SPhos to RuPhos was
necessary to secure higher yields. Seven ethoxyvinyl(amino)arenes were produced in this
way, one of which (3-Bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidine) was a novel compound.
The original aim of creating a one-step method to convert them into 3-bromopyrrolopyridines was met through use of NBS and TFA in acetonitrile, but the method only
proved to be successful on isomers whose amino group was out of conjugation with the
pyridine nitrogen atom. This initial, promising result is a strong foundation for future
optimisation of a general method which would be more convenient than previously
published methods.
The remaining isomers and analogues were converted to the 3-
bromopyrrolopyridines in two steps using the reported cyclisation to pyrroloarenes using
acetic acid followed by bromination with NBS.
The difficulty in synthesising ethoxyvinyl(hydroxy)pyridines from halohydroxypyridines
meant that testing their conversion into furopyridines and the development of a one-step
method for the formation of bromo-furopyridines could not be realised. Therefore, its
complete versatility as a method is still unclear.
Research into the use of these 3-bromopyrroloarenes as building blocks in medicinal
chemistry was begun by attempting to convert them into antimalarial precursors. Novel
methodlogy was embarked upon for this which involved Heck and Suzuki palladium crosscoupling reactions glutarimyl-based reactants that were not commercially available.
Therefore, as part of this research, a method for synthesising vinyl glutarimide was
developed. This method was much safer than the previously published method, which
involved using mercury under pressure, but was low yielding. As well as this, a method for
the synthesis of the novel compound, glutarimylethylborolane, was produced for use in the
109
Suzuki reaction. Unfortunately, the Heck coupling of vinyl glutarimide and sp 3-sp2 Suzuki
coupling of glutarimylethylborolane with 3-bromopyrrolopyridines was unsuccessful.
In the future, this project could be taken in a number of directions. Firstly, the one-step
method of synthesising bromo-pyrrolopyridines from ethoxyvinylarene intermediates when
done using the easier of the isomers, was only carried out using NBS as the brominating
agent along with one equiv. of TFA. However, when earlier research was carried out on the
more difficult isomer in the absence of acid, DBDMH was the only brominating agent that
produced any reaction, albeit a suspected polymerisation/oligomerisation reaction.
Research into using other bromine sources such as DBDMH with acid to promote the loss of
the ethoxy group may produce a more versatile method. Furthermore, the acid could be
varied in terms of its strength, by testing TsOH, acetic acid or H2SO4, for example Rajesh et
al. brominate deactivated aromatic compounds using H2SO4 and NBS (Scheme 3.1).181 The
acid could also be varied in terms of its nature by testing Lewis acids such as TiCl4, BF3, for
example Prakash et al. brominate deactivated aromatics using NBS/BF3-H2O (Scheme 3.2).182
The acid could also be varied in terms of using more mild lithium salts, for example Shao et
al. use NBS and lithium Bromide to dibrominate unsaturated carbon-carbon bonds (Scheme
3.3).183
Scheme 3.1
Scheme 3.2
110
Scheme 3.3
Alternatively, the ethoxyvinylarene intermediates may be more amenable than their
product azaindoles to reactions such as the Diels Alder reaction or the Heck reaction
(Scheme 3.4). These would create other structures that could have use as building blocks in
medicinal chemistry.
Scheme 3.4
Another future angle would be to replace bromine with a different halogen. Replacing the
bromine with chlorine for example, may have an effect on both the method and its use as a
‘handle’ for further reactions (Scheme 3.5).
111
Scheme 3.5
Other future work would be to further investigate the palladium catalysed cross coupling
reactions of the bromo-pyrrolopyridine molecules. Literature searches show that the
conditions for these reactions have great variety nowadays and so although the conditions
tried in this research remain unsuccessful, there are still many more that can be tried. For
example, the Suzuki reaction originally required a base, a palladium catalyst with ligands
and an organic solvent (Scheme 3.6).
Scheme 3.6
More recently, ligands can be completely negated and the organic solvent can be swapped
for water (Scheme 3.7).184
Scheme 3.7
112
4 Experimental
General Procedures
All reactions were carried out under a nitrogen atmosphere in glassware dried under
vacuum by a heat-gun unless stated otherwise.
Solvents
40-60 Pet. ether refers to the fraction of petroleum ether boiling between 40 and 60°C.
Ether refers to diethyl ether. Acetonitrile was dried by distillation under nitrogen from a
suspension of calcium sulphate or by passage through an activated alumina column using a
PureSolv Micro solvent purification system. Dichloromethane was dried by distillation
under nitrogen from a suspension of calcium hydride or by passage through an activated
alumina column using a PureSolv Micro solvent purification system. THF was dried by
passage through an activated alumina column using PureSolv Micro solvent purification
system. Anhydrous DMA and DMF were purchased from Sigma Aldrich.
Reagents
Reagents were used as supplied unless otherwise stated. KOH was supplied as pellets,
ground down to a fine powder using a pestle and mortar, dried under vacuum at 100°C for 2
hours and stored under nitrogen.
Chromatography
Flash column chromatography was carried out using silica gel 40-63u 60A. Analytical thin
layer chromatography (TLC) was performed using precoated aluminium backed plates (silica
gel 60 F254) and visualised by UV radiation at 254 nm or using a stain made from potassium
permanganate and Na2CO3 in water, or a stain made from ammonium molybdate and ceric
ammonium molybdate with concentrated sulphuric acid, dissolved in water.
113
Gas chromatography mass spectrometry (GC-MS)
GC-MS was carried out on an Agilent 7890A-5975C with an electron ionisation (EI) detector.
Column length was 30 m, injection volume was 2 µL, temperature was 50 °C for 3 minutes
followed by an increase of 10 °C per minute to 250 °C and held for 2 minutes.
Liquid chromatography mass spectrometry (LC-MS)
LC-MS was carried out on a Waters Alliance HPLC connected to a Micromass Quattro Ultima
mass spectrometer with an ultra violet (UV) detector. The column was a Phenomenex Onyx
monolithic C8 column, 100 mm by 2 mm. Injection volume was 10 µL, flow rate was 1
mL/min. Samples were run in positive mode with acetonitrile and water as solvents, both
containing 0.1 % formic acid.
High resolution mass spectrometry (HRMS)
HRMS was performed at the Institute of Cancer Research, Sutton using an Agilent HPLC system
connected to an Agilent Quadrupole Time of Flight (qToF) mass spectrometer (simultaneous ESI and
APCI or ESI only).
NMR spectroscopy
1H
NMR spectra were recorded in CDCl3 or CD3OD on a bruker DRX500NMR or AV300NMR
and are reported as follows: chemical shift δ (ppm) (intergration, multiplicity, coupling
constant J (Hz), assignment). All chemical shifts are quoted in parts per million relative to
tetramethylsilane (δH = 0.00 ppm, δC = 0.00 ppm) and coupling constants are given in Hertz
to the nearest 0.3 Hz. In CDCl3, TMS at 0.00 ppm or residual CHCl3 at 7.26 ppm was used as
the reference. In CD3OD, residual CHD2OD at 3.31 ppm was used as the reference. 13C NMR
spectra were recorded on a DRX500NMR or AV300NMR spectrometer and the central
resonance of CDCl3 (δc = 77.0 ppm) or CD3COD (δc = 49.0 ppm) was used as the reference.
114
(E)-2-(2-Ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Method 1
Ethoxyethyne (50% w/w solution in hexane, 3.95 g, 21.4 mmol) was dissolved in DCM (36
ml) under nitrogen and cooled to 0 °C. To this was added 4,4,5,5-tetramethyl-1,3,2dioxaborolane (3 g, 23.5 mmol) followed by the catalyst bis(cyclopentadienyl)zirconium (IV)
chloride hydride (3.19 g, 1.24 mmol). The reaction mixture was warmed to room
temperature and stirred overnight. The solvent was evaporated and petrol 40-60 was added
to precipitate the catalyst. It was then filtered through a pad of neutral alumina topped with
a layer of celite and eluted with petrol 40-60. Fractions containing product (TLC) were
combined, evaporated and dried in vacuo to give the product as a pale orange oil. (3.24 g,
76%); Rf=0.32 (hexane/Et2O 9:1); δH (500 MHz, CDCl3) 7.03 (1H, d, J=14.5 Hz [CH=CH-O]),
4.42 (1H, d, J=14.5Hz [B-CH=CH]), 3.83 (2H, q, J=7.2Hz [CH2]), 1.28 (3H, t, J=7.2Hz [CH2-CH3]),
1.25 (12H, s [C-CH3]); δc (125 MHz, CDCl3) 86.9 (very broad) (B-CH=CH), 82.6 (CH=CH-O), 64.3
(O-CH2), 24.6 (C-O), 14.4 (CH3) ; IR (NaCl) ν (cm-1) 3675, 3035, 2945, 2925, 1630, 1610; m/z
(GC-MS, EI) 198.1 (M+, 80%), 183.1 ([M-Me]+, 66%), 157.1 (91%), 140.1 (20%), 125.1 (22%),
113.1 (33%), 99.1 (100%), 85.1 (33%), 73.1 (77%), 55.1 (18%).
Method 2
4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.1 ml, 7.5 mmol) was added to a solution of ethyl
vinyl ether (0.5 ml, 5 mmol) and chlorotris(triphenylphosphine)rhodium(I) (231.5 mg, 0.25
mmol) in THF (50 ml) under N2. The reaction mixture was heated at reflux for 3 h. Solvent
was removed and the product was pushed through a plug of alumina topped with a layer of
celite. Product was not isolatable through purification, GC-MS suggests yield of 40%
assuming the three impurities are from materials affecting the yield.
115
(E)-3-(2-Ethoxyvinyl)pyridin-4-amine

Method 1
3-Chloro-4-aminopyridine (100 mg, 0.78 mmol), KOH (88 mg, 1.56 mmol) and
ethoxyvinylborolane 230 (309 mg, 1.56 mmol) were added to a flask and under nitrogen.
Dry acetonitrile (7.8 ml) was added, and the solution was briefly degassed by applying
vacuum until boiling occurred and then flushing with nitrogen (x3). Palladium(II) acetate (11
mg, 0.05 mmol) and RuPhos (48 mg, 0.10 mmol) were added and the mixture was further
degassed as described above. The mixture was then heated at reflux overnight after which
time the reaction was worked up by the addition of water (10 ml) and extraction with DCM
(3 x 10 ml). The combined organic layers were dried over MgSO4, filtered, concentrated and
purified by flash chromatography, gradient elution (DCM only, DCM/1 M NH3 in MeOH, 9:1)
to yield the title compound as a brown solid; (68 mg, 54%); m.p. = 75-77 °C; Rf=0.27 (DCM/1
M NH3 in MeOH solution 9:1); δH (500 MHz, CDCl3) 8.15 (1H, s [ArH]), 8.10 (1H, d, J=5.5 Hz
[ArH]), 6.76 (1H, d, J=12.7 Hz [CH=CH-O]), 6.51 (1H, d, J=5.5 Hz [ArH]), 5.60 (1H, d, J=12.7 Hz
[C-CH=CH]), 4.14 (2H, br s [NH2]), 3.93 (2H, q, J=7.0 Hz [CH2]), 1.36 (3H, t, J=7.0 Hz [CH3]); δc
(125 MHz, CDCl3) 150.2 (Ar), 149.9 (Ar), 147.9 (Ar), 147.6 (Ar), 117.7 (Ar), 109.2 (C-CH=CH),
97.4 (CH=CH-O), 65.9 (CH2), 14.8 (CH3); IR ν (cm-1) 3330, 3192, 2977, 2932, 1630, 1591; m/z
(GC-MS, EI) 164.1 (M+, 87%), 135.1 [M-CH2CH3]+ (48%), 119.1 [M-OCH2CH3]+ (29%), 107.1
(100%), 92.0 (5%), 80.0 (36%), 65.0 (5%), 52.0 (13%). All data agreed with that given in the
literature.8

Method 2
3-Chloro-4-aminopyridine (100 mg, 0.78 mmol), KOH (88 mg, 1.56 mmol) and
ethoxyvinylborolane 230 (309 mg, 1.56 mmol) were added to a flask under nitrogen. Dry
acetonitrile (8 ml) was added, and the solution was briefly degassed by applying vacuum
until boiling occurred and then flushing with nitrogen (x3). Palladium (II) acetate (11 mg,
0.05 mmol) and SPhos (48 mg, 0.18 mmol) were added, and the mixture was further
degassed as described above. The mixture was then heated at reflux overnight after which
116
time the reaction was worked up by the addition of water (10 ml) and extraction with DCM
(3 x 10 ml). The combined organic layers were dried over MgSO4, filtered, concentrated and
purified by flash chromatography (DCM/1 M NH3 in MeOH solution 9:1) to yield the title
compound as a brown solid (56 mg, 44%).
(E)-4-(2-ethoxyvinyl)pyridin-3-amine
3-Amino-4-chloropyridine (2.0 g, 0.015 mol), ethoxyvinylborolane 230 (6.1 g, 0.031 mol) and
potassium phosphate (6.5 g, 0.031 mol) were added to a flask under N2. Acetonitrile (92.6
ml) and water (61.8 ml) were added and the solution was briefly degassed by applying
vacuum until boiling occurred and then flushing with nitrogen (x3). Palladium (II) acetate
(0.2 g, 0.93 mmol) and RuPhos (1.1 g, 2.3 mmol) were added, and the mixture was further
degassed. It was then heated at reflux overnight after which time the reaction was worked
up by the addition of water (30 ml) and extraction with DCM (3 x 30 ml). The combined
organic layers were dried over MgSO4, filtered, concentrated, and purified by flash
chromatography (DCM/MeOH 9:1), to yield the title compound as a brown solid. (1.7 g,
69%); m.p. 84-85 °C; Rf = 0.35 (DCM/MeOH 9:1); δH NMR (500 MHz, CD3OD) 7.89 (1H, s
[ArH]), 7.69 (1H, d, J = 5.0 Hz [ArH]), 7.18 (1H, d, J = 12.8 Hz [CH=CH-O]), 7.13 (1H, d, J = 5.0
Hz [ArH]), 5.84 (1H, d, J = 12.8 Hz [C-CH=CH]), 3.9 (2H, q, J = 7.1 Hz, -OCH2CH3), 1.32 (3H, t, J
= 7.1 Hz, -OCH2CH3); δC NMR (125 MHz, CD3OD) 152.7 (ArH), 142.3 (ArH), 139.1 (ArH), 137.7
(ArH), 131.7 (ArH), 120.3 (C-CH=CH), 99.9 (CH=CH-O), 66.9 (-OCH2CH3), 15.1 (-OCH2CH3); IR ν
(cm-1) 3426.2, 3340.8, 3195.3, 2979.9, 2930.5, 1626.7, 1588.4 cm-1; m/z (GC-MS, EI) 164.0
(M+, 78%), 135.0 [M-CH2CH3]+ (18%), 119.0 [M-OCH2CH3]+ (100%), 107.0 (50%), 80.0 (20%),
53.0 (15%).
117
(E)-3-(2-ethoxyvinyl)pyrazin-2-amine
2-Amino-3-chloropyrazine (2.0 g, 0.015 mol), ethoxyvinylborolane 230 (6.1 g, 0.031 mol) and
potassium phosphate (6.5 g, 0.031 mol) were added to a flask under nitrogen. Acetonitrile
(92.6 ml) and water (61.8 ml) were added and the solution was briefly degassed by applying
vacuum until boiling occurred and then flushing with nitrogen (x3). Palladium (II) acetate
(0.2 g, 0.93 mmol) and RuPhos (1.1 g, 2.3 mmol) were added, and the mixture was further
degassed. The mixture was then heated at reflux overnight after which time the reaction
was worked up by the addition of water (30 ml) and extraction with DCM (3 x 30 ml). The
combined organic layers were dried over MgSO4, filtered, concentrated, and purified by
flash chromatography (DCM/MeOH 9:1) to yield the title compound as a brown solid. (2.06
g, 81%, approx.. 80% pure by NMR); m.p. = 104-105 °C; Rf = 0.34 (DCM/MeOH 9:1); δH NMR
(500 MHz, CDCl3) 7.80 (1H, d, J = 2.5 Hz [ArH]), 7.77 (1H, d, J = 2.5 Hz [ArH]), 7.51 (1H, d, J =
12.2 Hz [CH=CH-O]), 5.71 (1H, d, J = 12.3 Hz [C-CH=CH]), 4.53 (2H, br s [NH2]), 3.98 (2H, q, J =
7.1 Hz [CH2]), 1.35 (3H, t, J = 7.0 Hz [CH3]); δC NMR (125 MHz, CDCl3) 154.5 (ArH), 150.9
(ArH), 138.7 (ArH), 138.4 (ArH), 134.1 (C-CH=CH), 99.1 (CH=CH-O), 66.9 (CH2), 14.8 (CH3); IR
ν (cm-1) 3346, 3222, 2978, 1637, cm-1; m/z (GC-MS, EI) 165.1 (M+, 80%), 150.0 [M-CH3]+
(21%), 136.0 [M-CH2CH3]+ (42%), 122.1 (100%), 108.0 (64%), 81.1 (35%).
2-Chloro-5-[(E)-2-ethoxyvinyl]pyrimidin-4-amine
4-Amino-5-bromo-2-chloropyrimidine (2.0 g, 9.6 mmol), ethoxyvinylborolane 230 (3.8 g,
19.2 mmol) and potassium phosphate (4.1 g, 19.2 mmol) were added to a flask under
nitrogen. Acetonitrile (57.0 ml) and water (38.0 ml) were added and the solution was briefly
degassed by applying vacuum until boiling occurred and then flushing with nitrogen (x3).
Palladium(II) acetate (0.1 g, 0.57 mmol) and RuPhos (0.6 g, 1.4 mmol) were added, and the
118
mixture was further degassed. It was then heated at reflux overnight after which time the
reaction was worked up by the addition of water (30 ml) and extraction with DCM (3 x 30
ml). The combined organic layers were dried over MgSO4, filtered, concentrated, and
purified by flash chromatography (DCM/MeOH 9:1) to yield the title compound as a brown
solid. (0.7 g, 36 %, approx.. 85% pure by NMR); m.p. = 107-110 °C; Rf = 0.34 (DCM/MeOH
9:1); δH NMR (500 MHz, CDCl3) 7.92 (1H, s [ArH]), 6.73 (1H, d, J = 12.6 Hz [CH=CH-O]), 5.39
(1H, d, J = 12.6 Hz [C-CH=CH]), 5.37 (2H, br s, NH2), 3.91 (2H, q, J = 7.1 Hz [CH2]), 1.34 (3H, t, J
= 7.1 Hz [CH3]); δC NMR (125 MHz, CDCl3) 162.5 (ArH), 158.0 (ArH), 153.6 (ArH), 151.2 (ArH),
112.9 (C-CH=CH), 95.0 (CH=CH-O), 66.3 (CH2), 14.7 (CH3); IR ν (cm-1) 3316, 3161, 2978, 2933,
1653 cm-1; m/z (GC-MS, EI) 201.1 (M+, 23%), 200.1 (10%), 199.1 (M+, 100%), 170.0 [MCH2CH3]+ (50%), 154.1 [M-OCH2CH3]+ (75%), 128.0 (35%), 81.1 (30%).
(E)-3-(2-Ethoxyvinyl)-5-methylpyridin-2-amine
2-Amino-3-bromo-5-methylpyridine (2.0 g, 0.011 mol), ethoxyvinylborolane 230 (4.3 g,
0.021 mol) and potassium phosphate (4.6 g, 0.021 mol) were added to a flask under N2.
Acetonitrile (65.4 ml) and water (43.6 ml) were added and the solution was briefly degassed
by applying vacuum until boiling occurred and then flushing with nitrogen (x3). Palladium(II)
acetate (0.15 g, 0.65 mmol) and RuPhos (0.67 g, 1.6 mmol) were added, and the mixture
was further degassed. The mixture was then heated at reflux overnight after which time it
was worked up by the addition of water (30 ml) and extraction with DCM (3 x 30 ml). The
combined organic layers were dried over MgSO4, filtered, concentrated, and purified by
flash chromatography (DCM/MeOH 9:1) to yield the title compound as a brown oil. (1.6 g,
84%); Rf = 0.23 (DCM:MeOH 9:1); δH NMR (500 MHz, CDCl3) 7.65 (1H, s [ArH]), 7.05 (1H, s
[ArH]), 6.68 (1H, d, J = 12.7 Hz [CH=CH=O]), 5.54 (1H, d, 12.7 Hz [C-CH=CH)]), 4.35 (2H, br s
[NH2]), 3.78 (2H, q, J = 7.2 Hz [CH2]), 2.07 (3H, s [C-CH3]), 1.24 (3H, t, J = 6.8 Hz [CH2-CH3]); δC
NMR (125 MHz, CDCl3) 153.9 (ArH), 149.6 (ArH), 145.1 (ArH), 135.1 (ArH), 123.3 (ArH), 116.6
(C-CH=CH), 100.1 (CH=CH-O), 65.6 (CH2), 17.3 (CH3), 14.7 (CH3); IR (NaCl) ν (cm-1) 3459,
3346, 3198, 2978, 2927, 1733, 1637 cm-1; m/z (GC-MS, EI) 178.1 (M+, 85%), 149.1 [MCH2CH3]+ (50%), 133.1 [M-OCH2CH3]+ (100%) 121.1 (45%).
119
1H-pyrrolo[3,2-c]pyridine
4-Amino-3-ethoxyvinylpyridine (2 g, 12.2 mmol) was dissolved in acetic acid (6.9 ml, 122
mmol), under N2. The solution was heated at reflux for 4 h. The solvent was then
evaporated and residual acetic acid removed by azeotropic evaporation with toluene. The
residue was purified by flash chromatography (pet 40-60/EtOAc 1:1) to yield the title
compound as a cream solid. (1.3 g, 93%); m.p. 108-110 °C; Rf=0.2 (DCM/MeOH 9:1); δH (500
MHz, CDCl3) 8.85 (1H, s [ArH]), 8.11 (1H, d, J = 5.9 Hz [ArH]), 7.57 (1H, d, J = 6.1 Hz [ArH]),
7.43 (1H, d, J = 3.2 Hz [ArH]), 6.66 (1H, d, J = 3.2 Hz [ArH]); δC (125 MHz, CDCl3) 141.2 (ArH),
138.7 (ArH), 134.5 (ArH), 129.1 (ArH), 128.7 (ArH), 124.8 (ArH), 108.4 (ArH); IR ν (cm-1)
3106.5, 3071.4, 1687.7, 1613.3, 1554.4 cm-1; m/z (EI) 118.0 (M+, 100%), 91.0 (25%), 63.0
(11%).
1H-pyrrolo[2,3-c]pyridine
3-amino-4-ethoxyvinylpyridine (1.3 g, 7.9 mmol) was dissolved in acetic acid (4.5 ml, 79
mmol), under N2 and heated at reflux for 4 h. The solvent was then evaporated and residual
acetic acid removed by azeotropic evaporation with toluene. The residue was purified by
flash chromatography (DCM/MeOH 9:1) to yield the title compound as a cream solid. (0.79
g, 85%); m.p. 136-138 °C; Rf=0.2 (DCM/MeOH 9:1); δH (500 MHz, CD3OD) 8.80 (1H, s [ArH]),
8.03 (1H, d, J = 6.0 Hz [ArH]), 7.74 (1H, d, J = 3.0 Hz [ArH]), 7.68 (1H, d, J = 6.0 Hz [ArH]), 6.62
(1H, d, J = 3.0 Hz [ArH]); δC (125 MHz, CD3OD) 138.2 (ArH), 134.0 (ArH), 133.3 (ArH), 132.9
(ArH), 128.6 (ArH), 115.4 (ArH), 101.9 (ArH); IR ν (cm-1) 3106.5, 3071.4, 1687.7, 1613.3,
120
1554.4 cm-1; m/z (EI) 118.0 (M+, 100%), 91.0 (20%), 63.0 (15%). All data agrees with that
published in the literature.
Pyrrolo[2,3-b]pyrazine
(E)-3-(2-Ethoxyvinyl)pyrazin-2-amine (2.06 g, 12.4 mmol) was dissolved in acetic acid (7.1 ml,
124 mmol), under N2. The reaction mixture was heated at reflux for 4 h then concentrated
and residual acetic acid removed by azeotropic evaporation with toluene. The residue was
purified by flash chromatography (DCM/EtOAc 1:1) to yield the title compound as a brown
solid. (1.1 g, 75%); m.p. 145-147 °C; Rf=0.2 (DCM/EtOAc 1:1); δH (500 MHz, CDCl3) 10.05 (1H,
br s [NH]), 8.50 (1H, d, J = 2.7 Hz [ArH]), 8.28 (1H, d, J = 2.7 Hz [ArH]), 7.66 (1H, dd, J = 3.5,
2.9 Hz [ArH]), 6.77 (1H, dd, J = 3.5, 1.9 Hz [ArH]); δC (125 MHz, CDCl3) 141.5 (ArH), 140.0
(ArH), 138.8 (ArH), 136.8 (ArH), 129.5 (ArH), 102.3 (ArH); ([b]); IR ν (cm-1) 3106, 2976, 2744,
1594 cm-1; m/z (EI) 119.0 (M+, 100%), 92.0 (35%), 65.0 (15%).
2-Chloro-7H-pyrrolo[2,3-d]pyrimidine
To a round bottom flask was added 4-amino-2-chloro-3-ethoxyvinylpyrimidine (700 mg, 3.5
mmol) followed by acetic acid (2 ml, 35 mmol) under N2. The reaction mixture was heated at
reflux for 4 h. It was then concentrated and the residual acetic acid was removed by
azeotropic evaporation with toluene. The residue was purified by flash chromatography
(DCM/EtOAc 1:1) to yield the title compound as a white solid. (610 mg, 87%); m.p. 185-188
°C; Rf=0.6 (DCM/EtOAc 1:1); δH (500 MHz, CD3OD) 8.81 (1H, s [ArH]), 7.47 (1H, d, J=3.6 Hz
[ArH]), 6.64 (1H, d, J=3.6 Hz [ArH]). δC (125 MHz, CD3OD) 150.1 (ArCl), 127.7 (ArH), 117.5
121
(ArH), 107.7 (ArH), 100.0 (ArH), 71.4 (ArH). IR ν (cm-1) 3056, 2967, 2805, 2530, 1598, 1565
cm-1; m/z (EI) 155 (M+, 35%), 153.0 (M+, 100%), 118.0 [M-Cl]+ (40%), 91.0 (12%), 64.0 (12%).
5-Methyl-1H-pyrrolo[2,3-b]pyridine
(E)-3-(2-ethoxyvinylEthoxyvinyl)-5-methylpyridin-2-amine (0.7 g, 3.9 mmol) was dissolved in
acetic acid (2.2 ml, 39 mmol), under N2. This was heated at reflux for 4 h. The solvent was
then evaporated and residual acetic acid removed by azeotropic evaporation with toluene.
The residue was purified by flash chromatography (DCM/MeOH 9:1) to yield the title
compound as a cream solid. (0.39 g, 77%); m.p. 139-142 °C; Rf=0.3 (DCM/MeOH 9:1); δH
(500 MHz, CD3OD) 8.01 (1H, d, J=1.4 Hz, [ArH]), 7.79 (1H, d, J=1.4 Hz, [ArH]), 7.32 (1H, d,
J=3.5 Hz, [ArH]), 6.39 (1H, d, J=3.5 Hz, [ArH]), 2.41 (3H, s, [-CH3]); δC (125 MHz, CD3OD) 147.8
(ArH), 143.7 (ArH), 130.3 (ArH), 127.0 (ArH), 125.8 (ArH), 122.3 (ArH), 100.8 (ArH) 18.4 (CH3);
IR ν (cm-1) 3107.1, 3006.9, 2852.2, 1581.8 cm-1; m/z (EI) 132.1 (M+, 100%), 131.2 (90%),
104.0 (20%), 77.0 (10%), 51.0 (8%).
3-bromo-1H-pyrrolo[2,3-b]pyridine

Method 1
To a round bottom flask was added 7-azaindole (700 mg, 5.9 mmol) followed by Nbromosuccinimide (1.25 g, 7 mmol) and DMF (13.3 ml) under N2. The reaction mixture was
stirred for 4 h at room temperature before being concentrated and purified by flash
chromatography (DCM/MeOH 9:1) to yield the title compound as a red powder. (952 mg,
122
82%); m.p. 210-212 °C; Rf=0.3 (DCM/MeOH 9:1); δH (500 MHz, CDCl3) 9.2 (1H, br s [NH]), 8.3
(1H, dd, J=4.8, 0.9 Hz [ArH]), 8.0 (1H, dd, J=7.8, 1.2 Hz [ArH]), 7.4 (1H, s [ArH]), 7.2 (1H, dd,
J=7.9, 4.9 Hz [ArH]); δC (125 MHz, CDCl3) 177.8 (ArBr), 142.3 (ArH), 129.0 (ArH), 124.7 (ArH),
120.6 (ArH), 116.5 (ArH); IR ν (cm-1) 3090, 2819, 1689, 1607 cm-1; m/z (EI) 198.0 (M+, 100%),
196.0 (M+, 100%), 117.0 [M-Br]+ (30%), 90.0 (35%), 63.1 (15%).

Method 2
In a round bottom flask, 2-amino-3-ethoxyvinylpyridine (50 mg, 0.3 mmol) was dissolved in
MeCN (4.0 ml) under N2, and cooled to 0°C. Trifluoroacetic acid was added (0.04 ml, 0.3
mmol) followed by N-bromosuccinimide (53.1 mg, 0.3 mmol). The reaction mixture was
stirred at 0°C for 30 minutes before being concentrated and purified by flash
chromatograohy (DCM/MeOH 9:1) to yield the title compound as a red powder. (12 mg,
21%)
3-bromo-1H-pyrrolo[3,2-c]pyridine
To a round bottom flask was added 5-azaindole (1.30 g, 11.0 mmol) followed by Nbromosuccinimide (2.31 g, 13 mmol) and DMF (24.6 ml) under N2. The reaction mixture was
stirred for 4 h at room temperature and was then concentrated under vacuum and the
residue purified by flash chromatography (DCM/MeOH 9:1) to yield the title compound as a
brown solid. (1.56 g, 72%); m.p. 190-192 °C; Rf=0.3 (DCM/MeOH 9:1); δH (500 MHz, CD3OD)
8.74 (1H, s [ArH]), 8.18 (1H, d, J = 5.7 Hz [ArH]), 7.70 (1H, s [ArH]), 7.56 (1H, d, J = 5.7 Hz
[ArH]); δC (125 MHz, CD3OD) 141.2 (ArBr), 136.4 (ArH), 133.2 (ArH), 129.1 (ArH), 128.7 (ArH),
113.2 (ArH), 89.1 (ArH); IR ν (cm-1) 3381.8, 3053.6, 1613.2, 1502.5 cm-1; m/z (EI) 197.9 (M+,
100%), 195.9 (M+, 100%), 117.0 [M-Br]+ (60%), 90.0 (30%), 63.0 (26%).
123
3-bromo-1H-pyrrolo[2,3-c]pyridine (have COSY)

Method 1
To a round bottom flask was added 6-azaindole (0.79 g, 6.7 mmol) followed by Nbromosuccinimide (1.41 g, 7.9 mmol) and DMF (14.6 ml) under N2. The reaction mixture was
stirred for 4 h at room temperature. It was then concentrated and the residue purified by
flash chromatography (DCM/MeOH 9:1) to yield the title compound as a brown solid. (0.98
g, 74%); m.p. 205-206 °C; Rf=0.3 (DCM/MeOH 9:1); δH (500 MHz, CD3OD) 8.84 (1H, br s
[ArH]), 8.22 (1H, d, J = 5.9 Hz [ArH]), 7.87 (1H, s [ArH]), 7.69 (1H, dd, J = 5.9, 0.9 Hz [ArH]); δC
(125 MHz, CD3OD) 135.8 (ArBr), 134.8 (ArH), 133.8 (ArH), 133.7 (ArH), 133.3 (ArH), 115.3
(ArH), 91.1 (ArH); IR ν (cm-1) 3381.6, 3097.9, 3052.1, 1705.7, 1611.7, 1503.3 cm-1; m/z (EI)
197.9 (M+, 100%), 195.9 (M+, 100%), 117.0 [M-Br]+ (55%), 90.0 (28%), 63.0 (26%). All data
agrees with that published in the literature.

Method 2
In a round bottom flask, 3-amino-4-ethoxyvinylpyridine (50 mg, 0.3 mmol) was dissolved in
MeCN (4.0 ml) under N2, and cooled to 0°C. Trifluoroacetic acid was added (0.04 ml, 0.3
mmol) followed by N-bromosuccinimide (53.1 mg, 0.3 mmol). The reaction mixture was
stirred at 0°C for 30 minutes before being concentrated and purified by flash
chromatograohy (DCM/MeOH 9:1) to yield the title compound as a red powder. (52 mg,
89%)
124
3-bromo-1H-pyrrolo[3,2-b]pyridine

Method 1
To a round bottom flask was added 4-azaindole (1.00 g, 8.5 mmol) followed by Nbromosuccinimide (1.78 g, 10 mmol) and DMF (18.6 ml) under N2. The reaction mixture was
stirred for 4 h at room temperature. It was then concentrated and the residue was purified
by flash chromatography (DCM/MeOH 9:1) to yield the title compound as a brown solid.
(1.21 g, 73%); m.p. 235-238 °C; Rf=0.3 (DCM/MeOH 9:1); δH (500 MHz, CDCl3) 8.4 (1H, dd, J =
4.6, 1.3 Hz [ArH]), 7.9 (1H, dd, J = 8.2, 1.3 Hz [ArH]), 7.6 (1H, s [ArH]), 7.2 (1H, dd, J = 4.6, 3.6
Hz [ArH]); δC (125 MHz, CDCl3) 178.9 (ArBr), 145.1 (ArH), 143.8 (ArH), 129.0 (ArH), 126.9
(ArH), 120.6 (ArH), 119.3 (ArH); IR ν (cm-1) 3176.1, 3075.1, 1692.4, cm-1; m/z (EI) 197.9 (M+,
100%), 195.9 (M+, 100%), 117.0 [M-Br]+ (65%), 90.0 (30%), 63.0 (15%). All data agrees with
that given in the literature.

Method 2
In a round bottom flask, 3-amino-2-ethoxyvinylpyridine (50 mg, 0.3 mmol) was dissolved in
MeCN (4.0 ml) under N2, and cooled to 0°C. Trifluoroacetic acid was added (0.04 ml, 0.3
mmol) followed by N-bromosuccinimide (53.1 mg, 0.3 mmol). The reaction mixture was
stirred at 0°C for 30 minutes before being concentrated and purified by flash
chromatograohy (DCM/MeOH 9:1) to yield the title compound as a red powder. (37 mg,
67%)
125
7-bromo-5H-pyrrolo[2,3-b]pyrazine
To a round bottom flask was added pyrrolopyrazine (1.10 g, 9.20 mmol), followed by Nbromosuccinimide (1.94 g, 10.9 mmol) and DMF (20.5 ml) under N2. The reaction mixture
was stirred for 4 h at room temperature. It was then concentrated under vacuum and the
residue was purified by flash chromatography (DCM/EtOAc 1:1) to yieldg the title compound
as a brown solid. (1.22 g, 67%); m.p. 250-253 °C; Rf=0.4 (DCM/EtOAc 1:1); δH (500 MHz,
CD3OD) 8.42 (1H, d, J = 2.6 Hz [ArH]), 8.33 (1H, d, J = 2.6 Hz [ArH]), 7.88 (1H, s [ArH]); δC (125
MHz, CD3OD) 141.5 (ArBr), 138.1 (ArH), 138.0 (ArH), 136.8 (ArH), 130.2 (ArH), 102.3 (ArH); IR
ν (cm-1) 3189.2, 3092.4, 3048.1, 1702.2, 1663.5, 1592.7 cm-1; m/z (EI) 197.9 (M+, 100%),
196.9 (M+ 8%), 195.9 (M+, 100%), 171.9 [M-Br]+ (20%), 169.9 (20%), 118.0 (18%), 91.0 (15%),
64.0 (16%).
3-Bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidine
To a round bottom flask was added 2-Chloropyrrolopyrimidine (200 mg, 1.30 mmol)
followed by N-bromosuccinimide (274 mg, 1.54 mmol) and DMF (3.7 ml) under N 2. The
reaction mixture was stirred for 4 h at room temperature. It was then concentrated and the
residue was purified by flash chromatography (DCM/MeOH 9:1) to yield the title compound
as a brown solid. (230 mg, 76%); m.p. 205-208 °C; Rf=0.3 (DCM/MeOH 9:1); δH (500 MHz,
CD3OD) 8.75 (1H, s [ArH]), 7.58 (1H, s [ArH]); δC (125 MHz, CD3OD) 181.5 (ArHal), 155.2
(ArHal), 150.8 (ArH), 128.7 (ArH), 118.4 (ArH), 89.3 (ArH); IR ν (cm-1) 3152.3, 3054.3, 2926.2,
1770.6, 1689.9, 1601.5, 1560.4 cm-1; HRMS (ESI) Found: [M+H]+, 231.9274 C6H379Br35ClN3
requires [M+H]+, 231.9272.
126
3-Bromo-5-methyl-1H-pyrrolo[2,3-b]pyridine
To a round bottom flask was added 5-methylpyrrolopyridine (0.91 g, 6.9 mmol) followed by
N-bromosuccinimide (1.44 g, 8.1 mmol) and DMF (16.9 ml) under N 2. The reaction mixture
was stirred for 4 h at room temperature. It was then concentrated and the residue purified
by flash chromatography (DCM/MeOH 9:1) to yield the title compound as a brown solid.
(1.13 g, 78%, approx.. 90% pure by NMR); m.p. 162-165 °C; Rf=0.2 (DCM/MeOH 9:1); δH (500
MHz, CD3OD) 8.10 (1H, d, J=1.4 Hz [ArH]), 7.71 (1H, d, J=1.4 Hz, [ArH]), 7.41 (1H, s [ArH]),
2.46 (3H, s [CH3]); δC (125 MHz, CD3OD) 146.4 (ArBr), 144.0 (ArH), 127.0 (ArH), 125.5 (ArH),
125.0 (ArH), 119.7 (ArH), 99.3, (ArH) 16.9 (CH3); IR ν (cm-1) 3301.5, 3108.9, 3069.5, 2991.2,
2853.9, 1696.1, 1618.7, 1586.0 cm-1; HRMS (ESI) Found: [M+H]+, 210.9868 C8H879BrN2
requires [M+H]+, 210.9865.
(E)-2-(2-Ethoxyvinyl)aniline
2-Bromoaniline (0.09 ml, 0.77 mmol), ethoxyvinylborolane 230 (308 mg, 1.55 mmol) and
potassium phosphate (329 mg, 1.55 mmol) were added to a flask and put under N2.
Acetonitrile (4.2 ml) and water (2.8 ml) were added and the solution was briefly degassed by
applying vacuum until boiling occurred and then flushing with nitrogen (x3). Palladium(II)
acetate (10.3 mg, 0.04 mmol) and RuPhos (53.2 mg, 0.11 mmol) were added, and the
mixture was further degassed. The mixture was then heated at reflux overnight after which
time itwas worked up by the addition of water (30 ml) and extraction with DCM (3 x 30 ml).
The combined organic layers were dried over MgSO4, filtered, concentrated, and purified by
flash chromatography (DCM/EtOAc 1:1) to yield the title compound as an orange oil. (113
127
mg, 90%); Rf = 0.35 (DCM/EtOAc 1:1); δH NMR (500 MHz, CDCl3) 7.11 (1H, d, J = 7.6 Hz
[ArH]), 7.03 (1H, td, J = 7.6, 1.4 Hz [ArH]), 6.79 (1H, d, J = 12.7 Hz [CH=CH-O]), 6.74 (1H, t, J =
7.6 Hz [ArH]), 6.68 (1H, d, J = 7.6 Hz [ArH]), 5.80 (1H, d, J = 12.7 Hz [C-CH=CH]), 3.91 (2H, q, J
= 7.0 Hz [CH2]), 3.5 (2H, br s [NH2]), 1.36 (3H, t, J = 7.0 Hz [CH3]) δC NMR (125 MHz, CDCl3)
149.0 (ArH), 143.5 (ArH), 127.2 (ArH), 122.4 (ArH), 118.9 (ArH), 115.6 (C-CH=CH), 101.4
(CH=CH-O), 66.6 (CH2), 14.9 (CH3); IR ν (cm-1) 3429.9, 3370.5, 3025.2, 2978.1, 1636.8,
1615.7, 1574.2 cm-1; m/z (GC-MS, EI) 163.1 (M+, 90%), 134.0 [M-CH2CH3]+ (40%), 118.0 [MOCH2CH3]+ (100%), 106.0 (100%), 91.0 (10%), 77.0 (30%).
Phenyldimethylcarbamate
A mixture of phenol (0.9 g, 10 mmol), N,N-dimethylcarbamoyl chloride (1.6 g, 14.9 mmol)
and potassium carbonate (2.07 g, 14.9 mmol) in acetonitrile was heated at reflux for 5 h.
The reaction mixture was cooled to room temperature and concentrated under vacuum.
The residue was dissolved in water (50 ml), extracted with diethyl ether (2 x 20 ml), and
washed successively with 1M KOH (25 ml) and water (25 ml). It was then dried over MgSO4,
concentrated and dried under vacuum to leave the title product as an opaque crystalline
solid (0.83 g, 50%); m.p. = 44-45 °C; δH NMR (CDCl3, 500 MHz) 7.34 (2H, t, J=8.1 Hz [ArH]),
7.17 (1H, t, J=8.1 Hz [ArH]), 7.10 (2H, d, J=8.1 Hz [ArH]), 3.09 (s, 3H [CH3]), 3.00 (s, 3H [CH3]);
δC NMR (CDCl3, 125 MHz) 154.9 (C=O), 151.5 (ArH), 129.2 (ArH), 125.1 (ArH), 121.7 (ArH),
36.6 (CH3), 36.4 (CH3); IR (NaCl) ν (cm-1) 3050, 2930, 2000, 1920, 1860, 1730; m/z (GC-MS,
EI) 165.0 (M+, 34%), 72.0 [M-PhO]+ (100%).
128
3-Hydroxy-4-bromopyridine

Method 1
NBS (186 mg, 1.05 mmol) was weighed into a Schlenk tube. A solution of H2SO4 (0.011 ml,
0.21 mmol) in DCE (2.1 ml) was added followed by 3-hydroxypyridine (100 mg, 1.05 mmol).
The resulting reaction mixture was stirred for 16 h at room temperature. 5M NaOH was
added dropwise until the solution was neutral pH (monitored using pH paper), while cooling
the flask in ice. The mixture was then extracted with DCM (3 x 10 ml) and dried over MgSO4.
The solvent was evaporated and the product dissolved in DCM. Flash chromatography
yielded an inseparable mixture of products.

Method 2
NBS (186 mg, 1.05 mmol) was weighed into a Schlenk tube. A solution of AuCl 3 (3 mg, 0.01
mmol) in DCE (4 ml) was added. DCE (16 ml) and 3-hydroxypyridine (100 mg, 1.05 mmol)
were then added to the flask in succession. The resulting reaction mixture was stirred for 16
h at room temperature. The solution was then concentrated under reduced pressure and
the residue was purified by flash chromatography which yielded an inseparable mixture of
products.
129
Attempted synthesis of 2-ethoxyvinyl-3-hydroxypyridine
2-Chloro-3-hydroxypyridine (100 mg, 0.77 mmol), KOH (86.4 mg, 1.54 mmol) and
ethoxyvinylborolane 230 (305 mg, 1.54 mmol) were added to a flask and under N 2. Dry
acetonitrile (7.7 ml) was added and the solution was briefly degassed by applying vacuum
until boiling occurred and then flushing with nitrogen (x3). Palladium (II) acetate (5.47 mg,
0.025 mmol) and RuPhos (24.0 mg, 0.09 mmol) were added, and the mixture was further
degassed. The mixture was then heated at reflux overnight after which time the reaction
was worked up by the addition of 0.1 M HCl (10 ml) and extracted with DCM (3 x 10 ml). The
combined organic layers were dried over MgSO4, filtered, concentrated, and purified by
flash chromatography. The target product was not produced.
Instead
2,6-
diisopropoxybiphenyl was isolated, as a degradation product of the catalyst ligand RuPhos,
as a white powder;
(0.15g, 80%); Rf=0.70 (pet/EtO2 9:1); δH (500 MHz; CDCl3) 7.35-7.36 (4H, m [ArH]), 7.24-7.26
(m [ArH]), 7.16-7.19 (1H, t, J= 8.2 Hz [ArH]), 6.63-6.64 (2H, d, J= 8.2 Hz [ArH]), 4.28-4.33 (2H,
m [CH-O]), 1.13-1.15 (12H, d, J=6.1 Hz [CH3]); δc (125 MHz; CDCl3) 156.3 (ArH), 134.6 (ArH),
131.2 (ArH), 128.0 (ArH), 127.0 (ArH), 126.1 (ArH), 123.3 (ArH), 108.6 (ArH), 71.3 (CHO), 22.0
(CH3); IR (NaCl) ν (cm-1) 3630, 3585, 3450, 2985, 2950, 2900, 2850, 2370, 2100, 1900, 1750.
130
1-ethenylpiperidine-2,6-dione [have HMBC, HSQC, COSY]
To a stirred solution of glutarimide (250 mg, 2.20 mmol) in vinyl pivalate (8.7 ml, 59.0 mmol)
under N2, was added disodium tetrachloropaladate (13 mg, 0.04 mmol). The resulting
mixture was heated at reflux for 16 h. It was then cooled to room temperature and
concentrated. The residue was purified by flash chromatography (Hexane/EtOAc 1:1), to
yield the title compound as a brown oil. (171 mg, 56%); Rf=0.45 (Hexane/EtOAc 1:1); δH (500
MHz, CDCl3) 6.66 (1H, dd, J=16.2, 9.5 Hz [-CH=CH2]), 5.65-5.68 (1H, d, J=16.2 Hz [=CHH
(trans)]), 5.25-5.27 (1H, d, J=9.5 Hz =CHH (cis)), 2.71-2.75 (4H, t, J=6.6 Hz 3-H), 1.96-2.01 (2H,
p, J=6.6 Hz 4-H); δC (125 MHz, CDCl3) 171.8 (C=O), 126.5 (N-CH=), 112.3 (=CH2), 33.4 (3-C),
16.9 (4-C); IR ν (cm-1) 3172, 3087, 2970, 2908, 2850, 1722, cm-1; m/z (EI) 139.0 (M+, 100%),
111.0 [M-CH2=CH2]+ (100%), 83.0 (36%), 68.0 (38%), 55.0 (70%).
1-[2-(Tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]piperidine-2,6-dione
(Acetylacetonato)(1,5-cyclooctadiene)rhodium(I) (2.17 mg, 0.007 mmol) and bis(2diphenylphosphinophenyl)ether (3.77 mg, 0.007 mmol) were combined in DCM (3 ml) under
N2 and stirred for 2 minutes. Vinyl glutarimide (100 mg, 0.7 mmol) was then added, followed
by pinacolborane (0.11 ml, 0.77 mmol). The reaction mixture was stirred for 18 h at room
temperature. It was then concentrated and the residue purified by flash chromatography
(Petrol/EtOAc 1:1) to yield the title compound as a yellow oil. (74 mg, 42 %); Rf=0.25
(Petrol/EtOAc 1:1); δH NMR (500 MHz, CDCl3) 3.88 (2H, t, J = 7.9 Hz [N-CH2-CH2]), 2.62 (4H, t,
J = 6.5 Hz [3-H]), 1.92 (2H, p, J = 6.5 Hz [4-H]), 1.23 (12H, s [CH3]), 1.07 (2H, t, J = 7.9 Hz [CH2131
CH2-B]); δC NMR (125 MHz, CDCl3) 172.3 (C=O), 83.1 (B-CH2), 35. 5 (CH2), 33.0 (CH2), 31.7
(CH2), 24.9 (C-O), 17.9 (CH3), 17.1 (CH3); IR ν (cm-1) 3193.2, 3099.6, 2973.6, 2926.6, 1704.8,
1664.7 cm-1; HRMS (ESI) Found: [M+H]+, 268.1716. C13H22BNO4 requires [M+H]+, 268.1717.
1-[1-(Tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]piperidine-2,6-dione
(Acetylacetonato)(1,5-cyclooctadiene)rhodium(I)
(2.17
mg,
0.007
mmol)
and
tricyclohexylphosphine (1.96 mg, 0.007 mmol) were combined in DCM (3 ml) under N 2 and
stirred for 2 minutes. Vinyl glutarimide (100 mg, 0.7 mmol) was then added, followed by
pinacolborane (0.11 ml, 0.77 mmol). The reaction mixture was stirred for 18 h at room
temperature. It was then concentrated and the residue purified by flash chromatography
(Petrol/EtOAc 1:1) to yield the title compound as a yellow oil. (52 mg, 29 %); Rf=0.25
(Petrol/EtOAc 1:1); δH NMR (500 MHz, CDCl3) 3.74 (1H, q, J = 7.1 Hz [CH-CH3]), 2.55 (4H, t, J =
6.6 Hz [3-H]), 1.85 (2H, p, J = 6.6 Hz [4-H]), 1.23 (15H, s [CH3]); δC NMR (125 MHz, CDCl3)
172.6 (C=O), 83.3 (B-CH), 32.2 (CH2), 31.6 (CH2), 29.7 (CH2), 24.9 (C-O), 17.8 (CH3), 17.0 (CH3)
14.8 (CH3); IR ν (cm-1) 3188.6, 3099.7, 2973.7, 2926.4, 2360.0, 1705.1, 1664.7 cm-1; HRMS
(ESI) Found: [M+Na]+, 290.1532. C13H22BNO4 requires [M+Na]+, 290.1537.
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